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Overcoming death anxiety: Understanding our lives and legacies
Disappointment – “I failed this exam, my life is ruined” or regret – “I am getting a divorce, I wasted so much of my life.” Patients present with a wide variety of complaints that can be understood as a form of death anxiety.
Fundamentally, patients come to see us to understand and explain their lives. One can reinterpret this as a patient asking, “If I died today, would my life have been good enough?” or “When I die, how will I look back at this moment in time and judge the choices I made?”
Other patients come to us attempting to use the same maladaptive defenses that did not serve them well in the past in the hopes of achieving a new outcome that will validate their lives. While it may be understandable that a child dissociates when facing abuse, hoping that this defense mechanism – as an adult – will work, it is unlikely to be fruitful and will certainly not validate or repair the past. This hope to repair one’s past can be interpreted as a fear of death – “I cannot die without correcting this.” This psychic conflict can intensify if one does not adopt a more adaptive understanding of his or her life.
Death anxiety is the feeling associated with the finality of life. Not only is life final, but a constant reminder of that fact is the idea that any one moment is final. Other than in science fiction, one cannot return to a prior moment and repair the past in the hope of a better future. Time goes only in one direction and death is the natural outcome of all life.
Death may have some evolutionary purpose that encourages the promotion of newer and more fitter genes, but one doesn’t have to consider its origin and reason to admit death’s constancy throughout humanity. People die and that is an anxiety-provoking fact of life. Death anxiety can feel especially tangible in our connected world. In a world of constant news, it can feel – for many people – that if your house wasn’t displaced because of global warming or that you are not a war refugee, you don’t deserve to be seen and heard.
This can be a particularly strong feeling for and among physicians, who don’t think that the mental health challenges generated by their own tough circumstances deserve to be labeled a mental disorder, so they designate themselves as having “burnout”1 – as they don’t deserve the sympathy of having the clinically significant impairments of “depression.” Our traumas don’t seem important enough to deserve notice, and thus we may feel like we could die without ever having truly mattered.
This can also be applied in the reverse fashion. Certain individuals, like celebrities, live such extravagant lives that our simpler achievements can feel futile in comparison. While the neighbor’s grass has always felt greener, we are now constantly exposed to perfectly manicured lawns on social media. When compounded, the idea that our successes and our pains are both simultaneously irrelevant can lead one to have very palpable death anxiety – my life will never matter if none of the things I do matter, or my life will never matter because I will never achieve the requisite number of “likes” or “views” on social media required to believe that one’s life was worth living.
A way of alleviating death anxiety can be through the concept of legacy, or what we leave behind. How will people remember me? Will people remember me, or will I disappear like a shadow into the distant memory of my near and dear ones? The idea of being forgotten or lost to memory is intolerable to some and can be a strong driving force to “make a name” for oneself. For those who crave fame, whether a celebrity or a generous alumnus, part of this is likely related to remaining well known after death. After all, one can argue that you are not truly dead as long as you continue to live in the memory and/or genes of others.
Legacy thus serves as a form of posthumous transitional object; a way of calming our fears about how we will be remembered. For many, reconciling their feelings towards their legacy is an avenue to tame death anxiety.
A case study
The case of Mr. B illustrates this. As a 72-year-old male with a long history of generalized anxiety, he once had a nightmare as a child, similar to the plot of Sleeping Beauty. In his dream, he walks up a spiral staircase in a castle and touches the spindle on a spinning wheel, thus ending his life. The dream was vivid and marked him.
His fear of death has subsequently reared its head throughout his life. In more recent years, he has suffered from cardiovascular disease. Although he is now quite stable on his current cardiac medications, he is constantly fearful that he will experience a cardiac event while asleep and suddenly die. He is so anxious about not waking up in the morning that falling asleep is nearly impossible.
Mr. B is single, with no close family besides a sister who lives in another state. He has a dog and few friends. He worries about what will happen to his dog if he doesn’t wake up in the morning, but perhaps most distressing to him is “there’s so much left for me to do, I have so much to write!” As an accomplished author, he continues to write, and hopes to publish many more novels in his lifetime. It is unsurprising that someone without a strong social network may fear death and feel pressured to somehow make a mark on the world before the curtain falls. It is scary to think that even without us, life goes on.
By bringing to Mr. B’s attention that his ever-present anxiety is rooted in fear of death, he was able to gain more insight into his own defensive behaviors. By confronting his death anxiety and processing his definition of a life well lived together in therapy, he’s acknowledged his lack of social connection as demoralizing, and has made significant strides to remedy this. He’s been able to focus on a more fulfilling life day to day, with less emphasis on his to-do list and aspirations. Instead, he’s connected more with his faith and members of his church. He’s gotten close to several neighbors and enjoys long dinners with them on his back patio.
At a recent meeting, he confessed that he feels “lighter” and not as fearful about sudden cardiac death, and thus has noticed that his overall anxiety has diminished greatly. He concluded that experiencing meaningful relationships in the present moment would give him greater joy than spending his remaining time engaged in preserving a future identity for himself. It seems elementary, but if we look within, we may find that we all suffer similarly: How much of our daily actions, thoughts, and fears are tied to the looming threat of death?
Conclusion
While modern psychiatry continues to advance with better understandings of our neurobiology, improved knowledge of pathophysiological processes of mental illness, and expanding discovery of novel pharmacotherapeutics, the modern psychiatrist should not forget fundamental truths of behavior and humanity that were once the staple of psychiatry.
Death anxiety is one of those truths; it is the ultimate stressor that we will all face and should be regular study and practice for psychiatrists. In this article, we explored some of those facets most meaningful to us but recommend you expand your study to the many more available.
Patients often come to physicians seeking validation of their lives or trying to use the same maladaptive defense mechanisms that did not serve them well in the past to achieve a better outcome.
