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Does adherence to a Mediterranean diet reduce the risk of Parkinson’s disease?
Among older adults, adherence to a Mediterranean diet is associated with lower probability of prodromal Parkinson’s disease, according to research published in Movement Disorders.
“Recommending the Mediterranean diet pattern, either to reduce the risk or lessen the effects ... of prodromal Parkinson’s disease, needs to be considered and further explored,” said lead author Maria I. Maraki, PhD, of the department of nutrition and dietetics at Harokopio University in Athens, Greece, and her research colleagues.
Evidence regarding the effect of a Mediterranean diet on Parkinson’s disease risk remains limited, however, and physicians should be cautious in interpreting the data, researchers noted in accompanying editorials.
“There is a puzzling constellation of information and data that cannot be reconciled with a simple model accounting for the role of diet, vascular risk factors, and the neurodegenerative process and mechanisms underlying Parkinson’s disease,” Connie Marras, MD, PhD, and Jose A. Obeso, MD, PhD, said in an editorial. Given Maraki et al.’s findings, “most of us would be glad to accept that such a causal inverse association exists and can therefore be strongly recommended to our patients,” but “further work is needed before definitive conclusions can be reached,” Dr. Marras and Dr. Obeso wrote. Dr. Marras is affiliated with the University Health Network and the University of Toronto. Dr. Obeso is affiliated with University Hospital HM Puerta del Sur, CEU San Pablo University, Móstoles, Spain.
The role of diet
Prior research has suggested that adherence to the Mediterranean diet – characterized by consumption of nonrefined cereals, fruits, vegetables, legumes, potatoes, fish, and olive oil – may be associated with reduced risk of Parkinson’s disease. In addition, studies have found that adherence to the Mediterranean diet may be protective in other diseases, including dementia and cardiovascular disease. Dr. Maraki and her colleagues sought to assess whether adherence to the Mediterranean diet is associated with the likelihood of prodromal Parkinson’s disease or its manifestations. To calculate the probability of prodromal Parkinson’s disease, the investigators used a tool created by the International Parkinson and Movement Disorder Society (MDS) that takes into account baseline risk factors as well as prodromal markers such as constipation and motor slowing.
They analyzed data from 1,731 participants in the population-based Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort in Greece. Participants, 41% of whom were male, were aged 65 years or older and did not have Parkinson’s disease. They completed a detailed food frequency questionnaire, and the researchers calculated how closely each participant’s diet adhered to the Mediterranean diet. Diet adherence scores ranged from 0 to 55, with higher scores indicating greater adherence.
The median probability of prodromal Parkinson’s disease was 1.9% (range, 0.2%-96.7%), and the probability was lower among those with greater adherence to the Mediterranean diet. This difference was “driven mostly by nonmotor markers of prodromal Parkinson’s disease,” including depression, constipation, urinary dysfunction, and daytime somnolence, the researchers said. “Each unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal Parkinson’s disease.” Compared with participants in the lowest quartile of Mediterranean diet adherence, those in the highest quartile had an approximately 21% lower probability for prodromal Parkinson’s disease.
Potential confounding
“This study pushes the prodromal criteria into performing a job they were never designed to do,” which presents potential pitfalls, Ronald B. Postuma, MD, of the department of neurology at Montreal General Hospital in Quebec, said in an accompanying editorial.
While the MDS criteria were designed to assess the likelihood that any person over age 50 years is in a state of prodromal Parkinson’s disease, the present study aimed to evaluate whether a single putative risk factor for Parkinson’s disease is associated with the likelihood of its prodromal state.
In addition, the analysis did not include some of the prodromal markers that are part of the MDS criteria, including olfaction, polysomnographic-proven REM sleep behavior disorder, and dopaminergic functional neuroimaging.
“As pointed out by the researchers, many of the risk factors in the prodromal criteria are potentially confounded by factors other than Parkinson’s disease; for example, one could imagine that older people, men, or farmers (with their higher pesticide exposure) are less likely to follow the Mediterranean diet simply because of different cultural lifestyle patterns,” Dr. Postuma said.
It is also possible that the Mediterranean diet affects prodromal markers such as constipation, sleep, or depression without affecting underlying neurodegenerative disease. In any case, the effect sizes observed in the study were small, and there was no evidence that participants who adhered most closely to a Mediterranean diet had less parkinsonism, Dr. Postuma said.
These limitations do not preclude physicians from recommending the diet for other reasons. “Numerous studies, reviews, meta-analyses, and randomized controlled trials consistently rank the Mediterranean diet as among the healthiest diets available,” Dr. Postuma said. “So, one can clearly recommend diets such as these, even if not necessarily for Parkinson’s disease prevention.”
Adding insights
The researchers used a Mediterranean diet score that was developed in a population of adults from metropolitan Athens, “an area not unlike the one in which the score is being applied in the HELIAD study,” Christy C. Tangney, PhD, professor of clinical nutrition and preventive medicine and associate dean for research at Rush University Medical Center, Chicago, said in a separate editorial. As expected, the average Mediterranean diet adherence score in this study was higher than that in the Chicago Health and Aging Project (33.2 vs. 28.2).
“If we can identify differences in diet or lifestyle patterns and risk of this latent phase of Parkinson’s disease neurodegeneration, we may be one step closer to identifying preventive measures,” she said. Follow-up reports from HELIAD and other cohorts may allow researchers to assess how changes in dietary patterns relate to changes in Parkinson’s disease markers, the probability of prodromal Parkinson’s disease, and incident Parkinson’s disease, Dr. Tangney said.
The study authors had no conflicts of interest or financial disclosures. The study was supported by a grant from the Alzheimer’s Association, an ESPA‐EU grant cofunded by the European Social Fund and Greek National resources, and a grant from the Ministry for Health and Social Solidarity (Greece). Dr. Maraki and a coauthor have received financial support from the Greek State Scholarships Foundation. Dr. Tangney and Dr. Postuma had no conflicts of interest.
SOURCE: Maraki MI et al. Mov Disord. 2018 Oct 10. doi: 10.1002/mds.27489.
Among older adults, adherence to a Mediterranean diet is associated with lower probability of prodromal Parkinson’s disease, according to research published in Movement Disorders.
“Recommending the Mediterranean diet pattern, either to reduce the risk or lessen the effects ... of prodromal Parkinson’s disease, needs to be considered and further explored,” said lead author Maria I. Maraki, PhD, of the department of nutrition and dietetics at Harokopio University in Athens, Greece, and her research colleagues.
Evidence regarding the effect of a Mediterranean diet on Parkinson’s disease risk remains limited, however, and physicians should be cautious in interpreting the data, researchers noted in accompanying editorials.
“There is a puzzling constellation of information and data that cannot be reconciled with a simple model accounting for the role of diet, vascular risk factors, and the neurodegenerative process and mechanisms underlying Parkinson’s disease,” Connie Marras, MD, PhD, and Jose A. Obeso, MD, PhD, said in an editorial. Given Maraki et al.’s findings, “most of us would be glad to accept that such a causal inverse association exists and can therefore be strongly recommended to our patients,” but “further work is needed before definitive conclusions can be reached,” Dr. Marras and Dr. Obeso wrote. Dr. Marras is affiliated with the University Health Network and the University of Toronto. Dr. Obeso is affiliated with University Hospital HM Puerta del Sur, CEU San Pablo University, Móstoles, Spain.
The role of diet
Prior research has suggested that adherence to the Mediterranean diet – characterized by consumption of nonrefined cereals, fruits, vegetables, legumes, potatoes, fish, and olive oil – may be associated with reduced risk of Parkinson’s disease. In addition, studies have found that adherence to the Mediterranean diet may be protective in other diseases, including dementia and cardiovascular disease. Dr. Maraki and her colleagues sought to assess whether adherence to the Mediterranean diet is associated with the likelihood of prodromal Parkinson’s disease or its manifestations. To calculate the probability of prodromal Parkinson’s disease, the investigators used a tool created by the International Parkinson and Movement Disorder Society (MDS) that takes into account baseline risk factors as well as prodromal markers such as constipation and motor slowing.
They analyzed data from 1,731 participants in the population-based Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort in Greece. Participants, 41% of whom were male, were aged 65 years or older and did not have Parkinson’s disease. They completed a detailed food frequency questionnaire, and the researchers calculated how closely each participant’s diet adhered to the Mediterranean diet. Diet adherence scores ranged from 0 to 55, with higher scores indicating greater adherence.
The median probability of prodromal Parkinson’s disease was 1.9% (range, 0.2%-96.7%), and the probability was lower among those with greater adherence to the Mediterranean diet. This difference was “driven mostly by nonmotor markers of prodromal Parkinson’s disease,” including depression, constipation, urinary dysfunction, and daytime somnolence, the researchers said. “Each unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal Parkinson’s disease.” Compared with participants in the lowest quartile of Mediterranean diet adherence, those in the highest quartile had an approximately 21% lower probability for prodromal Parkinson’s disease.
Potential confounding
“This study pushes the prodromal criteria into performing a job they were never designed to do,” which presents potential pitfalls, Ronald B. Postuma, MD, of the department of neurology at Montreal General Hospital in Quebec, said in an accompanying editorial.
While the MDS criteria were designed to assess the likelihood that any person over age 50 years is in a state of prodromal Parkinson’s disease, the present study aimed to evaluate whether a single putative risk factor for Parkinson’s disease is associated with the likelihood of its prodromal state.
In addition, the analysis did not include some of the prodromal markers that are part of the MDS criteria, including olfaction, polysomnographic-proven REM sleep behavior disorder, and dopaminergic functional neuroimaging.
“As pointed out by the researchers, many of the risk factors in the prodromal criteria are potentially confounded by factors other than Parkinson’s disease; for example, one could imagine that older people, men, or farmers (with their higher pesticide exposure) are less likely to follow the Mediterranean diet simply because of different cultural lifestyle patterns,” Dr. Postuma said.
It is also possible that the Mediterranean diet affects prodromal markers such as constipation, sleep, or depression without affecting underlying neurodegenerative disease. In any case, the effect sizes observed in the study were small, and there was no evidence that participants who adhered most closely to a Mediterranean diet had less parkinsonism, Dr. Postuma said.
These limitations do not preclude physicians from recommending the diet for other reasons. “Numerous studies, reviews, meta-analyses, and randomized controlled trials consistently rank the Mediterranean diet as among the healthiest diets available,” Dr. Postuma said. “So, one can clearly recommend diets such as these, even if not necessarily for Parkinson’s disease prevention.”
Adding insights
The researchers used a Mediterranean diet score that was developed in a population of adults from metropolitan Athens, “an area not unlike the one in which the score is being applied in the HELIAD study,” Christy C. Tangney, PhD, professor of clinical nutrition and preventive medicine and associate dean for research at Rush University Medical Center, Chicago, said in a separate editorial. As expected, the average Mediterranean diet adherence score in this study was higher than that in the Chicago Health and Aging Project (33.2 vs. 28.2).
“If we can identify differences in diet or lifestyle patterns and risk of this latent phase of Parkinson’s disease neurodegeneration, we may be one step closer to identifying preventive measures,” she said. Follow-up reports from HELIAD and other cohorts may allow researchers to assess how changes in dietary patterns relate to changes in Parkinson’s disease markers, the probability of prodromal Parkinson’s disease, and incident Parkinson’s disease, Dr. Tangney said.
The study authors had no conflicts of interest or financial disclosures. The study was supported by a grant from the Alzheimer’s Association, an ESPA‐EU grant cofunded by the European Social Fund and Greek National resources, and a grant from the Ministry for Health and Social Solidarity (Greece). Dr. Maraki and a coauthor have received financial support from the Greek State Scholarships Foundation. Dr. Tangney and Dr. Postuma had no conflicts of interest.
SOURCE: Maraki MI et al. Mov Disord. 2018 Oct 10. doi: 10.1002/mds.27489.
Among older adults, adherence to a Mediterranean diet is associated with lower probability of prodromal Parkinson’s disease, according to research published in Movement Disorders.
“Recommending the Mediterranean diet pattern, either to reduce the risk or lessen the effects ... of prodromal Parkinson’s disease, needs to be considered and further explored,” said lead author Maria I. Maraki, PhD, of the department of nutrition and dietetics at Harokopio University in Athens, Greece, and her research colleagues.