In today’s world, death anxiety can feel palpable due to the constant exposure to global news and social media that can make us feel irrelevant. However, legacy, or what we leave behind, can serve as a way to alleviate death anxiety. For many, reconciling their feelings toward their legacy is an avenue to tame death anxiety. Therapy can help individuals gain insight into their defensive behaviors and process their definition of a life well lived. By focusing on a life worth living, individuals can alleviate their death anxiety and gain a sense of fulfillment.
Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.
Reference
1. Badre N. Burnout: A concept that rebrands mental illness for professionals. Clinical Psychiatry News. 2020 Mar 5.
Disappointment – “I failed this exam, my life is ruined” or regret – “I am getting a divorce, I wasted so much of my life.” Patients present with a wide variety of complaints that can be understood as a form of death anxiety.
Fundamentally, patients come to see us to understand and explain their lives. One can reinterpret this as a patient asking, “If I died today, would my life have been good enough?” or “When I die, how will I look back at this moment in time and judge the choices I made?”
Other patients come to us attempting to use the same maladaptive defenses that did not serve them well in the past in the hopes of achieving a new outcome that will validate their lives. While it may be understandable that a child dissociates when facing abuse, hoping that this defense mechanism – as an adult – will work, it is unlikely to be fruitful and will certainly not validate or repair the past. This hope to repair one’s past can be interpreted as a fear of death – “I cannot die without correcting this.” This psychic conflict can intensify if one does not adopt a more adaptive understanding of his or her life.
Death anxiety is the feeling associated with the finality of life. Not only is life final, but a constant reminder of that fact is the idea that any one moment is final. Other than in science fiction, one cannot return to a prior moment and repair the past in the hope of a better future. Time goes only in one direction and death is the natural outcome of all life.
Death may have some evolutionary purpose that encourages the promotion of newer and more fitter genes, but one doesn’t have to consider its origin and reason to admit death’s constancy throughout humanity. People die and that is an anxiety-provoking fact of life. Death anxiety can feel especially tangible in our connected world. In a world of constant news, it can feel – for many people – that if your house wasn’t displaced because of global warming or that you are not a war refugee, you don’t deserve to be seen and heard.
This can be a particularly strong feeling for and among physicians, who don’t think that the mental health challenges generated by their own tough circumstances deserve to be labeled a mental disorder, so they designate themselves as having “burnout”1 – as they don’t deserve the sympathy of having the clinically significant impairments of “depression.” Our traumas don’t seem important enough to deserve notice, and thus we may feel like we could die without ever having truly mattered.
This can also be applied in the reverse fashion. Certain individuals, like celebrities, live such extravagant lives that our simpler achievements can feel futile in comparison. While the neighbor’s grass has always felt greener, we are now constantly exposed to perfectly manicured lawns on social media. When compounded, the idea that our successes and our pains are both simultaneously irrelevant can lead one to have very palpable death anxiety – my life will never matter if none of the things I do matter, or my life will never matter because I will never achieve the requisite number of “likes” or “views” on social media required to believe that one’s life was worth living.
A way of alleviating death anxiety can be through the concept of legacy, or what we leave behind. How will people remember me? Will people remember me, or will I disappear like a shadow into the distant memory of my near and dear ones? The idea of being forgotten or lost to memory is intolerable to some and can be a strong driving force to “make a name” for oneself. For those who crave fame, whether a celebrity or a generous alumnus, part of this is likely related to remaining well known after death. After all, one can argue that you are not truly dead as long as you continue to live in the memory and/or genes of others.
Legacy thus serves as a form of posthumous transitional object; a way of calming our fears about how we will be remembered. For many, reconciling their feelings towards their legacy is an avenue to tame death anxiety.
A case study
The case of Mr. B illustrates this. As a 72-year-old male with a long history of generalized anxiety, he once had a nightmare as a child, similar to the plot of Sleeping Beauty. In his dream, he walks up a spiral staircase in a castle and touches the spindle on a spinning wheel, thus ending his life. The dream was vivid and marked him.
His fear of death has subsequently reared its head throughout his life. In more recent years, he has suffered from cardiovascular disease. Although he is now quite stable on his current cardiac medications, he is constantly fearful that he will experience a cardiac event while asleep and suddenly die. He is so anxious about not waking up in the morning that falling asleep is nearly impossible.
Mr. B is single, with no close family besides a sister who lives in another state. He has a dog and few friends. He worries about what will happen to his dog if he doesn’t wake up in the morning, but perhaps most distressing to him is “there’s so much left for me to do, I have so much to write!” As an accomplished author, he continues to write, and hopes to publish many more novels in his lifetime. It is unsurprising that someone without a strong social network may fear death and feel pressured to somehow make a mark on the world before the curtain falls. It is scary to think that even without us, life goes on.
By bringing to Mr. B’s attention that his ever-present anxiety is rooted in fear of death, he was able to gain more insight into his own defensive behaviors. By confronting his death anxiety and processing his definition of a life well lived together in therapy, he’s acknowledged his lack of social connection as demoralizing, and has made significant strides to remedy this. He’s been able to focus on a more fulfilling life day to day, with less emphasis on his to-do list and aspirations. Instead, he’s connected more with his faith and members of his church. He’s gotten close to several neighbors and enjoys long dinners with them on his back patio.
At a recent meeting, he confessed that he feels “lighter” and not as fearful about sudden cardiac death, and thus has noticed that his overall anxiety has diminished greatly. He concluded that experiencing meaningful relationships in the present moment would give him greater joy than spending his remaining time engaged in preserving a future identity for himself. It seems elementary, but if we look within, we may find that we all suffer similarly: How much of our daily actions, thoughts, and fears are tied to the looming threat of death?