Evidence regarding the effect of a Mediterranean diet on Parkinson’s disease risk remains limited, however, and physicians should be cautious in interpreting the data, researchers noted in accompanying editorials.
“There is a puzzling constellation of information and data that cannot be reconciled with a simple model accounting for the role of diet, vascular risk factors, and the neurodegenerative process and mechanisms underlying Parkinson’s disease,” Connie Marras, MD, PhD, and Jose A. Obeso, MD, PhD, said in an editorial. Given Maraki et al.’s findings, “most of us would be glad to accept that such a causal inverse association exists and can therefore be strongly recommended to our patients,” but “further work is needed before definitive conclusions can be reached,” Dr. Marras and Dr. Obeso wrote. Dr. Marras is affiliated with the University Health Network and the University of Toronto. Dr. Obeso is affiliated with University Hospital HM Puerta del Sur, CEU San Pablo University, Móstoles, Spain.
The role of diet
Prior research has suggested that adherence to the Mediterranean diet – characterized by consumption of nonrefined cereals, fruits, vegetables, legumes, potatoes, fish, and olive oil – may be associated with reduced risk of Parkinson’s disease. In addition, studies have found that adherence to the Mediterranean diet may be protective in other diseases, including dementia and cardiovascular disease. Dr. Maraki and her colleagues sought to assess whether adherence to the Mediterranean diet is associated with the likelihood of prodromal Parkinson’s disease or its manifestations. To calculate the probability of prodromal Parkinson’s disease, the investigators used a tool created by the International Parkinson and Movement Disorder Society (MDS) that takes into account baseline risk factors as well as prodromal markers such as constipation and motor slowing.
They analyzed data from 1,731 participants in the population-based Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort in Greece. Participants, 41% of whom were male, were aged 65 years or older and did not have Parkinson’s disease. They completed a detailed food frequency questionnaire, and the researchers calculated how closely each participant’s diet adhered to the Mediterranean diet. Diet adherence scores ranged from 0 to 55, with higher scores indicating greater adherence.
The median probability of prodromal Parkinson’s disease was 1.9% (range, 0.2%-96.7%), and the probability was lower among those with greater adherence to the Mediterranean diet. This difference was “driven mostly by nonmotor markers of prodromal Parkinson’s disease,” including depression, constipation, urinary dysfunction, and daytime somnolence, the researchers said. “Each unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal Parkinson’s disease.” Compared with participants in the lowest quartile of Mediterranean diet adherence, those in the highest quartile had an approximately 21% lower probability for prodromal Parkinson’s disease.
Potential confounding
“This study pushes the prodromal criteria into performing a job they were never designed to do,” which presents potential pitfalls, Ronald B. Postuma, MD, of the department of neurology at Montreal General Hospital in Quebec, said in an accompanying editorial.
While the MDS criteria were designed to assess the likelihood that any person over age 50 years is in a state of prodromal Parkinson’s disease, the present study aimed to evaluate whether a single putative risk factor for Parkinson’s disease is associated with the likelihood of its prodromal state.
In addition, the analysis did not include some of the prodromal markers that are part of the MDS criteria, including olfaction, polysomnographic-proven REM sleep behavior disorder, and dopaminergic functional neuroimaging.
“As pointed out by the researchers, many of the risk factors in the prodromal criteria are potentially confounded by factors other than Parkinson’s disease; for example, one could imagine that older people, men, or farmers (with their higher pesticide exposure) are less likely to follow the Mediterranean diet simply because of different cultural lifestyle patterns,” Dr. Postuma said.
It is also possible that the Mediterranean diet affects prodromal markers such as constipation, sleep, or depression without affecting underlying neurodegenerative disease. In any case, the effect sizes observed in the study were small, and there was no evidence that participants who adhered most closely to a Mediterranean diet had less parkinsonism, Dr. Postuma said.
These limitations do not preclude physicians from recommending the diet for other reasons. “Numerous studies, reviews, meta-analyses, and randomized controlled trials consistently rank the Mediterranean diet as among the healthiest diets available,” Dr. Postuma said. “So, one can clearly recommend diets such as these, even if not necessarily for Parkinson’s disease prevention.”
Adding insights
The researchers used a Mediterranean diet score that was developed in a population of adults from metropolitan Athens, “an area not unlike the one in which the score is being applied in the HELIAD study,” Christy C. Tangney, PhD, professor of clinical nutrition and preventive medicine and associate dean for research at Rush University Medical Center, Chicago, said in a separate editorial. As expected, the average Mediterranean diet adherence score in this study was higher than that in the Chicago Health and Aging Project (33.2 vs. 28.2).
“If we can identify differences in diet or lifestyle patterns and risk of this latent phase of Parkinson’s disease neurodegeneration, we may be one step closer to identifying preventive measures,” she said. Follow-up reports from HELIAD and other cohorts may allow researchers to assess how changes in dietary patterns relate to changes in Parkinson’s disease markers, the probability of prodromal Parkinson’s disease, and incident Parkinson’s disease, Dr. Tangney said.
The study authors had no conflicts of interest or financial disclosures. The study was supported by a grant from the Alzheimer’s Association, an ESPA‐EU grant cofunded by the European Social Fund and Greek National resources, and a grant from the Ministry for Health and Social Solidarity (Greece). Dr. Maraki and a coauthor have received financial support from the Greek State Scholarships Foundation. Dr. Tangney and Dr. Postuma had no conflicts of interest.
SOURCE: Maraki MI et al. Mov Disord. 2018 Oct 10. doi: 10.1002/mds.27489.
FROM MOVEMENT DISORDERS
Key clinical point: Adherence to a Mediterranean diet is associated with lower probability of prodromal Parkinson’s disease.
Major finding: Each 1-unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal Parkinson’s disease.
Study details: A study of 1,731 older adults in the population-based Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort in Greece.
Disclosures: The study authors had no conflicts of interest or financial disclosures. The study was supported by a grant from the Alzheimer’s Association, an ESPA‐EU grant cofunded by the European Social Fund and Greek National resources, and a grant from the Ministry for Health and Social Solidarity (Greece). Dr. Maraki and a coauthor have received financial support from the Greek State Scholarships Foundation.
Source: Maraki MI et al. Mov Disord. 2018 Oct 10. doi:10.1002/mds.27489.
Breast Cancer Tumor Board
Case Presentation
This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.
A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.
Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?
Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.
The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.
Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.
JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?
Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.
However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.
Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?
Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.1 However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.
Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?
Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.
Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?
Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).
There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.
Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.
A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.
In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.
When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.
Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.2 Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status
Dr. Manning. I agree.
Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?
Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.
Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.
Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.
I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.
Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?
Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.6 The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.
You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.
Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.7
Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.
Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.
Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?
Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.
In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.
These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.
The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.
The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.
The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.
Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.
Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.8 Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.9 The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.
In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.
The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.
Mr. Crawford, How would you manage of these AEs from these treatments?
Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.
The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.
There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.
The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.
Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.
With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.
Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.
Click here to read the digital edition.
1. Feng Y, Rhie SK, Huo D, et al. Characterizing genetic susceptibility to breast cancer in women of african ancestry. Cancer Epidemiol Biomarkers. 2017;26(7):1016-1026.
2. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169-180.
3. Poortmans PM, Collette S, Kirkove C, et al; EORTC Radiation Oncology and Breast Cancer Groups. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317-327.
4. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-316.
5. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127-2135.
6. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015;16(3):266-273.
7. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.
8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
9. Davies C, Pan H, Godwin J, et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816.
Case Presentation
This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.
A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.
Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?
Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.
The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.
Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.
JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?
Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.
However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.
Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?
Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.1 However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.
Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?
Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.
Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?
Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).
There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.
Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.
A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.
In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.
When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.
Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.2 Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status
Dr. Manning. I agree.
Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?
Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.
Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.
Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.
I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.
Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?
Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.6 The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.
You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.
Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.7
Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.
Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.
Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?
Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.
In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.
These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.
The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.
The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.
The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.
Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.
Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.8 Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.9 The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.
In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.
The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.
Mr. Crawford, How would you manage of these AEs from these treatments?
Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.
The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.
There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.
The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.
Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.
With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.
Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.
Click here to read the digital edition.
Case Presentation
This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.
A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.
Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?
Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.
The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.
Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.
JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?
Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.
However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.
Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?
Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.1 However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.
Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?
Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.
Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?
Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).
There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.
Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.
A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.
In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.
When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.
Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.2 Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status
Dr. Manning. I agree.
Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?
Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.
Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.
Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.
I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.
Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?
Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.6 The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.
You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.
Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.7
Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.
Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.
Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?
Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.
In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.
These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.
The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.
The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.
The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.
Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.
Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.8 Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.9 The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.
In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.
The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.
Mr. Crawford, How would you manage of these AEs from these treatments?
Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.
The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.
There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.
The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.
Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.
With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.
Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.
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1. Feng Y, Rhie SK, Huo D, et al. Characterizing genetic susceptibility to breast cancer in women of african ancestry. Cancer Epidemiol Biomarkers. 2017;26(7):1016-1026.
2. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169-180.
3. Poortmans PM, Collette S, Kirkove C, et al; EORTC Radiation Oncology and Breast Cancer Groups. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317-327.
4. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-316.
5. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127-2135.
6. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015;16(3):266-273.
7. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.
8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
9. Davies C, Pan H, Godwin J, et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816.
1. Feng Y, Rhie SK, Huo D, et al. Characterizing genetic susceptibility to breast cancer in women of african ancestry. Cancer Epidemiol Biomarkers. 2017;26(7):1016-1026.
2. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169-180.
3. Poortmans PM, Collette S, Kirkove C, et al; EORTC Radiation Oncology and Breast Cancer Groups. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317-327.
4. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-316.
5. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127-2135.
6. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015;16(3):266-273.
7. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.
8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
9. Davies C, Pan H, Godwin J, et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816.
International survey probes oxygen’s efficacy for cluster headache
According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.
To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.
In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).
Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.
Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.
“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”
Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.
Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.
The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.
This article was updated 3/7/2019.
SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.
According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.
To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.
In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).
Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.
Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.
“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”
Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.
Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.
The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.
This article was updated 3/7/2019.
SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.
According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.
To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.
In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).
Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.
Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.
“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”
Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.
Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.
The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.
This article was updated 3/7/2019.
SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.
FROM HEADACHE
Key clinical point: Oxygen is a highly effective treatment for cluster headache with few complications.
Major finding: More than half of respondents (54%) reported that triptans and oxygen were completely or very effective.
Study details: Analysis of data from 1,604 people with cluster headache who completed the online Cluster Headache Questionnaire.
Disclosures: The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.
Source: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.
Breast cancer recurrence lower, survival better with dose-intensified regimens
Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
FROM THE LANCET
Key clinical point: Consider dose-intensification or sequential therapy for patients undergoing chemotherapy.
Major finding: Ten-year recurrence rates were 28% with dose intensification vs. 31.4% for standard dosing.
Study details: Meta-analysis of individual data on 37,298 women enrolled in 26 randomized trials.
Disclosures: The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
Source: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
Advances in CAR T-Cell Therapies (FULL)
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
Why Am I Being Treated Like a Female Breast Cancer Patient? (FULL)
Patient Perspective
Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.
In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.
Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.
My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.
The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.
While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.
It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.
In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.
The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.
While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.
While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.
I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.
Oncologist Perspective
Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.1 Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.2,3
Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.4 Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.
Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.
As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”
Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.
Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.
Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.
My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.
Click here to read the digital edition.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. American Cancer Society. Cancer facts and figures 2014. Atlanta, GA: American Cancer Society; 2014.
2. Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol. 2010;28(2):232-239.
3. Howlander N, Noone AM, Krapcho M, et al. eds. SEER cancer statistics review, 1975-2009: fast stats. http://seer.cancer.gov/csr/1975_2009_pops09. Updated April 2012. Accessed January 20, 2018.
4. Ly D, Forman D, Ferlay J, Brinton LA, Cook MB. An international comparison of male and female breast cancer incidence rates. Int J Cancer. 2013;132(8):1918-1926.
Patient Perspective
Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.
In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.
Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.
My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.
The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.
While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.
It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.
In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.
The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.
While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.
While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.
I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.
Oncologist Perspective
Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.1 Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.2,3
Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.4 Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.
Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.
As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”
Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.
Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.
Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.
My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.
Click here to read the digital edition.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Patient Perspective
Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.
In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.
Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.
My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.
The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.
While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.
It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.
In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.
The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.
While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.
While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.
I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.
Oncologist Perspective
Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.1 Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.2,3
Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.4 Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.
Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.
As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”
Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.
Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.
Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.
My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.
Click here to read the digital edition.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. American Cancer Society. Cancer facts and figures 2014. Atlanta, GA: American Cancer Society; 2014.
2. Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol. 2010;28(2):232-239.
3. Howlander N, Noone AM, Krapcho M, et al. eds. SEER cancer statistics review, 1975-2009: fast stats. http://seer.cancer.gov/csr/1975_2009_pops09. Updated April 2012. Accessed January 20, 2018.
4. Ly D, Forman D, Ferlay J, Brinton LA, Cook MB. An international comparison of male and female breast cancer incidence rates. Int J Cancer. 2013;132(8):1918-1926.
1. American Cancer Society. Cancer facts and figures 2014. Atlanta, GA: American Cancer Society; 2014.
2. Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol. 2010;28(2):232-239.
3. Howlander N, Noone AM, Krapcho M, et al. eds. SEER cancer statistics review, 1975-2009: fast stats. http://seer.cancer.gov/csr/1975_2009_pops09. Updated April 2012. Accessed January 20, 2018.
4. Ly D, Forman D, Ferlay J, Brinton LA, Cook MB. An international comparison of male and female breast cancer incidence rates. Int J Cancer. 2013;132(8):1918-1926.
Therapy ups breast cancer survivors’ cardiac risks
WASHINGTON – Oncologists and cardiologists need to work hand-in-hand when managing the care of women with breast cancer whose treatment plan includes cardiotoxic therapies and breast irradiation, reported specialists.
Depending on the cancer subtype, women with breast cancer may receive chemotherapy with a cardiotoxic anthracycline such as doxorubicin or epirubicin, or a HER2-targeted agent such as trastuzumab (Herceptin), pertuzumab (Perjeta), or ado-trastuzumab emtansine (Kadcyla).
“The cardiotoxicity related to breast cancer has been a well publicized issue, and chances are your patients know about it and are concerned as well,” Jennifer E. Liu, MD, director of cardiovascular laboratories at Memorial Sloan Kettering Cancer Center in New York, said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Anthracyclines, trastuzumab, and HF
In large adjuvant therapy trials of anthracyclines and trastuzumab in women with breast cancer, doxorubicin alone was associated with an asymptomatic decline in left ventricular ejection fraction (LVEF) of 4% to 11%, and a less than 1% incidence of heart failure (HF), Dr. Liu noted.
When patients received an anthracycline followed by trastuzumab, the incidence of asymptomatic LVEF decline ranged from 4% to 19%, the incidence of clinical HF was 2% to 4%, and the rate of trastuzumab interruption for cardiac adverse events ranged from 5% to 18%.
In comparison, in trials with trastuzumab in combination therapy that did not contain an anthracycline, the risk of cardiovascular complications was lower, with asymptomatic decline in LVEF ranging from 3.2% to 9.4%, and class III/IV HF occurring in just 0.5% of patients. In trials combining trastuzumab and pertuzumab, there were no increases in cardiac toxicity over trastuzumab alone.
Although with longer follow-up, the approximately 4% rate of HF in patients treated with anthracycline-based chemotherapy, paclitaxel, and trastuzumab in the NSABP B-31 trial has not changed significantly; retrospective claims-based studies reflecting daily practice have shown significantly higher rates of HF and or cardiomyopathy, Dr. Liu said.
She cited a 2012 study showing that among 45,537 women with a mean age of 76 years who were treated for breast cancer, the 3-year incidence rates of HF and/or cardiomyopathy were 32% for patients treated with trastuzumab alone, and 41.9% for those treated with an anthracycline followed by trastuzumab. Other, smaller studies also showed lower but significantly elevated risks for the drugs.
The discrepancy between clinical trial and “real world” results may be chalked up to the fact that claims-based data rely on diagnostic codes that may not accurately reflect the actual cardiac diagnosis, and by the fact that clinical trials have strict entry criteria that exclude patients with cardiovascular disease, she said.
Radiation risks
Radiation therapy is associated with a more than 7% increase in major coronary events per Gy of mean heart dose, Dr. Liu noted, citing a 2013 study (N Engl J Med. 2013;368:987-98).
Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, said that risk factors for radiation-induced heart disease include anterior or left chest irradiation, cumulative doses above 30 Gy, patient age younger than 50 years, doses of more than 2 Gy per fraction, presence and extent of tumor in or near the heart, lack of radiation shielding, concomitant chemotherapy (especially with anthracyclines), and preexisting cardiovascular disease or risk factors.
For patients with breast cancer, the risk of developing radiation-induced heart disease has diminished considerably with the adoption of heart-sparing techniques over the last several decades, including 3-D conformal techniques, intensity-modulated radiation therapy, proton beam therapy, novel patient positioning techniques that allow radiation only to the cancer-involved breast, and deep inspiration breath holds in which the radiation beam is gated to turn on only when the patient is holding a deep breath, Dr. Nguyen noted.
Treatment options for LVEF decline
The package insert for trastuzumab recommends withholding the drug for a minimum of 4 weeks if the patient has a 16% or greater decline in LVEF from baseline, or a 10% or greater decline from baseline to below the lower limit of normal. The insert recommends LVEF monitoring every 3 or 4 weeks, and says that trastuzumab can be resumed if LVEF improves to above the lower limit of normal with an absolute decrease from baseline of not more than 15%. The insert also states, however, that “the safety of continuation or resumption of trastuzumab in patients with trastuzumab induced LV dysfunction has never been studied, “ Dr. Liu noted.
She cited an American Society of Clinical Oncology guideline on the prevention and monitoring of cardiac dysfunction in survivors of adult cancers, which states in part that the decision to continue or discontinue cancer therapy in patients with evidence of cardiac dysfunction “made by the oncologist, should be informed by close collaboration with a cardiologist, fully evaluating the clinical circumstances and considering the risks and benefits of continuation of therapy responsible for the cardiac dysfunction.”
“I want to emphasize the importance of accepting and managing cardiovascular risk in patients priors to and during potentially cardiotoxic therapy. To optimize cardiologic and oncologic outcomes, we need to avoid or minimize treatment interruptions of life-saving therapy, and mitigate cardiac events with aggressive cardiovascular risk-factor modification,” Dr. Liu said.
She called for development of better risk stratification tools to tailor cardiac surveillance during therapy, based on both patient-specific and treatment-specific risk factors.
Dr. Liu reported nothing to disclose. Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics. Cota, Dendreon, Ferring Pharmaceuticals. GenomeDx, Janssen, and Nanobiotix.
WASHINGTON – Oncologists and cardiologists need to work hand-in-hand when managing the care of women with breast cancer whose treatment plan includes cardiotoxic therapies and breast irradiation, reported specialists.
Depending on the cancer subtype, women with breast cancer may receive chemotherapy with a cardiotoxic anthracycline such as doxorubicin or epirubicin, or a HER2-targeted agent such as trastuzumab (Herceptin), pertuzumab (Perjeta), or ado-trastuzumab emtansine (Kadcyla).
“The cardiotoxicity related to breast cancer has been a well publicized issue, and chances are your patients know about it and are concerned as well,” Jennifer E. Liu, MD, director of cardiovascular laboratories at Memorial Sloan Kettering Cancer Center in New York, said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Anthracyclines, trastuzumab, and HF
In large adjuvant therapy trials of anthracyclines and trastuzumab in women with breast cancer, doxorubicin alone was associated with an asymptomatic decline in left ventricular ejection fraction (LVEF) of 4% to 11%, and a less than 1% incidence of heart failure (HF), Dr. Liu noted.
When patients received an anthracycline followed by trastuzumab, the incidence of asymptomatic LVEF decline ranged from 4% to 19%, the incidence of clinical HF was 2% to 4%, and the rate of trastuzumab interruption for cardiac adverse events ranged from 5% to 18%.
In comparison, in trials with trastuzumab in combination therapy that did not contain an anthracycline, the risk of cardiovascular complications was lower, with asymptomatic decline in LVEF ranging from 3.2% to 9.4%, and class III/IV HF occurring in just 0.5% of patients. In trials combining trastuzumab and pertuzumab, there were no increases in cardiac toxicity over trastuzumab alone.
Although with longer follow-up, the approximately 4% rate of HF in patients treated with anthracycline-based chemotherapy, paclitaxel, and trastuzumab in the NSABP B-31 trial has not changed significantly; retrospective claims-based studies reflecting daily practice have shown significantly higher rates of HF and or cardiomyopathy, Dr. Liu said.
She cited a 2012 study showing that among 45,537 women with a mean age of 76 years who were treated for breast cancer, the 3-year incidence rates of HF and/or cardiomyopathy were 32% for patients treated with trastuzumab alone, and 41.9% for those treated with an anthracycline followed by trastuzumab. Other, smaller studies also showed lower but significantly elevated risks for the drugs.
The discrepancy between clinical trial and “real world” results may be chalked up to the fact that claims-based data rely on diagnostic codes that may not accurately reflect the actual cardiac diagnosis, and by the fact that clinical trials have strict entry criteria that exclude patients with cardiovascular disease, she said.
Radiation risks
Radiation therapy is associated with a more than 7% increase in major coronary events per Gy of mean heart dose, Dr. Liu noted, citing a 2013 study (N Engl J Med. 2013;368:987-98).
Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, said that risk factors for radiation-induced heart disease include anterior or left chest irradiation, cumulative doses above 30 Gy, patient age younger than 50 years, doses of more than 2 Gy per fraction, presence and extent of tumor in or near the heart, lack of radiation shielding, concomitant chemotherapy (especially with anthracyclines), and preexisting cardiovascular disease or risk factors.
For patients with breast cancer, the risk of developing radiation-induced heart disease has diminished considerably with the adoption of heart-sparing techniques over the last several decades, including 3-D conformal techniques, intensity-modulated radiation therapy, proton beam therapy, novel patient positioning techniques that allow radiation only to the cancer-involved breast, and deep inspiration breath holds in which the radiation beam is gated to turn on only when the patient is holding a deep breath, Dr. Nguyen noted.
Treatment options for LVEF decline
The package insert for trastuzumab recommends withholding the drug for a minimum of 4 weeks if the patient has a 16% or greater decline in LVEF from baseline, or a 10% or greater decline from baseline to below the lower limit of normal. The insert recommends LVEF monitoring every 3 or 4 weeks, and says that trastuzumab can be resumed if LVEF improves to above the lower limit of normal with an absolute decrease from baseline of not more than 15%. The insert also states, however, that “the safety of continuation or resumption of trastuzumab in patients with trastuzumab induced LV dysfunction has never been studied, “ Dr. Liu noted.
She cited an American Society of Clinical Oncology guideline on the prevention and monitoring of cardiac dysfunction in survivors of adult cancers, which states in part that the decision to continue or discontinue cancer therapy in patients with evidence of cardiac dysfunction “made by the oncologist, should be informed by close collaboration with a cardiologist, fully evaluating the clinical circumstances and considering the risks and benefits of continuation of therapy responsible for the cardiac dysfunction.”
“I want to emphasize the importance of accepting and managing cardiovascular risk in patients priors to and during potentially cardiotoxic therapy. To optimize cardiologic and oncologic outcomes, we need to avoid or minimize treatment interruptions of life-saving therapy, and mitigate cardiac events with aggressive cardiovascular risk-factor modification,” Dr. Liu said.
She called for development of better risk stratification tools to tailor cardiac surveillance during therapy, based on both patient-specific and treatment-specific risk factors.
Dr. Liu reported nothing to disclose. Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics. Cota, Dendreon, Ferring Pharmaceuticals. GenomeDx, Janssen, and Nanobiotix.
WASHINGTON – Oncologists and cardiologists need to work hand-in-hand when managing the care of women with breast cancer whose treatment plan includes cardiotoxic therapies and breast irradiation, reported specialists.
Depending on the cancer subtype, women with breast cancer may receive chemotherapy with a cardiotoxic anthracycline such as doxorubicin or epirubicin, or a HER2-targeted agent such as trastuzumab (Herceptin), pertuzumab (Perjeta), or ado-trastuzumab emtansine (Kadcyla).