Conclusion
While modern psychiatry continues to advance with better understandings of our neurobiology, improved knowledge of pathophysiological processes of mental illness, and expanding discovery of novel pharmacotherapeutics, the modern psychiatrist should not forget fundamental truths of behavior and humanity that were once the staple of psychiatry.
Death anxiety is one of those truths; it is the ultimate stressor that we will all face and should be regular study and practice for psychiatrists. In this article, we explored some of those facets most meaningful to us but recommend you expand your study to the many more available.
Patients often come to physicians seeking validation of their lives or trying to use the same maladaptive defense mechanisms that did not serve them well in the past to achieve a better outcome.
In today’s world, death anxiety can feel palpable due to the constant exposure to global news and social media that can make us feel irrelevant. However, legacy, or what we leave behind, can serve as a way to alleviate death anxiety. For many, reconciling their feelings toward their legacy is an avenue to tame death anxiety. Therapy can help individuals gain insight into their defensive behaviors and process their definition of a life well lived. By focusing on a life worth living, individuals can alleviate their death anxiety and gain a sense of fulfillment.
Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.
Reference
1. Badre N. Burnout: A concept that rebrands mental illness for professionals. Clinical Psychiatry News. 2020 Mar 5.
Disappointment – “I failed this exam, my life is ruined” or regret – “I am getting a divorce, I wasted so much of my life.” Patients present with a wide variety of complaints that can be understood as a form of death anxiety.
Fundamentally, patients come to see us to understand and explain their lives. One can reinterpret this as a patient asking, “If I died today, would my life have been good enough?” or “When I die, how will I look back at this moment in time and judge the choices I made?”
Other patients come to us attempting to use the same maladaptive defenses that did not serve them well in the past in the hopes of achieving a new outcome that will validate their lives. While it may be understandable that a child dissociates when facing abuse, hoping that this defense mechanism – as an adult – will work, it is unlikely to be fruitful and will certainly not validate or repair the past. This hope to repair one’s past can be interpreted as a fear of death – “I cannot die without correcting this.” This psychic conflict can intensify if one does not adopt a more adaptive understanding of his or her life.
Death anxiety is the feeling associated with the finality of life. Not only is life final, but a constant reminder of that fact is the idea that any one moment is final. Other than in science fiction, one cannot return to a prior moment and repair the past in the hope of a better future. Time goes only in one direction and death is the natural outcome of all life.
Death may have some evolutionary purpose that encourages the promotion of newer and more fitter genes, but one doesn’t have to consider its origin and reason to admit death’s constancy throughout humanity. People die and that is an anxiety-provoking fact of life. Death anxiety can feel especially tangible in our connected world. In a world of constant news, it can feel – for many people – that if your house wasn’t displaced because of global warming or that you are not a war refugee, you don’t deserve to be seen and heard.
This can be a particularly strong feeling for and among physicians, who don’t think that the mental health challenges generated by their own tough circumstances deserve to be labeled a mental disorder, so they designate themselves as having “burnout”1 – as they don’t deserve the sympathy of having the clinically significant impairments of “depression.” Our traumas don’t seem important enough to deserve notice, and thus we may feel like we could die without ever having truly mattered.
This can also be applied in the reverse fashion. Certain individuals, like celebrities, live such extravagant lives that our simpler achievements can feel futile in comparison. While the neighbor’s grass has always felt greener, we are now constantly exposed to perfectly manicured lawns on social media. When compounded, the idea that our successes and our pains are both simultaneously irrelevant can lead one to have very palpable death anxiety – my life will never matter if none of the things I do matter, or my life will never matter because I will never achieve the requisite number of “likes” or “views” on social media required to believe that one’s life was worth living.
A way of alleviating death anxiety can be through the concept of legacy, or what we leave behind. How will people remember me? Will people remember me, or will I disappear like a shadow into the distant memory of my near and dear ones? The idea of being forgotten or lost to memory is intolerable to some and can be a strong driving force to “make a name” for oneself. For those who crave fame, whether a celebrity or a generous alumnus, part of this is likely related to remaining well known after death. After all, one can argue that you are not truly dead as long as you continue to live in the memory and/or genes of others.
Legacy thus serves as a form of posthumous transitional object; a way of calming our fears about how we will be remembered. For many, reconciling their feelings towards their legacy is an avenue to tame death anxiety.
A case study
The case of Mr. B illustrates this. As a 72-year-old male with a long history of generalized anxiety, he once had a nightmare as a child, similar to the plot of Sleeping Beauty. In his dream, he walks up a spiral staircase in a castle and touches the spindle on a spinning wheel, thus ending his life. The dream was vivid and marked him.
His fear of death has subsequently reared its head throughout his life. In more recent years, he has suffered from cardiovascular disease. Although he is now quite stable on his current cardiac medications, he is constantly fearful that he will experience a cardiac event while asleep and suddenly die. He is so anxious about not waking up in the morning that falling asleep is nearly impossible.
Mr. B is single, with no close family besides a sister who lives in another state. He has a dog and few friends. He worries about what will happen to his dog if he doesn’t wake up in the morning, but perhaps most distressing to him is “there’s so much left for me to do, I have so much to write!” As an accomplished author, he continues to write, and hopes to publish many more novels in his lifetime. It is unsurprising that someone without a strong social network may fear death and feel pressured to somehow make a mark on the world before the curtain falls. It is scary to think that even without us, life goes on.
By bringing to Mr. B’s attention that his ever-present anxiety is rooted in fear of death, he was able to gain more insight into his own defensive behaviors. By confronting his death anxiety and processing his definition of a life well lived together in therapy, he’s acknowledged his lack of social connection as demoralizing, and has made significant strides to remedy this. He’s been able to focus on a more fulfilling life day to day, with less emphasis on his to-do list and aspirations. Instead, he’s connected more with his faith and members of his church. He’s gotten close to several neighbors and enjoys long dinners with them on his back patio.