“The cardiotoxicity related to breast cancer has been a well publicized issue, and chances are your patients know about it and are concerned as well,” Jennifer E. Liu, MD, director of cardiovascular laboratories at Memorial Sloan Kettering Cancer Center in New York, said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Anthracyclines, trastuzumab, and HF
In large adjuvant therapy trials of anthracyclines and trastuzumab in women with breast cancer, doxorubicin alone was associated with an asymptomatic decline in left ventricular ejection fraction (LVEF) of 4% to 11%, and a less than 1% incidence of heart failure (HF), Dr. Liu noted.
When patients received an anthracycline followed by trastuzumab, the incidence of asymptomatic LVEF decline ranged from 4% to 19%, the incidence of clinical HF was 2% to 4%, and the rate of trastuzumab interruption for cardiac adverse events ranged from 5% to 18%.
In comparison, in trials with trastuzumab in combination therapy that did not contain an anthracycline, the risk of cardiovascular complications was lower, with asymptomatic decline in LVEF ranging from 3.2% to 9.4%, and class III/IV HF occurring in just 0.5% of patients. In trials combining trastuzumab and pertuzumab, there were no increases in cardiac toxicity over trastuzumab alone.
Although with longer follow-up, the approximately 4% rate of HF in patients treated with anthracycline-based chemotherapy, paclitaxel, and trastuzumab in the NSABP B-31 trial has not changed significantly; retrospective claims-based studies reflecting daily practice have shown significantly higher rates of HF and or cardiomyopathy, Dr. Liu said.
She cited a 2012 study showing that among 45,537 women with a mean age of 76 years who were treated for breast cancer, the 3-year incidence rates of HF and/or cardiomyopathy were 32% for patients treated with trastuzumab alone, and 41.9% for those treated with an anthracycline followed by trastuzumab. Other, smaller studies also showed lower but significantly elevated risks for the drugs.
The discrepancy between clinical trial and “real world” results may be chalked up to the fact that claims-based data rely on diagnostic codes that may not accurately reflect the actual cardiac diagnosis, and by the fact that clinical trials have strict entry criteria that exclude patients with cardiovascular disease, she said.
Radiation risks
Radiation therapy is associated with a more than 7% increase in major coronary events per Gy of mean heart dose, Dr. Liu noted, citing a 2013 study (N Engl J Med. 2013;368:987-98).
Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, said that risk factors for radiation-induced heart disease include anterior or left chest irradiation, cumulative doses above 30 Gy, patient age younger than 50 years, doses of more than 2 Gy per fraction, presence and extent of tumor in or near the heart, lack of radiation shielding, concomitant chemotherapy (especially with anthracyclines), and preexisting cardiovascular disease or risk factors.
For patients with breast cancer, the risk of developing radiation-induced heart disease has diminished considerably with the adoption of heart-sparing techniques over the last several decades, including 3-D conformal techniques, intensity-modulated radiation therapy, proton beam therapy, novel patient positioning techniques that allow radiation only to the cancer-involved breast, and deep inspiration breath holds in which the radiation beam is gated to turn on only when the patient is holding a deep breath, Dr. Nguyen noted.
Treatment options for LVEF decline
The package insert for trastuzumab recommends withholding the drug for a minimum of 4 weeks if the patient has a 16% or greater decline in LVEF from baseline, or a 10% or greater decline from baseline to below the lower limit of normal. The insert recommends LVEF monitoring every 3 or 4 weeks, and says that trastuzumab can be resumed if LVEF improves to above the lower limit of normal with an absolute decrease from baseline of not more than 15%. The insert also states, however, that “the safety of continuation or resumption of trastuzumab in patients with trastuzumab induced LV dysfunction has never been studied, “ Dr. Liu noted.
She cited an American Society of Clinical Oncology guideline on the prevention and monitoring of cardiac dysfunction in survivors of adult cancers, which states in part that the decision to continue or discontinue cancer therapy in patients with evidence of cardiac dysfunction “made by the oncologist, should be informed by close collaboration with a cardiologist, fully evaluating the clinical circumstances and considering the risks and benefits of continuation of therapy responsible for the cardiac dysfunction.”
“I want to emphasize the importance of accepting and managing cardiovascular risk in patients priors to and during potentially cardiotoxic therapy. To optimize cardiologic and oncologic outcomes, we need to avoid or minimize treatment interruptions of life-saving therapy, and mitigate cardiac events with aggressive cardiovascular risk-factor modification,” Dr. Liu said.
She called for development of better risk stratification tools to tailor cardiac surveillance during therapy, based on both patient-specific and treatment-specific risk factors.
Dr. Liu reported nothing to disclose. Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics. Cota, Dendreon, Ferring Pharmaceuticals. GenomeDx, Janssen, and Nanobiotix.
REPORTING FROM ACC CARDIO-ONCOLOGY
Key clinical point: Oncologists should work with cardiologists to mitigate heart disease risk.
Major finding: Anthracyclines followed by trastuzumab significantly increase risk of HF.
Study details: Review of risk for heart disease in breast cancer survivors.
Disclosures: Dr. Liu reported nothing to disclose. Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics, Cota, Dendreon, Ferring Pharmaceuticals, GenomeDx, Janssen, and Nanobiotix.
Cloud of inconsistency hangs over cannabis data
More people are using medical cannabis as it becomes legal in more states, but the lack of standardization in states’ data collection hindered investigators’ efforts to track that use.
Legalized medical cannabis is now available in 33 states and the District of Columbia, and the number of users has risen from just over 72,000 in 2009 to almost 814,000 in 2017. That 814,000, however, covers only 16 states and D.C., since 1 state (Connecticut) does not publish reports on medical cannabis use, 12 did not have statistics available, 2 (New York and Vermont) didn’t report data for 2017, and 2 (California and Maine) have voluntary registries that are unlikely to be accurate, according to Kevin F. Boehnke, PhD, of the University of Michigan, Ann Arbor, and his associates.
Michigan had the largest reported number of patients enrolled in its medical cannabis program in 2017, almost 270,000. California – the state with the oldest medical cannabis legislation (passed in 1996) and the largest overall population but a voluntary cannabis registry – reported its highest number of enrollees, 12,659, in 2009-2010, the investigators said. Colorado had more than 116,000 patients in its medical cannabis program in 2010 (Health Aff. 2019;38[2]:295-302).
The “many inconsistencies in data quality across states [suggest] the need for further standardization of data collection. Such standardization would add transparency to understanding how medical cannabis programs are used, which would help guide both research and policy needs,” Dr. Boehnke and his associates wrote.
More consistency was seen in the reasons for using medical cannabis. Chronic pain made up 62.2% of all qualifying conditions reported by patients during 1999-2016, with the annual average varying between 33.3% and 73%. Multiple sclerosis spasticity symptoms had the second-highest number of reports over the study period, followed by chemotherapy-induced nausea and vomiting, posttraumatic stress disorder, and cancer, they reported.
The investigators also looked at the appropriateness of cannabis and determined that its use in 85.5% of patient-reported conditions was “supported by conclusive or substantial evidence of therapeutic effectiveness, according to the 2017 National Academies report” on the health effects of cannabis.
“We believe not only that it is inappropriate for cannabis to remain a Schedule I substance, but also that state and federal policy makers should begin evaluating evidence-based ways for safely integrating cannabis research and products into the health care system,” they concluded.
SOURCE: Boehnke KF et al. Health Aff. 2019;38(2):295-302.
More people are using medical cannabis as it becomes legal in more states, but the lack of standardization in states’ data collection hindered investigators’ efforts to track that use.
Legalized medical cannabis is now available in 33 states and the District of Columbia, and the number of users has risen from just over 72,000 in 2009 to almost 814,000 in 2017. That 814,000, however, covers only 16 states and D.C., since 1 state (Connecticut) does not publish reports on medical cannabis use, 12 did not have statistics available, 2 (New York and Vermont) didn’t report data for 2017, and 2 (California and Maine) have voluntary registries that are unlikely to be accurate, according to Kevin F. Boehnke, PhD, of the University of Michigan, Ann Arbor, and his associates.
Michigan had the largest reported number of patients enrolled in its medical cannabis program in 2017, almost 270,000. California – the state with the oldest medical cannabis legislation (passed in 1996) and the largest overall population but a voluntary cannabis registry – reported its highest number of enrollees, 12,659, in 2009-2010, the investigators said. Colorado had more than 116,000 patients in its medical cannabis program in 2010 (Health Aff. 2019;38[2]:295-302).
The “many inconsistencies in data quality across states [suggest] the need for further standardization of data collection. Such standardization would add transparency to understanding how medical cannabis programs are used, which would help guide both research and policy needs,” Dr. Boehnke and his associates wrote.
More consistency was seen in the reasons for using medical cannabis. Chronic pain made up 62.2% of all qualifying conditions reported by patients during 1999-2016, with the annual average varying between 33.3% and 73%. Multiple sclerosis spasticity symptoms had the second-highest number of reports over the study period, followed by chemotherapy-induced nausea and vomiting, posttraumatic stress disorder, and cancer, they reported.
The investigators also looked at the appropriateness of cannabis and determined that its use in 85.5% of patient-reported conditions was “supported by conclusive or substantial evidence of therapeutic effectiveness, according to the 2017 National Academies report” on the health effects of cannabis.
“We believe not only that it is inappropriate for cannabis to remain a Schedule I substance, but also that state and federal policy makers should begin evaluating evidence-based ways for safely integrating cannabis research and products into the health care system,” they concluded.
SOURCE: Boehnke KF et al. Health Aff. 2019;38(2):295-302.
More people are using medical cannabis as it becomes legal in more states, but the lack of standardization in states’ data collection hindered investigators’ efforts to track that use.
Legalized medical cannabis is now available in 33 states and the District of Columbia, and the number of users has risen from just over 72,000 in 2009 to almost 814,000 in 2017. That 814,000, however, covers only 16 states and D.C., since 1 state (Connecticut) does not publish reports on medical cannabis use, 12 did not have statistics available, 2 (New York and Vermont) didn’t report data for 2017, and 2 (California and Maine) have voluntary registries that are unlikely to be accurate, according to Kevin F. Boehnke, PhD, of the University of Michigan, Ann Arbor, and his associates.
Michigan had the largest reported number of patients enrolled in its medical cannabis program in 2017, almost 270,000. California – the state with the oldest medical cannabis legislation (passed in 1996) and the largest overall population but a voluntary cannabis registry – reported its highest number of enrollees, 12,659, in 2009-2010, the investigators said. Colorado had more than 116,000 patients in its medical cannabis program in 2010 (Health Aff. 2019;38[2]:295-302).
The “many inconsistencies in data quality across states [suggest] the need for further standardization of data collection. Such standardization would add transparency to understanding how medical cannabis programs are used, which would help guide both research and policy needs,” Dr. Boehnke and his associates wrote.
More consistency was seen in the reasons for using medical cannabis. Chronic pain made up 62.2% of all qualifying conditions reported by patients during 1999-2016, with the annual average varying between 33.3% and 73%. Multiple sclerosis spasticity symptoms had the second-highest number of reports over the study period, followed by chemotherapy-induced nausea and vomiting, posttraumatic stress disorder, and cancer, they reported.
The investigators also looked at the appropriateness of cannabis and determined that its use in 85.5% of patient-reported conditions was “supported by conclusive or substantial evidence of therapeutic effectiveness, according to the 2017 National Academies report” on the health effects of cannabis.
“We believe not only that it is inappropriate for cannabis to remain a Schedule I substance, but also that state and federal policy makers should begin evaluating evidence-based ways for safely integrating cannabis research and products into the health care system,” they concluded.
SOURCE: Boehnke KF et al. Health Aff. 2019;38(2):295-302.
FROM HEALTH AFFAIRS
Clearance of Psoriasis After Ischemic Stroke
The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.1 One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,2 and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.3 There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection4 as well as cerebrovascular accident.5 We present a case of total psoriasis clearance following ischemic stroke.
Case Report
A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.
Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.
Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.
Comment
The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.6
Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al7 first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher8 and lower9 levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.2,10 Specifically, NGF prevents apoptosis of keratinocytes11 and is found in higher levels in psoriatic skin compared to controls.12 Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation13 and has been found at increased levels in psoriatic skin.14 Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.8
Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.6 Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.15
Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.5 Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.16,17 In cases in which patients regained neurologic function, Zhu et al10 found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,10 confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides3 and that central nervous system injury also can cause similar downstream effects.10
Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).18 Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.21
A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.22 Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.
- Boehncke WH. Etiology and pathogenesis of psoriasis. Rheum Dis Clin North Am. 2015;41:665-675.
- Saraceno R, Kleyn CE, Terenghi G, et al. The role of neuropeptides in psoriasis. Br J Dermatol. 2006;155:876-882.
- Ostrowski SM, Belkai A, Loyd CM, et al. Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptide-dependent manner. J Invest Dermatol. 2011;131:1530-1538.
- Dewing SB. Remission of psoriasis associated with cutaneous nerve section. Arch Dermatol. 1971;104:220-221.
- Stratigos AJ, Katoulis AK, Stavrianeas NG. Spontaneous clearing of psoriasis after stroke. J Am Acad Dermatol. 1998;38(5, pt 1):768-770.
- Raychaudhuri SP, Farber EM. Neuroimmunologic aspects of psoriasis. Cutis. 2000;66:357-362.
- Farber EM, Nickoloff BJ, Recht B, et al. Stress, symmetry, and psoriasis: possible role of neuropeptides. J Am Acad Dermatol. 1986;14(2, pt 1):305-311.
- Al’Abadie MS, Senior HJ, Bleehen SS, et al. Neuropeptides and general neuronal marker in psoriasis—an immunohistochemical study. Clin Exp Dermatol. 1995;20:384-389.
- Pincelli C, Fantini F, Romualdi P, et al. Substance P is diminished and vasoactive intestinal peptide is augmented in psoriatic lesions and these peptides exert disparate effects on the proliferation of cultured human keratinocytes. J Invest Dermatol. 1992;98:421-427.
- Zhu TH, Nakamura M, Farahnik B, et al. The role of the nervous system in the pathophysiology of psoriasis: a review of cases of psoriasis remission or improvement following denervation injury. Am J Clin Dermatol. 2016;17:257-263.
- Pincelli C. Nerve growth factor and keratinocytes: a role in psoriasis. Eur J Dermatol. 2000;10:85-90.
- Raychaudhuri SP, Jiang WY, Farber EM. Psoriatic keratinocytes express high levels of nerve growth factor. Acta Derm Venereol. 1998;78:84-86.
- He Y, Ding G, Wang X, et al. Calcitonin gene‐related peptide in Langerhans cells in psoriatic plaque lesions. Chin Med J (Engl). 2000;113:747-751.
- Chu DQ, Choy M, Foster P, et al. A comparative study of the ability of calcitonin gene‐related peptide and adrenomedullin13–52 to modulate microvascular but not thermal hyperalgesia responses. Br J Pharmacol. 2000;130:1589-1596.
- Nakamura M, Toyoda M, Morohashi M. Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors. Br J Dermatol. 2003;149:718-730.
- Wang TS, Tsai TF. Psoriasis sparing the lower limb with postpoliomeylitis residual paralysis. Br J Dermatol. 2014;171:429-431.
- Weiner SR, Bassett LW, Reichman RP. Protective effect of poliomyelitis on psoriatic arthritis. Arthritis Rheum. 1985;28:703-706.
- Cohen AD, Bonneh DY, Reuveni H, et al. Drug exposure and psoriasis vulgaris: case control and case-crossover studies. Acta Derm Venereol. 2005;85:299-303.
- Faghihi T, Radfar M, Mehrabian Z, et al. Atorvastatin for the treatment of plaque-type psoriasis. Pharmacotherapy. 2011;31:1045-1050.
- Chua SHH, Tioleco GMS, Dayrit CAF, et al. Atorvastatin as adjunctive therapy for chronic plaque type psoriasis versus betamethasone valerate alone: a randomized, double-blind, placebo-controlled trial. Indian J Dermatol Venereol Leprol. 2017;83:441-447.
- Jekel LG. Use of heparin in treatment of psoriasis. AMA Arch Derm Syphilol. 1953;68:80-82.
- Farber EM, Cohen EN, Trozak DJ, et al. Peptide T improves psoriasis when infused into lesions in nanogram amounts. J Am Acad Dermatol. 1991;25:658-664.
The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.1 One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,2 and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.3 There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection4 as well as cerebrovascular accident.5 We present a case of total psoriasis clearance following ischemic stroke.
Case Report
A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.
Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.
Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.
Comment
The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.6
Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al7 first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher8 and lower9 levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.2,10 Specifically, NGF prevents apoptosis of keratinocytes11 and is found in higher levels in psoriatic skin compared to controls.12 Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation13 and has been found at increased levels in psoriatic skin.14 Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.8
Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.6 Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.15
Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.5 Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.16,17 In cases in which patients regained neurologic function, Zhu et al10 found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,10 confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides3 and that central nervous system injury also can cause similar downstream effects.10
Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).18 Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.21
A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.22 Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.
The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.1 One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,2 and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.3 There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection4 as well as cerebrovascular accident.5 We present a case of total psoriasis clearance following ischemic stroke.
Case Report
A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.
Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.
Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.
Comment
The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.6
Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al7 first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher8 and lower9 levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.2,10 Specifically, NGF prevents apoptosis of keratinocytes11 and is found in higher levels in psoriatic skin compared to controls.12 Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation13 and has been found at increased levels in psoriatic skin.14 Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.8
Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.6 Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.15
Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.5 Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.16,17 In cases in which patients regained neurologic function, Zhu et al10 found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,10 confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides3 and that central nervous system injury also can cause similar downstream effects.10
Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).18 Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.21
A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.22 Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.
- Boehncke WH. Etiology and pathogenesis of psoriasis. Rheum Dis Clin North Am. 2015;41:665-675.
- Saraceno R, Kleyn CE, Terenghi G, et al. The role of neuropeptides in psoriasis. Br J Dermatol. 2006;155:876-882.
- Ostrowski SM, Belkai A, Loyd CM, et al. Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptide-dependent manner. J Invest Dermatol. 2011;131:1530-1538.
- Dewing SB. Remission of psoriasis associated with cutaneous nerve section. Arch Dermatol. 1971;104:220-221.
- Stratigos AJ, Katoulis AK, Stavrianeas NG. Spontaneous clearing of psoriasis after stroke. J Am Acad Dermatol. 1998;38(5, pt 1):768-770.
- Raychaudhuri SP, Farber EM. Neuroimmunologic aspects of psoriasis. Cutis. 2000;66:357-362.
- Farber EM, Nickoloff BJ, Recht B, et al. Stress, symmetry, and psoriasis: possible role of neuropeptides. J Am Acad Dermatol. 1986;14(2, pt 1):305-311.
- Al’Abadie MS, Senior HJ, Bleehen SS, et al. Neuropeptides and general neuronal marker in psoriasis—an immunohistochemical study. Clin Exp Dermatol. 1995;20:384-389.
- Pincelli C, Fantini F, Romualdi P, et al. Substance P is diminished and vasoactive intestinal peptide is augmented in psoriatic lesions and these peptides exert disparate effects on the proliferation of cultured human keratinocytes. J Invest Dermatol. 1992;98:421-427.
- Zhu TH, Nakamura M, Farahnik B, et al. The role of the nervous system in the pathophysiology of psoriasis: a review of cases of psoriasis remission or improvement following denervation injury. Am J Clin Dermatol. 2016;17:257-263.
- Pincelli C. Nerve growth factor and keratinocytes: a role in psoriasis. Eur J Dermatol. 2000;10:85-90.
- Raychaudhuri SP, Jiang WY, Farber EM. Psoriatic keratinocytes express high levels of nerve growth factor. Acta Derm Venereol. 1998;78:84-86.
- He Y, Ding G, Wang X, et al. Calcitonin gene‐related peptide in Langerhans cells in psoriatic plaque lesions. Chin Med J (Engl). 2000;113:747-751.
- Chu DQ, Choy M, Foster P, et al. A comparative study of the ability of calcitonin gene‐related peptide and adrenomedullin13–52 to modulate microvascular but not thermal hyperalgesia responses. Br J Pharmacol. 2000;130:1589-1596.
- Nakamura M, Toyoda M, Morohashi M. Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors. Br J Dermatol. 2003;149:718-730.
- Wang TS, Tsai TF. Psoriasis sparing the lower limb with postpoliomeylitis residual paralysis. Br J Dermatol. 2014;171:429-431.
- Weiner SR, Bassett LW, Reichman RP. Protective effect of poliomyelitis on psoriatic arthritis. Arthritis Rheum. 1985;28:703-706.
- Cohen AD, Bonneh DY, Reuveni H, et al. Drug exposure and psoriasis vulgaris: case control and case-crossover studies. Acta Derm Venereol. 2005;85:299-303.
- Faghihi T, Radfar M, Mehrabian Z, et al. Atorvastatin for the treatment of plaque-type psoriasis. Pharmacotherapy. 2011;31:1045-1050.
- Chua SHH, Tioleco GMS, Dayrit CAF, et al. Atorvastatin as adjunctive therapy for chronic plaque type psoriasis versus betamethasone valerate alone: a randomized, double-blind, placebo-controlled trial. Indian J Dermatol Venereol Leprol. 2017;83:441-447.
- Jekel LG. Use of heparin in treatment of psoriasis. AMA Arch Derm Syphilol. 1953;68:80-82.
- Farber EM, Cohen EN, Trozak DJ, et al. Peptide T improves psoriasis when infused into lesions in nanogram amounts. J Am Acad Dermatol. 1991;25:658-664.
- Boehncke WH. Etiology and pathogenesis of psoriasis. Rheum Dis Clin North Am. 2015;41:665-675.
- Saraceno R, Kleyn CE, Terenghi G, et al. The role of neuropeptides in psoriasis. Br J Dermatol. 2006;155:876-882.
- Ostrowski SM, Belkai A, Loyd CM, et al. Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptide-dependent manner. J Invest Dermatol. 2011;131:1530-1538.
- Dewing SB. Remission of psoriasis associated with cutaneous nerve section. Arch Dermatol. 1971;104:220-221.
- Stratigos AJ, Katoulis AK, Stavrianeas NG. Spontaneous clearing of psoriasis after stroke. J Am Acad Dermatol. 1998;38(5, pt 1):768-770.
- Raychaudhuri SP, Farber EM. Neuroimmunologic aspects of psoriasis. Cutis. 2000;66:357-362.
- Farber EM, Nickoloff BJ, Recht B, et al. Stress, symmetry, and psoriasis: possible role of neuropeptides. J Am Acad Dermatol. 1986;14(2, pt 1):305-311.
- Al’Abadie MS, Senior HJ, Bleehen SS, et al. Neuropeptides and general neuronal marker in psoriasis—an immunohistochemical study. Clin Exp Dermatol. 1995;20:384-389.
- Pincelli C, Fantini F, Romualdi P, et al. Substance P is diminished and vasoactive intestinal peptide is augmented in psoriatic lesions and these peptides exert disparate effects on the proliferation of cultured human keratinocytes. J Invest Dermatol. 1992;98:421-427.
- Zhu TH, Nakamura M, Farahnik B, et al. The role of the nervous system in the pathophysiology of psoriasis: a review of cases of psoriasis remission or improvement following denervation injury. Am J Clin Dermatol. 2016;17:257-263.
- Pincelli C. Nerve growth factor and keratinocytes: a role in psoriasis. Eur J Dermatol. 2000;10:85-90.
- Raychaudhuri SP, Jiang WY, Farber EM. Psoriatic keratinocytes express high levels of nerve growth factor. Acta Derm Venereol. 1998;78:84-86.
- He Y, Ding G, Wang X, et al. Calcitonin gene‐related peptide in Langerhans cells in psoriatic plaque lesions. Chin Med J (Engl). 2000;113:747-751.
- Chu DQ, Choy M, Foster P, et al. A comparative study of the ability of calcitonin gene‐related peptide and adrenomedullin13–52 to modulate microvascular but not thermal hyperalgesia responses. Br J Pharmacol. 2000;130:1589-1596.
- Nakamura M, Toyoda M, Morohashi M. Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors. Br J Dermatol. 2003;149:718-730.