At a recent meeting, he confessed that he feels “lighter” and not as fearful about sudden cardiac death, and thus has noticed that his overall anxiety has diminished greatly. He concluded that experiencing meaningful relationships in the present moment would give him greater joy than spending his remaining time engaged in preserving a future identity for himself. It seems elementary, but if we look within, we may find that we all suffer similarly: How much of our daily actions, thoughts, and fears are tied to the looming threat of death?
Conclusion
While modern psychiatry continues to advance with better understandings of our neurobiology, improved knowledge of pathophysiological processes of mental illness, and expanding discovery of novel pharmacotherapeutics, the modern psychiatrist should not forget fundamental truths of behavior and humanity that were once the staple of psychiatry.
Death anxiety is one of those truths; it is the ultimate stressor that we will all face and should be regular study and practice for psychiatrists. In this article, we explored some of those facets most meaningful to us but recommend you expand your study to the many more available.
Patients often come to physicians seeking validation of their lives or trying to use the same maladaptive defense mechanisms that did not serve them well in the past to achieve a better outcome.
In today’s world, death anxiety can feel palpable due to the constant exposure to global news and social media that can make us feel irrelevant. However, legacy, or what we leave behind, can serve as a way to alleviate death anxiety. For many, reconciling their feelings toward their legacy is an avenue to tame death anxiety. Therapy can help individuals gain insight into their defensive behaviors and process their definition of a life well lived. By focusing on a life worth living, individuals can alleviate their death anxiety and gain a sense of fulfillment.
Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.
Reference
1. Badre N. Burnout: A concept that rebrands mental illness for professionals. Clinical Psychiatry News. 2020 Mar 5.
Preventing breaks and falls in older adults
LONG BEACH, CALIF. – Ms. S had recently arrived home after a stay at a skilled nursing facility to recover from a hip fracture resulting from osteoporosis. For many patients, follow-up care would have included a DEXA scan or a prescription for a bisphosphonate from a primary care clinician not trained in geriatrics.
But the 85-year-old received care that went further and that is considered best practice for the management of geriatric fractures: A physical therapist visited her after discharge and provided education on the importance of maintaining mobility. Ms. S also underwent assessment for fall risk and gait balance, and a team of multidisciplinary clinicians managed other factors, from postural hypotension to footwear and foot problems.
Sonja Rosen, MD, professor of medicine and chief of geriatric medicine at Cedars-Sinai Medical Center, Los Angeles, talked about Ms. S as part of a panel discussion on applying the “Geriatric 5Ms” for patients with osteoporosis at the annual meeting of the American Geriatrics Society.
“You have to figure out why they are falling and help them not fall again,” Dr. Rosen said.
Approximately 10 million Americans have osteoporosis, and another 44 million have low bone density. One in two women and up to one in four men will experience a bone fracture as a result of osteoporosis, according to the Bone Health and Osteoporosis Foundation.
, which involves considering the care preferences and goals for health care outcomes of individuals.
Ms. S eventually visited a geriatrician through the Cedars-Sinai Geriatric Fracture Program, which has been shown to lower costs and shorten hospital stays. In the program, she was advised to use a walker. Initially, she saw the aid as a hindrance – she felt she should be able to walk without it, like before. But with education, she learned that it is impossible to predict falls and that the walking aid could reduce her risk of a stumble.
Dr. Rosen said clinicians should address any vision problems, prescriptions for psychotropic drugs,which can affect balance, and heart rate and rhythm abnormalities, and they should suggest modifications to the home environment, such as installing grab bars in showers and removing rugs that can easily be tripped over.
The program at Cedars-Sinai, like similar initiatives, offers a team with resources that some clinicians may not have access to, such as a care coordinator and bone-health coach. But health care providers can utilize aspects, such as making referrals to community exercise classes.
Dr. Rosen and her colleagues studied the effects of such exercise programs and found that the programs lessen loneliness and social isolation. Fear of falling decreased in 75% of participants, “which is so key to these postfracture patients in getting back out into the world and engaging in their prior level of functional status,” Dr. Rosen said.
The second ‘M’: Medication management
The second “M,” medications, can help clinicians sequence osteoporosis drugs, depending on patient characteristics and scenarios.
Cathleen Colon-Emeric, MD, MHS, chief of geriatrics at Duke University, in Durham, N.C., dived into the case history of Ms. S, who had hypertension and insomnia in addition to osteoporosis.
First-line treatment for Ms. S – and for most patients – was an oral bisphosphonate, Dr. Colon-Emeric said. Compared with placebo, the drugs decrease the risk of overall osteoporotic fractures by nearly 40% (odds ratio, 0.62). But the medications are linked to injury of the esophageal mucosa. This risk is decreased when a patient stays upright for 30 minutes after taking oral bisphosphonates. Dr. Colon-Emeric displayed a slide of a woman receiving a pedicure at a nail salon.
“The picture of the pedicure is to share the wonderful idea I got from one skilled nursing facility I was working with, who makes sure they do safe administration to prevent esophagitis in their patients by having them all go to a spa day, where they all sit up and get their nails done while they wait their 30 minutes [after taking the pill] sitting up safely,” Dr. Colon-Emeric said.
This strategy drew applause from the audience.
Dr. Colon-Emeric advised that clinicians use judgment in the interpretation of results from the Fracture Risk Assessment Tool (FRAX). Incorporating race into estimates of fracture risk has pros and cons. While there are racial and ethnic differences in average bone density, the data for race calibrations to estimate risk are dated, she said. Clinicians should compare FRAX estimates with and without race input to help patients understand a range of risks.