- Wang TS, Tsai TF. Psoriasis sparing the lower limb with postpoliomeylitis residual paralysis. Br J Dermatol. 2014;171:429-431.
- Weiner SR, Bassett LW, Reichman RP. Protective effect of poliomyelitis on psoriatic arthritis. Arthritis Rheum. 1985;28:703-706.
- Cohen AD, Bonneh DY, Reuveni H, et al. Drug exposure and psoriasis vulgaris: case control and case-crossover studies. Acta Derm Venereol. 2005;85:299-303.
- Faghihi T, Radfar M, Mehrabian Z, et al. Atorvastatin for the treatment of plaque-type psoriasis. Pharmacotherapy. 2011;31:1045-1050.
- Chua SHH, Tioleco GMS, Dayrit CAF, et al. Atorvastatin as adjunctive therapy for chronic plaque type psoriasis versus betamethasone valerate alone: a randomized, double-blind, placebo-controlled trial. Indian J Dermatol Venereol Leprol. 2017;83:441-447.
- Jekel LG. Use of heparin in treatment of psoriasis. AMA Arch Derm Syphilol. 1953;68:80-82.
- Farber EM, Cohen EN, Trozak DJ, et al. Peptide T improves psoriasis when infused into lesions in nanogram amounts. J Am Acad Dermatol. 1991;25:658-664.
Practice Points
- Psoriasis is exacerbated in the presence of stress, and psoriatic lesions often have a symmetric distribution, which is evidence that the nervous system is involved in the pathophysiology of the condition.
- Various neuropeptides are involved in the pathophysiology of psoriasis, including substance P, nerve growth factor, calcitonin gene-related peptide, and vasoactive intestinal peptide.
- Peripheral nerve damage results in decreased secretion of neuropeptides, which can lead to remission of psoriasis.
Barriers and Facilitators to the Use of Genomic-Based Targeted Therapy in the VA: Qualitative Findings(FULL)
Lung cancer is the most frequent cause of cancer-related mortality worldwide.1 The most prevalent type of lung cancer is non-small cell lung cancer (NSCLC), which comprises about 85% of lung cancer cases.2 As there are no cost-effective approaches to screening for lung cancer, most lung cancers are identified at an advanced stage (stage IIIB or IV).
New approaches to managing advanced lung cancer have emerged in recent years, including drugs designed to target specific genetic mutations in some tumors.3 The National Comprehensive Cancer Network (NCCN) recommends erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) for first-line treatment of advanced NSCLC with EGFR mutation.4 Crizotinib is recommended to treat cancers that test positive for the anaplastic lymphoma kinase (ALK) mutation.4 Utilization of targeting agents has been found to extend the survival times for patients with the specified mutations.5 Both erlotinib and crizotinib are available at the VHA.
Previous research showed that VHA providers expressed overall favorable attitudes about genomic medicine.6 Providers perceived genomic medicine to have an important and possibly transformative role in medicine. Barriers to utilization of genomic medicine involved concerns about coordination of care, changes in workload, and increased length of patient visits. In addition to these system-level barriers, many providers had concerns about the proficiency of VHA-based practitioners to appropriately use genomic medicine.
Previous research has evaluated utilization of genomic testing and genomic-based targeted therapy (GBTT) in VA and community settings.5-8 It is unclear whether VHA-based providers are following clinical guidelines regarding genomic testing and utilization of GBTT.4 The authors set out to identify factors that impede and encourage guideline-consistent care in the management of NSCLC at the VHA. The authors specifically sought information about oncologists’ perceptions and experiences with EGFR and ALK mutation testing in patients with advanced NSCLC, as well as use of erlotinib and crizotinib in treating such patients.
Methods
This study was approved by the institutional review boards at Michael E. DeBakey VAMC in Houston, Texas and Baylor College of Medicine. In-depth qualitative interviews were conducted with VHA oncologists to examine their reported barriers and facilitators to mutation testing and prescribing of genomic-based treatment in patients with advanced NSCLC.
The sample of participants was recruited from a list of VHA medical oncologists, compiled by the study project coordinator. Investigators stratified the list by American College of Surgeons Commission on Cancer (CoC) accreditation status (yes/no) and used a stratified purposive sampling technique to recruit participants from CoC-accredited facilities and nonaccredited facilities. Recruitment and data collection occurred between March 2015 and February 2016. Oncologists were considered for inclusion if they (1) were specialists in oncology; (2) practiced at the VHA during the time of recruitment; and (3) had experience treating lung cancer at a VHA facility. During recruitment, potential participants were told that the investigators were interested in learning about oncologists’ experiences and decisions about using GBTT to treat advanced lung cancer in the VHA. Participants were scheduled for telephone-based interviews, and verbal consent was obtained prior to all interviews. Interviews ranged from 19 to 90 minutes (average, 40 min).
Recruitment was stopped at the point of thematic saturation, defined a priori as the point when 2 independent coders agreed that 3 consecutive transcripts for a given interview category (see below) rendered no new thematic concepts.9,10 Consistent with the theoretical framework developed by Cabana and colleagues, interviews were designed to elicit information about oncologists’ knowledge, attitudes, intent to use GBTT, and perceived facilitators and barriers to using GBTT in the VHA.11 Additional findings are presented elsewhere.12 The interview guide was pilot tested and revised prior to initiating data collection. All interviews were recorded, transcribed, and analyzed for content.
Analysis
Data were analyzed using framework analysis methodology, which allows for the inclusion of existing concepts as well as emergent themes within an established theoretical framework.13 Two independent coders with expertise in framework analysis independently created codes and indexed the data using Atlas.ti 6.2 (Scientific Software Development, Berlin, Germany). Disagreements about coding decisions were resolved through group consensus. Coding centered on 2 themes:
- Barriers and facilitators to mutation testing. This includes system or facility factors and testing weaknesses that act as barriers to ordering mutation testing, system or facility factors that facilitate ordering mutation testing, and oncologists’ suggestions for ways to encourage more testing in the VHA.
- Barriers and facilitators to prescribing GBTT. This includes system or facility factors that act as barriers to prescribing GBTT, system or facility factors that facilitate prescribing GBTT, and oncologists’ suggestions for ways to encourage more prescribing of GBTT in the VHA.
Thirty medical oncologists were interviewed. Participant demographics are presented in the Table.
Barriers to testing
The 2 most commonly cited barriers to ordering mutation testing can be considered weaknesses in the testing process: lack of tissue and wait time for results. Almost all providers identified lack of tissue as a barrier to ordering a mutation test.
Another frequently cited testing weakness involved the wait time for results. Because the mutation analysis is not conducted in the VHA facility, providers often must wait 2 to 4 weeks to receive results. This can present a problem because some providers do not want to wait for the results before recommending a course of treatment.
Several providers cited system and facility factors as barriers to mutation testing. The most common of these involves the ordering process. Oncology providers often remarked that ordering the mutation test is cumbersome or inconvenient because there is no ordering mechanism in the Computerized Patient Record System (CPRS). Many different approaches for ordering a mutation test exist, including e-mailing the pathology department, calling to place the order, or requesting the test in person. As providers can order many, if not most, other tests via CPRS, it is clear that this presents an inconvenient exception.
Budgetary constraints were another frequently cited system or facility-level barrier. Providers sometimes were unable to access the test due to the cost
Finally, several providers noted that in some cases patients did not wish to undergo a biopsy. Thus, patient preference can act as a barrier to mutation testing. Some patients wish to forgo treatment, which eliminates the need for a mutation test. Other patients believe that due to their smoking history, they are unlikely to have an ALK or EGFR mutation and instead immediately opt for chemotherapy. Only a small minority of participants identified no barriers to mutation testing.
Facilitators for Testing
Many providers complimented the availability of the mutation test. Interestingly, while some providers mentioned that lack of CPRS ordering was a barrier to testing, several also listed access to a CPRS order as a facilitator. These providers commented that ordering a test was streamlined and easy, given the mechanism in CPRS. Some VHA facilities offer CPRS order capabilities, and others do not. Other oncologists commented more generally on the cooperativeness of the pathology department in ordering mutation tests. It seems that facilities may use different ordering procedures, but in most of these facilities, a high degree of cooperation exists between departments to send out for tests that are requested.
Providers offered many ideas for ways to improve mutation testing or to facilitate the testing. By far, the most commonly cited way to improve the testing process was to make mutation testing reflexive for metastatic nonsquamous NSCLC. Some acknowledged that to achieve this would require a change to the budgeting process such that the test would not drain the pathology department’s budget. Implementing reflexive testing of patients, as recommended by guidelines, would understandably address several of the barriers that were identified in this study. Other providers recommended standardizing the ordering procedure and location of results. Specifically, providers recommended creating a button in CPRS for ordering and always reporting the results in the same place in CPRS.
Barriers to GBTT Prescribing
The clear majority of providers identified no barriers to prescribing GBTTs. A few mentioned that they were required to submit a nonformulary consult. A representative quote described this as “more out of a formality, and the pharmacist basically is there with me and he approves it on the spot and provides the prescription on the day, right when I’m seeing the patient.” Only a very small minority of providers identified medication cost as a barrier, but even those respondents did not indicate that cost prevented them from offering GBTTs to their patients. Rather, cost consciousness simply made them more mindful and judicious when making decisions about prescribing GBTTs.
Facilitators to GBTT Prescribing
Several providers listed availability of the costly medication in the VHA as a facilitator to prescribing. Veterans can obtain GBTTs with little to no insurance cost or copayment, which is not always the case outside the VHA.
One recommendation for further facilitating prescribing of GBTTs involved eliminating the preauthorization requirement, particularly in first-line use for patients testing positive for ALK or EGFR mutations. Although the preauthorization was not seen as a significant barrier, removal of this formality could make prescribing easier.
Discussion
Although in some cases, testing weaknesses (lack of tissue, wait time to receive results) can interrupt a treatment trajectory, many of the barriers identified in this study are modifiable. Overwhelmingly, oncologists recommended making mutation testing reflexive for metastatic nonsquamous NSCLC. Implementing reflexive testing of patients, as recommended by guidelines, would understandably address issues related to variable utilization of genomic testing in VHA.12 Additionally, in response to system and facility barriers to mutation testing, other providers recommended standardizing the ordering procedure and location of results. Utilization of GBTT can be facilitated by eliminating the preauthorization requirement, particularly in first-line use for patients with positive mutations. Although the preauthorization was not seen as a significant barrier, removal of this formality could make prescribing easier.
This study extends previous research that identified underuse of genomic testing in community-based practices. The authors sought to interview a broad sample of providers from various facilities (small, large, CoC accredited, nonaccredited) to understand the range of conditions faced by VA providers. Some providers face more barriers than do others, whereas some face few or no barriers. This wide range of experiences can help to better understand the factors that facilitate guideline-adherent care.
Limitations
The authors recognize that availability of resources and testing and prescribing practices are constantly evolving and perhaps have improved since the data were collected. Thus, the age of the study data might be a limitation to the study. Like most qualitative studies, these findings are limited in their generalizability beyond the study population. Additionally, the authors were limited to recruiting oncologists with reliable contact information listed in the VHA directory. Although this could have introduced some degree of sampling bias, the authors are confident that the sample sufficiently represents the population of VHA-based medical oncologists who treat lung cancer. Despite these limitations, these findings provide novel perspectives on barriers and facilitators to genomic testing GBTT prescribing in the VHA. The authors identify modifiable barriers to testing and prescribing that can be addressed to improve and standardize care of advanced lung cancer in the VHA.
Conclusion
Efforts should be made to address modifiable barriers to mutation testing and guideline-consistent prescribing of GBTT in the VA setting. Implementation of specific practices like reflexive testing for all metastatic nonsquamous NSCLC, standardization of the mutation test ordering procedure, standardization of results reporting, and elimination of the preauthorization to prescribe GBTT could impact the utilization of GBTT in VHA.
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. , , , Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
2. American Cancer Society. What is non-small cell lung cancer? https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Updated May 16, 2016. Accessed January 19, 2018.
3. , , . New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1097-1104.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). non-small cell lung cancer 2. 2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Updated December 19, 2017. Accessed Jan
5. Rosell R, Moran T, Queralt C, et al; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967.
6. Arar N, Seo J, Abboud HE, Parchman M, Noel P. Providers’ behavioral beliefs regarding the delivery of genomic medicine at the Veterans Health Administration. Per Med. 2010;7(5):485-494.
7. Lynch JA, Berse B, Dotson D, Khoury MJ, Coomer N, Kautter J. Utilization of genetic tests: analysis of gene-specific billing in Medicare claims data. Genet Med. 2017; 19(8):890-899.
8. Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer, 2017;18(6):651-659.
9. Morse JM. The significance of saturation. Qual Health Res.1995;5(2):147-149.
10. Aita VA, McIlvain HE. An armchair adventure in case study research. In: Crabtree BF, Miller WF, eds. Doing Qualitative Research. Thousand Oaks, CA: Sage; 1999:253-268.
11. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282(15):1458-1465.
12. Arney JB, Helm A, Crook T, Braun U, Chen GJ, Hayes TG. Utilization of genomic testing in advanced non-small cell lung cancer among oncologists in the Veterans Health Administration. Lung Cancer, 2018;116:25-29.
13. Ritchie J, Spencer L. Qualitative data analysis for applied policy research. In: Bryman A, Burgess RG, eds. Analyzing Qualitative Data. New York, NY: Routledge; 1994:173-194.
Lung cancer is the most frequent cause of cancer-related mortality worldwide.1 The most prevalent type of lung cancer is non-small cell lung cancer (NSCLC), which comprises about 85% of lung cancer cases.2 As there are no cost-effective approaches to screening for lung cancer, most lung cancers are identified at an advanced stage (stage IIIB or IV).
New approaches to managing advanced lung cancer have emerged in recent years, including drugs designed to target specific genetic mutations in some tumors.3 The National Comprehensive Cancer Network (NCCN) recommends erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) for first-line treatment of advanced NSCLC with EGFR mutation.4 Crizotinib is recommended to treat cancers that test positive for the anaplastic lymphoma kinase (ALK) mutation.4 Utilization of targeting agents has been found to extend the survival times for patients with the specified mutations.5 Both erlotinib and crizotinib are available at the VHA.
Previous research showed that VHA providers expressed overall favorable attitudes about genomic medicine.6 Providers perceived genomic medicine to have an important and possibly transformative role in medicine. Barriers to utilization of genomic medicine involved concerns about coordination of care, changes in workload, and increased length of patient visits. In addition to these system-level barriers, many providers had concerns about the proficiency of VHA-based practitioners to appropriately use genomic medicine.
Previous research has evaluated utilization of genomic testing and genomic-based targeted therapy (GBTT) in VA and community settings.5-8 It is unclear whether VHA-based providers are following clinical guidelines regarding genomic testing and utilization of GBTT.4 The authors set out to identify factors that impede and encourage guideline-consistent care in the management of NSCLC at the VHA. The authors specifically sought information about oncologists’ perceptions and experiences with EGFR and ALK mutation testing in patients with advanced NSCLC, as well as use of erlotinib and crizotinib in treating such patients.
Methods
This study was approved by the institutional review boards at Michael E. DeBakey VAMC in Houston, Texas and Baylor College of Medicine. In-depth qualitative interviews were conducted with VHA oncologists to examine their reported barriers and facilitators to mutation testing and prescribing of genomic-based treatment in patients with advanced NSCLC.
The sample of participants was recruited from a list of VHA medical oncologists, compiled by the study project coordinator. Investigators stratified the list by American College of Surgeons Commission on Cancer (CoC) accreditation status (yes/no) and used a stratified purposive sampling technique to recruit participants from CoC-accredited facilities and nonaccredited facilities. Recruitment and data collection occurred between March 2015 and February 2016. Oncologists were considered for inclusion if they (1) were specialists in oncology; (2) practiced at the VHA during the time of recruitment; and (3) had experience treating lung cancer at a VHA facility. During recruitment, potential participants were told that the investigators were interested in learning about oncologists’ experiences and decisions about using GBTT to treat advanced lung cancer in the VHA. Participants were scheduled for telephone-based interviews, and verbal consent was obtained prior to all interviews. Interviews ranged from 19 to 90 minutes (average, 40 min).
Recruitment was stopped at the point of thematic saturation, defined a priori as the point when 2 independent coders agreed that 3 consecutive transcripts for a given interview category (see below) rendered no new thematic concepts.9,10 Consistent with the theoretical framework developed by Cabana and colleagues, interviews were designed to elicit information about oncologists’ knowledge, attitudes, intent to use GBTT, and perceived facilitators and barriers to using GBTT in the VHA.11 Additional findings are presented elsewhere.12 The interview guide was pilot tested and revised prior to initiating data collection. All interviews were recorded, transcribed, and analyzed for content.
Analysis
Data were analyzed using framework analysis methodology, which allows for the inclusion of existing concepts as well as emergent themes within an established theoretical framework.13 Two independent coders with expertise in framework analysis independently created codes and indexed the data using Atlas.ti 6.2 (Scientific Software Development, Berlin, Germany). Disagreements about coding decisions were resolved through group consensus. Coding centered on 2 themes:
- Barriers and facilitators to mutation testing. This includes system or facility factors and testing weaknesses that act as barriers to ordering mutation testing, system or facility factors that facilitate ordering mutation testing, and oncologists’ suggestions for ways to encourage more testing in the VHA.
- Barriers and facilitators to prescribing GBTT. This includes system or facility factors that act as barriers to prescribing GBTT, system or facility factors that facilitate prescribing GBTT, and oncologists’ suggestions for ways to encourage more prescribing of GBTT in the VHA.
Thirty medical oncologists were interviewed. Participant demographics are presented in the Table.
Barriers to testing
The 2 most commonly cited barriers to ordering mutation testing can be considered weaknesses in the testing process: lack of tissue and wait time for results. Almost all providers identified lack of tissue as a barrier to ordering a mutation test.
Another frequently cited testing weakness involved the wait time for results. Because the mutation analysis is not conducted in the VHA facility, providers often must wait 2 to 4 weeks to receive results. This can present a problem because some providers do not want to wait for the results before recommending a course of treatment.
Several providers cited system and facility factors as barriers to mutation testing. The most common of these involves the ordering process. Oncology providers often remarked that ordering the mutation test is cumbersome or inconvenient because there is no ordering mechanism in the Computerized Patient Record System (CPRS). Many different approaches for ordering a mutation test exist, including e-mailing the pathology department, calling to place the order, or requesting the test in person. As providers can order many, if not most, other tests via CPRS, it is clear that this presents an inconvenient exception.
Budgetary constraints were another frequently cited system or facility-level barrier. Providers sometimes were unable to access the test due to the cost
Finally, several providers noted that in some cases patients did not wish to undergo a biopsy. Thus, patient preference can act as a barrier to mutation testing. Some patients wish to forgo treatment, which eliminates the need for a mutation test. Other patients believe that due to their smoking history, they are unlikely to have an ALK or EGFR mutation and instead immediately opt for chemotherapy. Only a small minority of participants identified no barriers to mutation testing.
Facilitators for Testing
Many providers complimented the availability of the mutation test. Interestingly, while some providers mentioned that lack of CPRS ordering was a barrier to testing, several also listed access to a CPRS order as a facilitator. These providers commented that ordering a test was streamlined and easy, given the mechanism in CPRS. Some VHA facilities offer CPRS order capabilities, and others do not. Other oncologists commented more generally on the cooperativeness of the pathology department in ordering mutation tests. It seems that facilities may use different ordering procedures, but in most of these facilities, a high degree of cooperation exists between departments to send out for tests that are requested.
Providers offered many ideas for ways to improve mutation testing or to facilitate the testing. By far, the most commonly cited way to improve the testing process was to make mutation testing reflexive for metastatic nonsquamous NSCLC. Some acknowledged that to achieve this would require a change to the budgeting process such that the test would not drain the pathology department’s budget. Implementing reflexive testing of patients, as recommended by guidelines, would understandably address several of the barriers that were identified in this study. Other providers recommended standardizing the ordering procedure and location of results. Specifically, providers recommended creating a button in CPRS for ordering and always reporting the results in the same place in CPRS.
Barriers to GBTT Prescribing
The clear majority of providers identified no barriers to prescribing GBTTs. A few mentioned that they were required to submit a nonformulary consult. A representative quote described this as “more out of a formality, and the pharmacist basically is there with me and he approves it on the spot and provides the prescription on the day, right when I’m seeing the patient.” Only a very small minority of providers identified medication cost as a barrier, but even those respondents did not indicate that cost prevented them from offering GBTTs to their patients. Rather, cost consciousness simply made them more mindful and judicious when making decisions about prescribing GBTTs.
Facilitators to GBTT Prescribing
Several providers listed availability of the costly medication in the VHA as a facilitator to prescribing. Veterans can obtain GBTTs with little to no insurance cost or copayment, which is not always the case outside the VHA.
One recommendation for further facilitating prescribing of GBTTs involved eliminating the preauthorization requirement, particularly in first-line use for patients testing positive for ALK or EGFR mutations. Although the preauthorization was not seen as a significant barrier, removal of this formality could make prescribing easier.
Discussion
Although in some cases, testing weaknesses (lack of tissue, wait time to receive results) can interrupt a treatment trajectory, many of the barriers identified in this study are modifiable. Overwhelmingly, oncologists recommended making mutation testing reflexive for metastatic nonsquamous NSCLC. Implementing reflexive testing of patients, as recommended by guidelines, would understandably address issues related to variable utilization of genomic testing in VHA.12 Additionally, in response to system and facility barriers to mutation testing, other providers recommended standardizing the ordering procedure and location of results. Utilization of GBTT can be facilitated by eliminating the preauthorization requirement, particularly in first-line use for patients with positive mutations. Although the preauthorization was not seen as a significant barrier, removal of this formality could make prescribing easier.
This study extends previous research that identified underuse of genomic testing in community-based practices. The authors sought to interview a broad sample of providers from various facilities (small, large, CoC accredited, nonaccredited) to understand the range of conditions faced by VA providers. Some providers face more barriers than do others, whereas some face few or no barriers. This wide range of experiences can help to better understand the factors that facilitate guideline-adherent care.
Limitations
The authors recognize that availability of resources and testing and prescribing practices are constantly evolving and perhaps have improved since the data were collected. Thus, the age of the study data might be a limitation to the study. Like most qualitative studies, these findings are limited in their generalizability beyond the study population. Additionally, the authors were limited to recruiting oncologists with reliable contact information listed in the VHA directory. Although this could have introduced some degree of sampling bias, the authors are confident that the sample sufficiently represents the population of VHA-based medical oncologists who treat lung cancer. Despite these limitations, these findings provide novel perspectives on barriers and facilitators to genomic testing GBTT prescribing in the VHA. The authors identify modifiable barriers to testing and prescribing that can be addressed to improve and standardize care of advanced lung cancer in the VHA.
Conclusion
Efforts should be made to address modifiable barriers to mutation testing and guideline-consistent prescribing of GBTT in the VA setting. Implementation of specific practices like reflexive testing for all metastatic nonsquamous NSCLC, standardization of the mutation test ordering procedure, standardization of results reporting, and elimination of the preauthorization to prescribe GBTT could impact the utilization of GBTT in VHA.
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Lung cancer is the most frequent cause of cancer-related mortality worldwide.1 The most prevalent type of lung cancer is non-small cell lung cancer (NSCLC), which comprises about 85% of lung cancer cases.2 As there are no cost-effective approaches to screening for lung cancer, most lung cancers are identified at an advanced stage (stage IIIB or IV).
New approaches to managing advanced lung cancer have emerged in recent years, including drugs designed to target specific genetic mutations in some tumors.3 The National Comprehensive Cancer Network (NCCN) recommends erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) for first-line treatment of advanced NSCLC with EGFR mutation.4 Crizotinib is recommended to treat cancers that test positive for the anaplastic lymphoma kinase (ALK) mutation.4 Utilization of targeting agents has been found to extend the survival times for patients with the specified mutations.5 Both erlotinib and crizotinib are available at the VHA.