Some patients may be reluctant to begin taking osteoporosis drugs because of misinformation originating from inaccurate news reports or anecdotes from friends. Dr. Colon-Emeric advised clinicians to remind patients that one in five who experience a fracture will have another injury in the following 2 years.
“A major osteoporotic fracture is akin to a heart attack; it has a very similar 1-year mortality rate and a very similar rate of a subsequent secondary event,” Dr. Colon-Emeric said. “We have a class of medications that decrease both those risks by nearly a third.”
Shared decision-making can help patients understand the risks and benefits of treatment, she said.
“People are really scared about the side effects,” Michelle Keller, PhD, MPH, a research scientist at Cedars-Sinai who attended the session, said. “The idea that a “bone attack” is like a heart attack gets the message across.”
Mind and multicomplexity
Medical complexity of a patient must be considered when making decisions on treatment, according to Joshua Niznik, PharmD, PhD, assistant professor of medicine in the Center for Aging and Health at the University of North Carolina at Chapel Hill.
“Medical complexity is an acknowledgment of the entire person, the burden of their multiple chronic conditions, advanced illnesses, and also their biopsychosocial needs and how those together might augment treatment selection and decision-making,” Dr. Niznik said.
Studies by Dr. Niznik and others have shown that swallowing difficulties, severe dementia, and being older than 90 are linked with a lower likelihood of receiving treatment for osteoporosis.
But therapies for fracture prevention, especially bisphosphonates, appear to be at least as effective for adults with medical complexity as they are for people without such conditions, Dr. Niznik said. Physicians must consider the potential treatment burden and the likelihood of benefit, he said.
Dr. Niznik’s research has shown a lack of strong evidence on how clinicians can manage patients in nursing homes. In some cases, deprescribing is reasonable, such as for patients who have undergone treatment for several years and whose life expectancy is less than 2 years.
“In the absence of any of those, if they are not already treated for osteoporosis, it makes sense to initiate treatment at that time,” Dr. Niznik said.
Matters most: Patient input
Clinicians need to educate patients on how long they must undergo a treatment before they experience benefits, according to Sarah D. Berry, MD, MPH, associate professor of medicine at Harvard Medical School, in Boston.
A meta-analysis of studies that included more than 20,000 women who were randomly assigned to receive bisphosphonate or placebo found that one nonvertebral fracture was avoided during a 12-month period for every 100 persons treated. One hip fracture was avoided during a 20-month period for every 200 patients treated.
“In general, in persons with a 2-year life expectancy, time to benefit favors bisphosphonate use,” Dr. Berry said. “Anabolics may have an even quicker time to benefit.”
Dr. Berry said a shared a decision-making model can help clinicians facilitate discussions that help patients prioritize goals and compare options while considering results, benefits, and harms. And she offered a final tip: Use tools with absolute risk reduction to convey risks and benefits, as the relative risk calculations overestimate how effective treatment will be.
Dr. Rosen has disclosed no relevant financial relationships. Dr. Colon-Emeric has received grants from the National Institutes of Health and VA Health Services Research and Development Funding; has served as endpoint adjudication chair for UCB Pharma; and has received royalties from Wolters Kluwer. Dr. Niznik has received funding from the National Institute of Aging and the Centers for Disease Control and Prevention. Dr. Berry has received funding from the NIH and royalties from Wolters Kluwer.
A version of this article originally appeared on Medscape.com.
LONG BEACH, CALIF. – Ms. S had recently arrived home after a stay at a skilled nursing facility to recover from a hip fracture resulting from osteoporosis. For many patients, follow-up care would have included a DEXA scan or a prescription for a bisphosphonate from a primary care clinician not trained in geriatrics.
But the 85-year-old received care that went further and that is considered best practice for the management of geriatric fractures: A physical therapist visited her after discharge and provided education on the importance of maintaining mobility. Ms. S also underwent assessment for fall risk and gait balance, and a team of multidisciplinary clinicians managed other factors, from postural hypotension to footwear and foot problems.
Sonja Rosen, MD, professor of medicine and chief of geriatric medicine at Cedars-Sinai Medical Center, Los Angeles, talked about Ms. S as part of a panel discussion on applying the “Geriatric 5Ms” for patients with osteoporosis at the annual meeting of the American Geriatrics Society.
“You have to figure out why they are falling and help them not fall again,” Dr. Rosen said.
Approximately 10 million Americans have osteoporosis, and another 44 million have low bone density. One in two women and up to one in four men will experience a bone fracture as a result of osteoporosis, according to the Bone Health and Osteoporosis Foundation.
, which involves considering the care preferences and goals for health care outcomes of individuals.
Ms. S eventually visited a geriatrician through the Cedars-Sinai Geriatric Fracture Program, which has been shown to lower costs and shorten hospital stays. In the program, she was advised to use a walker. Initially, she saw the aid as a hindrance – she felt she should be able to walk without it, like before. But with education, she learned that it is impossible to predict falls and that the walking aid could reduce her risk of a stumble.
Dr. Rosen said clinicians should address any vision problems, prescriptions for psychotropic drugs,which can affect balance, and heart rate and rhythm abnormalities, and they should suggest modifications to the home environment, such as installing grab bars in showers and removing rugs that can easily be tripped over.
The program at Cedars-Sinai, like similar initiatives, offers a team with resources that some clinicians may not have access to, such as a care coordinator and bone-health coach. But health care providers can utilize aspects, such as making referrals to community exercise classes.
Dr. Rosen and her colleagues studied the effects of such exercise programs and found that the programs lessen loneliness and social isolation. Fear of falling decreased in 75% of participants, “which is so key to these postfracture patients in getting back out into the world and engaging in their prior level of functional status,” Dr. Rosen said.