Previous research showed that VHA providers expressed overall favorable attitudes about genomic medicine.6 Providers perceived genomic medicine to have an important and possibly transformative role in medicine. Barriers to utilization of genomic medicine involved concerns about coordination of care, changes in workload, and increased length of patient visits. In addition to these system-level barriers, many providers had concerns about the proficiency of VHA-based practitioners to appropriately use genomic medicine.
Previous research has evaluated utilization of genomic testing and genomic-based targeted therapy (GBTT) in VA and community settings.5-8 It is unclear whether VHA-based providers are following clinical guidelines regarding genomic testing and utilization of GBTT.4 The authors set out to identify factors that impede and encourage guideline-consistent care in the management of NSCLC at the VHA. The authors specifically sought information about oncologists’ perceptions and experiences with EGFR and ALK mutation testing in patients with advanced NSCLC, as well as use of erlotinib and crizotinib in treating such patients.
Methods
This study was approved by the institutional review boards at Michael E. DeBakey VAMC in Houston, Texas and Baylor College of Medicine. In-depth qualitative interviews were conducted with VHA oncologists to examine their reported barriers and facilitators to mutation testing and prescribing of genomic-based treatment in patients with advanced NSCLC.
The sample of participants was recruited from a list of VHA medical oncologists, compiled by the study project coordinator. Investigators stratified the list by American College of Surgeons Commission on Cancer (CoC) accreditation status (yes/no) and used a stratified purposive sampling technique to recruit participants from CoC-accredited facilities and nonaccredited facilities. Recruitment and data collection occurred between March 2015 and February 2016. Oncologists were considered for inclusion if they (1) were specialists in oncology; (2) practiced at the VHA during the time of recruitment; and (3) had experience treating lung cancer at a VHA facility. During recruitment, potential participants were told that the investigators were interested in learning about oncologists’ experiences and decisions about using GBTT to treat advanced lung cancer in the VHA. Participants were scheduled for telephone-based interviews, and verbal consent was obtained prior to all interviews. Interviews ranged from 19 to 90 minutes (average, 40 min).
Recruitment was stopped at the point of thematic saturation, defined a priori as the point when 2 independent coders agreed that 3 consecutive transcripts for a given interview category (see below) rendered no new thematic concepts.9,10 Consistent with the theoretical framework developed by Cabana and colleagues, interviews were designed to elicit information about oncologists’ knowledge, attitudes, intent to use GBTT, and perceived facilitators and barriers to using GBTT in the VHA.11 Additional findings are presented elsewhere.12 The interview guide was pilot tested and revised prior to initiating data collection. All interviews were recorded, transcribed, and analyzed for content.
Analysis
Data were analyzed using framework analysis methodology, which allows for the inclusion of existing concepts as well as emergent themes within an established theoretical framework.13 Two independent coders with expertise in framework analysis independently created codes and indexed the data using Atlas.ti 6.2 (Scientific Software Development, Berlin, Germany). Disagreements about coding decisions were resolved through group consensus. Coding centered on 2 themes:
- Barriers and facilitators to mutation testing. This includes system or facility factors and testing weaknesses that act as barriers to ordering mutation testing, system or facility factors that facilitate ordering mutation testing, and oncologists’ suggestions for ways to encourage more testing in the VHA.
- Barriers and facilitators to prescribing GBTT. This includes system or facility factors that act as barriers to prescribing GBTT, system or facility factors that facilitate prescribing GBTT, and oncologists’ suggestions for ways to encourage more prescribing of GBTT in the VHA.
Thirty medical oncologists were interviewed. Participant demographics are presented in the Table.
Barriers to testing
The 2 most commonly cited barriers to ordering mutation testing can be considered weaknesses in the testing process: lack of tissue and wait time for results. Almost all providers identified lack of tissue as a barrier to ordering a mutation test.
Another frequently cited testing weakness involved the wait time for results. Because the mutation analysis is not conducted in the VHA facility, providers often must wait 2 to 4 weeks to receive results. This can present a problem because some providers do not want to wait for the results before recommending a course of treatment.
Several providers cited system and facility factors as barriers to mutation testing. The most common of these involves the ordering process. Oncology providers often remarked that ordering the mutation test is cumbersome or inconvenient because there is no ordering mechanism in the Computerized Patient Record System (CPRS). Many different approaches for ordering a mutation test exist, including e-mailing the pathology department, calling to place the order, or requesting the test in person. As providers can order many, if not most, other tests via CPRS, it is clear that this presents an inconvenient exception.
Budgetary constraints were another frequently cited system or facility-level barrier. Providers sometimes were unable to access the test due to the cost
Finally, several providers noted that in some cases patients did not wish to undergo a biopsy. Thus, patient preference can act as a barrier to mutation testing. Some patients wish to forgo treatment, which eliminates the need for a mutation test. Other patients believe that due to their smoking history, they are unlikely to have an ALK or EGFR mutation and instead immediately opt for chemotherapy. Only a small minority of participants identified no barriers to mutation testing.
Facilitators for Testing
Many providers complimented the availability of the mutation test. Interestingly, while some providers mentioned that lack of CPRS ordering was a barrier to testing, several also listed access to a CPRS order as a facilitator. These providers commented that ordering a test was streamlined and easy, given the mechanism in CPRS. Some VHA facilities offer CPRS order capabilities, and others do not. Other oncologists commented more generally on the cooperativeness of the pathology department in ordering mutation tests. It seems that facilities may use different ordering procedures, but in most of these facilities, a high degree of cooperation exists between departments to send out for tests that are requested.
Providers offered many ideas for ways to improve mutation testing or to facilitate the testing. By far, the most commonly cited way to improve the testing process was to make mutation testing reflexive for metastatic nonsquamous NSCLC. Some acknowledged that to achieve this would require a change to the budgeting process such that the test would not drain the pathology department’s budget. Implementing reflexive testing of patients, as recommended by guidelines, would understandably address several of the barriers that were identified in this study. Other providers recommended standardizing the ordering procedure and location of results. Specifically, providers recommended creating a button in CPRS for ordering and always reporting the results in the same place in CPRS.
Barriers to GBTT Prescribing
The clear majority of providers identified no barriers to prescribing GBTTs. A few mentioned that they were required to submit a nonformulary consult. A representative quote described this as “more out of a formality, and the pharmacist basically is there with me and he approves it on the spot and provides the prescription on the day, right when I’m seeing the patient.” Only a very small minority of providers identified medication cost as a barrier, but even those respondents did not indicate that cost prevented them from offering GBTTs to their patients. Rather, cost consciousness simply made them more mindful and judicious when making decisions about prescribing GBTTs.
Facilitators to GBTT Prescribing
Several providers listed availability of the costly medication in the VHA as a facilitator to prescribing. Veterans can obtain GBTTs with little to no insurance cost or copayment, which is not always the case outside the VHA.
One recommendation for further facilitating prescribing of GBTTs involved eliminating the preauthorization requirement, particularly in first-line use for patients testing positive for ALK or EGFR mutations. Although the preauthorization was not seen as a significant barrier, removal of this formality could make prescribing easier.
Discussion
Although in some cases, testing weaknesses (lack of tissue, wait time to receive results) can interrupt a treatment trajectory, many of the barriers identified in this study are modifiable. Overwhelmingly, oncologists recommended making mutation testing reflexive for metastatic nonsquamous NSCLC. Implementing reflexive testing of patients, as recommended by guidelines, would understandably address issues related to variable utilization of genomic testing in VHA.12 Additionally, in response to system and facility barriers to mutation testing, other providers recommended standardizing the ordering procedure and location of results. Utilization of GBTT can be facilitated by eliminating the preauthorization requirement, particularly in first-line use for patients with positive mutations. Although the preauthorization was not seen as a significant barrier, removal of this formality could make prescribing easier.
This study extends previous research that identified underuse of genomic testing in community-based practices. The authors sought to interview a broad sample of providers from various facilities (small, large, CoC accredited, nonaccredited) to understand the range of conditions faced by VA providers. Some providers face more barriers than do others, whereas some face few or no barriers. This wide range of experiences can help to better understand the factors that facilitate guideline-adherent care.
Limitations
The authors recognize that availability of resources and testing and prescribing practices are constantly evolving and perhaps have improved since the data were collected. Thus, the age of the study data might be a limitation to the study. Like most qualitative studies, these findings are limited in their generalizability beyond the study population. Additionally, the authors were limited to recruiting oncologists with reliable contact information listed in the VHA directory. Although this could have introduced some degree of sampling bias, the authors are confident that the sample sufficiently represents the population of VHA-based medical oncologists who treat lung cancer. Despite these limitations, these findings provide novel perspectives on barriers and facilitators to genomic testing GBTT prescribing in the VHA. The authors identify modifiable barriers to testing and prescribing that can be addressed to improve and standardize care of advanced lung cancer in the VHA.
Conclusion
Efforts should be made to address modifiable barriers to mutation testing and guideline-consistent prescribing of GBTT in the VA setting. Implementation of specific practices like reflexive testing for all metastatic nonsquamous NSCLC, standardization of the mutation test ordering procedure, standardization of results reporting, and elimination of the preauthorization to prescribe GBTT could impact the utilization of GBTT in VHA.
Click here to read the digital edition.
. , , , Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
2. American Cancer Society. What is non-small cell lung cancer? https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Updated May 16, 2016. Accessed January 19, 2018.
3. , , . New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1097-1104.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). non-small cell lung cancer 2. 2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Updated December 19, 2017. Accessed Jan
5. Rosell R, Moran T, Queralt C, et al; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967.
6. Arar N, Seo J, Abboud HE, Parchman M, Noel P. Providers’ behavioral beliefs regarding the delivery of genomic medicine at the Veterans Health Administration. Per Med. 2010;7(5):485-494.
7. Lynch JA, Berse B, Dotson D, Khoury MJ, Coomer N, Kautter J. Utilization of genetic tests: analysis of gene-specific billing in Medicare claims data. Genet Med. 2017; 19(8):890-899.
8. Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer, 2017;18(6):651-659.
9. Morse JM. The significance of saturation. Qual Health Res.1995;5(2):147-149.
10. Aita VA, McIlvain HE. An armchair adventure in case study research. In: Crabtree BF, Miller WF, eds. Doing Qualitative Research. Thousand Oaks, CA: Sage; 1999:253-268.
11. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282(15):1458-1465.
12. Arney JB, Helm A, Crook T, Braun U, Chen GJ, Hayes TG. Utilization of genomic testing in advanced non-small cell lung cancer among oncologists in the Veterans Health Administration. Lung Cancer, 2018;116:25-29.
13. Ritchie J, Spencer L. Qualitative data analysis for applied policy research. In: Bryman A, Burgess RG, eds. Analyzing Qualitative Data. New York, NY: Routledge; 1994:173-194.
. , , , Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
2. American Cancer Society. What is non-small cell lung cancer? https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Updated May 16, 2016. Accessed January 19, 2018.
3. , , . New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1097-1104.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). non-small cell lung cancer 2. 2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Updated December 19, 2017. Accessed Jan
5. Rosell R, Moran T, Queralt C, et al; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967.
6. Arar N, Seo J, Abboud HE, Parchman M, Noel P. Providers’ behavioral beliefs regarding the delivery of genomic medicine at the Veterans Health Administration. Per Med. 2010;7(5):485-494.
7. Lynch JA, Berse B, Dotson D, Khoury MJ, Coomer N, Kautter J. Utilization of genetic tests: analysis of gene-specific billing in Medicare claims data. Genet Med. 2017; 19(8):890-899.
8. Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer, 2017;18(6):651-659.
9. Morse JM. The significance of saturation. Qual Health Res.1995;5(2):147-149.
10. Aita VA, McIlvain HE. An armchair adventure in case study research. In: Crabtree BF, Miller WF, eds. Doing Qualitative Research. Thousand Oaks, CA: Sage; 1999:253-268.
11. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282(15):1458-1465.
12. Arney JB, Helm A, Crook T, Braun U, Chen GJ, Hayes TG. Utilization of genomic testing in advanced non-small cell lung cancer among oncologists in the Veterans Health Administration. Lung Cancer, 2018;116:25-29.
13. Ritchie J, Spencer L. Qualitative data analysis for applied policy research. In: Bryman A, Burgess RG, eds. Analyzing Qualitative Data. New York, NY: Routledge; 1994:173-194.