The second ‘M’: Medication management
The second “M,” medications, can help clinicians sequence osteoporosis drugs, depending on patient characteristics and scenarios.
Cathleen Colon-Emeric, MD, MHS, chief of geriatrics at Duke University, in Durham, N.C., dived into the case history of Ms. S, who had hypertension and insomnia in addition to osteoporosis.
First-line treatment for Ms. S – and for most patients – was an oral bisphosphonate, Dr. Colon-Emeric said. Compared with placebo, the drugs decrease the risk of overall osteoporotic fractures by nearly 40% (odds ratio, 0.62). But the medications are linked to injury of the esophageal mucosa. This risk is decreased when a patient stays upright for 30 minutes after taking oral bisphosphonates. Dr. Colon-Emeric displayed a slide of a woman receiving a pedicure at a nail salon.
“The picture of the pedicure is to share the wonderful idea I got from one skilled nursing facility I was working with, who makes sure they do safe administration to prevent esophagitis in their patients by having them all go to a spa day, where they all sit up and get their nails done while they wait their 30 minutes [after taking the pill] sitting up safely,” Dr. Colon-Emeric said.
This strategy drew applause from the audience.
Dr. Colon-Emeric advised that clinicians use judgment in the interpretation of results from the Fracture Risk Assessment Tool (FRAX). Incorporating race into estimates of fracture risk has pros and cons. While there are racial and ethnic differences in average bone density, the data for race calibrations to estimate risk are dated, she said. Clinicians should compare FRAX estimates with and without race input to help patients understand a range of risks.
Some patients may be reluctant to begin taking osteoporosis drugs because of misinformation originating from inaccurate news reports or anecdotes from friends. Dr. Colon-Emeric advised clinicians to remind patients that one in five who experience a fracture will have another injury in the following 2 years.
“A major osteoporotic fracture is akin to a heart attack; it has a very similar 1-year mortality rate and a very similar rate of a subsequent secondary event,” Dr. Colon-Emeric said. “We have a class of medications that decrease both those risks by nearly a third.”
Shared decision-making can help patients understand the risks and benefits of treatment, she said.
“People are really scared about the side effects,” Michelle Keller, PhD, MPH, a research scientist at Cedars-Sinai who attended the session, said. “The idea that a “bone attack” is like a heart attack gets the message across.”
Mind and multicomplexity
Medical complexity of a patient must be considered when making decisions on treatment, according to Joshua Niznik, PharmD, PhD, assistant professor of medicine in the Center for Aging and Health at the University of North Carolina at Chapel Hill.
“Medical complexity is an acknowledgment of the entire person, the burden of their multiple chronic conditions, advanced illnesses, and also their biopsychosocial needs and how those together might augment treatment selection and decision-making,” Dr. Niznik said.
Studies by Dr. Niznik and others have shown that swallowing difficulties, severe dementia, and being older than 90 are linked with a lower likelihood of receiving treatment for osteoporosis.
But therapies for fracture prevention, especially bisphosphonates, appear to be at least as effective for adults with medical complexity as they are for people without such conditions, Dr. Niznik said. Physicians must consider the potential treatment burden and the likelihood of benefit, he said.
Dr. Niznik’s research has shown a lack of strong evidence on how clinicians can manage patients in nursing homes. In some cases, deprescribing is reasonable, such as for patients who have undergone treatment for several years and whose life expectancy is less than 2 years.
“In the absence of any of those, if they are not already treated for osteoporosis, it makes sense to initiate treatment at that time,” Dr. Niznik said.
Matters most: Patient input
Clinicians need to educate patients on how long they must undergo a treatment before they experience benefits, according to Sarah D. Berry, MD, MPH, associate professor of medicine at Harvard Medical School, in Boston.
A meta-analysis of studies that included more than 20,000 women who were randomly assigned to receive bisphosphonate or placebo found that one nonvertebral fracture was avoided during a 12-month period for every 100 persons treated. One hip fracture was avoided during a 20-month period for every 200 patients treated.
“In general, in persons with a 2-year life expectancy, time to benefit favors bisphosphonate use,” Dr. Berry said. “Anabolics may have an even quicker time to benefit.”
Dr. Berry said a shared a decision-making model can help clinicians facilitate discussions that help patients prioritize goals and compare options while considering results, benefits, and harms. And she offered a final tip: Use tools with absolute risk reduction to convey risks and benefits, as the relative risk calculations overestimate how effective treatment will be.
Dr. Rosen has disclosed no relevant financial relationships. Dr. Colon-Emeric has received grants from the National Institutes of Health and VA Health Services Research and Development Funding; has served as endpoint adjudication chair for UCB Pharma; and has received royalties from Wolters Kluwer. Dr. Niznik has received funding from the National Institute of Aging and the Centers for Disease Control and Prevention. Dr. Berry has received funding from the NIH and royalties from Wolters Kluwer.
A version of this article originally appeared on Medscape.com.
LONG BEACH, CALIF. – Ms. S had recently arrived home after a stay at a skilled nursing facility to recover from a hip fracture resulting from osteoporosis. For many patients, follow-up care would have included a DEXA scan or a prescription for a bisphosphonate from a primary care clinician not trained in geriatrics.
But the 85-year-old received care that went further and that is considered best practice for the management of geriatric fractures: A physical therapist visited her after discharge and provided education on the importance of maintaining mobility. Ms. S also underwent assessment for fall risk and gait balance, and a team of multidisciplinary clinicians managed other factors, from postural hypotension to footwear and foot problems.
Sonja Rosen, MD, professor of medicine and chief of geriatric medicine at Cedars-Sinai Medical Center, Los Angeles, talked about Ms. S as part of a panel discussion on applying the “Geriatric 5Ms” for patients with osteoporosis at the annual meeting of the American Geriatrics Society.
“You have to figure out why they are falling and help them not fall again,” Dr. Rosen said.
Approximately 10 million Americans have osteoporosis, and another 44 million have low bone density. One in two women and up to one in four men will experience a bone fracture as a result of osteoporosis, according to the Bone Health and Osteoporosis Foundation.
, which involves considering the care preferences and goals for health care outcomes of individuals.
Ms. S eventually visited a geriatrician through the Cedars-Sinai Geriatric Fracture Program, which has been shown to lower costs and shorten hospital stays. In the program, she was advised to use a walker. Initially, she saw the aid as a hindrance – she felt she should be able to walk without it, like before. But with education, she learned that it is impossible to predict falls and that the walking aid could reduce her risk of a stumble.
Dr. Rosen said clinicians should address any vision problems, prescriptions for psychotropic drugs,which can affect balance, and heart rate and rhythm abnormalities, and they should suggest modifications to the home environment, such as installing grab bars in showers and removing rugs that can easily be tripped over.
The program at Cedars-Sinai, like similar initiatives, offers a team with resources that some clinicians may not have access to, such as a care coordinator and bone-health coach. But health care providers can utilize aspects, such as making referrals to community exercise classes.
Dr. Rosen and her colleagues studied the effects of such exercise programs and found that the programs lessen loneliness and social isolation. Fear of falling decreased in 75% of participants, “which is so key to these postfracture patients in getting back out into the world and engaging in their prior level of functional status,” Dr. Rosen said.
The second ‘M’: Medication management
The second “M,” medications, can help clinicians sequence osteoporosis drugs, depending on patient characteristics and scenarios.
Cathleen Colon-Emeric, MD, MHS, chief of geriatrics at Duke University, in Durham, N.C., dived into the case history of Ms. S, who had hypertension and insomnia in addition to osteoporosis.
First-line treatment for Ms. S – and for most patients – was an oral bisphosphonate, Dr. Colon-Emeric said. Compared with placebo, the drugs decrease the risk of overall osteoporotic fractures by nearly 40% (odds ratio, 0.62). But the medications are linked to injury of the esophageal mucosa. This risk is decreased when a patient stays upright for 30 minutes after taking oral bisphosphonates. Dr. Colon-Emeric displayed a slide of a woman receiving a pedicure at a nail salon.
“The picture of the pedicure is to share the wonderful idea I got from one skilled nursing facility I was working with, who makes sure they do safe administration to prevent esophagitis in their patients by having them all go to a spa day, where they all sit up and get their nails done while they wait their 30 minutes [after taking the pill] sitting up safely,” Dr. Colon-Emeric said.
This strategy drew applause from the audience.
Dr. Colon-Emeric advised that clinicians use judgment in the interpretation of results from the Fracture Risk Assessment Tool (FRAX). Incorporating race into estimates of fracture risk has pros and cons. While there are racial and ethnic differences in average bone density, the data for race calibrations to estimate risk are dated, she said. Clinicians should compare FRAX estimates with and without race input to help patients understand a range of risks.
Some patients may be reluctant to begin taking osteoporosis drugs because of misinformation originating from inaccurate news reports or anecdotes from friends. Dr. Colon-Emeric advised clinicians to remind patients that one in five who experience a fracture will have another injury in the following 2 years.
“A major osteoporotic fracture is akin to a heart attack; it has a very similar 1-year mortality rate and a very similar rate of a subsequent secondary event,” Dr. Colon-Emeric said. “We have a class of medications that decrease both those risks by nearly a third.”
Shared decision-making can help patients understand the risks and benefits of treatment, she said.
“People are really scared about the side effects,” Michelle Keller, PhD, MPH, a research scientist at Cedars-Sinai who attended the session, said. “The idea that a “bone attack” is like a heart attack gets the message across.”
Mind and multicomplexity
Medical complexity of a patient must be considered when making decisions on treatment, according to Joshua Niznik, PharmD, PhD, assistant professor of medicine in the Center for Aging and Health at the University of North Carolina at Chapel Hill.
“Medical complexity is an acknowledgment of the entire person, the burden of their multiple chronic conditions, advanced illnesses, and also their biopsychosocial needs and how those together might augment treatment selection and decision-making,” Dr. Niznik said.
Studies by Dr. Niznik and others have shown that swallowing difficulties, severe dementia, and being older than 90 are linked with a lower likelihood of receiving treatment for osteoporosis.
But therapies for fracture prevention, especially bisphosphonates, appear to be at least as effective for adults with medical complexity as they are for people without such conditions, Dr. Niznik said. Physicians must consider the potential treatment burden and the likelihood of benefit, he said.
Dr. Niznik’s research has shown a lack of strong evidence on how clinicians can manage patients in nursing homes. In some cases, deprescribing is reasonable, such as for patients who have undergone treatment for several years and whose life expectancy is less than 2 years.
“In the absence of any of those, if they are not already treated for osteoporosis, it makes sense to initiate treatment at that time,” Dr. Niznik said.
Matters most: Patient input
Clinicians need to educate patients on how long they must undergo a treatment before they experience benefits, according to Sarah D. Berry, MD, MPH, associate professor of medicine at Harvard Medical School, in Boston.
A meta-analysis of studies that included more than 20,000 women who were randomly assigned to receive bisphosphonate or placebo found that one nonvertebral fracture was avoided during a 12-month period for every 100 persons treated. One hip fracture was avoided during a 20-month period for every 200 patients treated.
“In general, in persons with a 2-year life expectancy, time to benefit favors bisphosphonate use,” Dr. Berry said. “Anabolics may have an even quicker time to benefit.”
Dr. Berry said a shared a decision-making model can help clinicians facilitate discussions that help patients prioritize goals and compare options while considering results, benefits, and harms. And she offered a final tip: Use tools with absolute risk reduction to convey risks and benefits, as the relative risk calculations overestimate how effective treatment will be.
Dr. Rosen has disclosed no relevant financial relationships. Dr. Colon-Emeric has received grants from the National Institutes of Health and VA Health Services Research and Development Funding; has served as endpoint adjudication chair for UCB Pharma; and has received royalties from Wolters Kluwer. Dr. Niznik has received funding from the National Institute of Aging and the Centers for Disease Control and Prevention. Dr. Berry has received funding from the NIH and royalties from Wolters Kluwer.
A version of this article originally appeared on Medscape.com.
AT AGS 2023
Mohs surgery workforce continues to increase
SEATTLE – At least for now, and that has been the case for the past 5 years.
Using CMS billing codes as a surrogate, the researchers found that there was a steady increase in the number of physicians who billed from 2015 to 2020. With the exception of 2020, which was the height of the COVID-19 pandemic, the number of times that a specific code was billed for increased on average by 4.7% annually.
“Thus, if the attrition rate remains stable, even with changes in board certification and potential payer eligibility restrictions, the number of physicians will continue to increase,” study author Ji Won Ahn, MD, who specializes in dermatology and Mohs surgery at University of Pittsburgh Medical Center, said at the annual meeting of the American College of Mohs Surgery, where she presented the results.
The growth in the number of Mohs surgeons has been fueled by several factors, including a rising incidence of skin cancer as well as the superior cure rates and cosmetic outcomes with the procedure. Reimbursement has been favorable and training pathways have expanded. A 2019 retrospective study reported that there were 2,240 dermatologists who performed Mohs surgery in the United States, with nearly all of them (94.6%) residing in metropolitan areas.
Dr. Ahn explained that it was important to define the workforce because of several new factors that will be affecting it in the future. “With the establishment of Micrographic Surgery and Dermatologic Oncology [MSDO] board certification that went into effect 2 years ago, potential future payer eligibility restrictions may be coming,” she said. “The adequacy of the Mohs surgery workforce is an important consideration.”
Another issue is that new board certification will be limited to fellowship-trained physicians after the first 5 years. “We wanted to compare these numbers with the fellowship numbers,” she said. “Although fellowship numbers are something that the college potentially has the power to change.”
Dr. Ahn and colleagues used the Centers for Medicare & Medicaid Services database to evaluate the use of the Current Procedural Terminology (CPT) code 17311, which is one of the most common billing codes for Mohs micrographic technique. Looking at data from 2015-2020, they found that there was an annual increase in the number of unique national provider identifiers (NPIs) billing for 17311, at an average rate of 75.6 per year.
The total number of times that 17311 was billed also increased from 2015 to 2019 at an average rate of 4.7% per year but declined in 2020 by 8.4%. “Overall, there was an average of 135 new NPIs that appeared and an average of 59.4 NPIs that stopped billing for 17311,” thus, an attrition rate of 59 surgeons, Dr. Ahn explained.
She emphasized that notably, the number of approved MSDO fellowship spots has remained stable since 2016 and is about 92 to 93 per year. “There are about 135 new surgeons and about two-thirds are new fellowship graduates,” she said.
The researchers were also interested in seeing how saturated each surgeon was and looked at the approximate number of cases that they were handling.
Of the physicians who billed 17311 through CMS, over 26% billed less than 100 times and more than 45% billed less than 200 times, and over 80% billed less than 500 times.
“One might be able to conclude that there might be some potential flexibility depending on the future need for surgeons,” she said.
The study was limited by several factors, one being that the researchers looked only at CPT code 17311 and not other designated codes for Mohs surgery. Other factors such as staff and space limitations were not accounted for since only billing data were used.
Dr. Ahn and her team are going to continue their work, and the next steps are to look at geographic trends and monitor for insurance network eligibility changes. “We are currently doing a workforce survey so we can better understand our current workforce rather than just historical data,” she concluded.
Asked to comment on the results, Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who was not involved with the study, noted that the increase in the “billing rates of the first stage of Mohs micrographic surgery highlights not only the growing skin cancer epidemic, but also the number of providers who are providing these services. This underscores the importance of standardized training guidelines and board certifications of Mohs micrographic surgeons to assure high levels of patient care and the appropriate use of Mohs micrographic surgery,” he said.
No external funding of the study was reported. Dr. Ahn reported no relevant financial relationships. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
A version of this article originally appeared on Medscape.com.
SEATTLE – At least for now, and that has been the case for the past 5 years.
Using CMS billing codes as a surrogate, the researchers found that there was a steady increase in the number of physicians who billed from 2015 to 2020. With the exception of 2020, which was the height of the COVID-19 pandemic, the number of times that a specific code was billed for increased on average by 4.7% annually.
“Thus, if the attrition rate remains stable, even with changes in board certification and potential payer eligibility restrictions, the number of physicians will continue to increase,” study author Ji Won Ahn, MD, who specializes in dermatology and Mohs surgery at University of Pittsburgh Medical Center, said at the annual meeting of the American College of Mohs Surgery, where she presented the results.
The growth in the number of Mohs surgeons has been fueled by several factors, including a rising incidence of skin cancer as well as the superior cure rates and cosmetic outcomes with the procedure. Reimbursement has been favorable and training pathways have expanded. A 2019 retrospective study reported that there were 2,240 dermatologists who performed Mohs surgery in the United States, with nearly all of them (94.6%) residing in metropolitan areas.
Dr. Ahn explained that it was important to define the workforce because of several new factors that will be affecting it in the future. “With the establishment of Micrographic Surgery and Dermatologic Oncology [MSDO] board certification that went into effect 2 years ago, potential future payer eligibility restrictions may be coming,” she said. “The adequacy of the Mohs surgery workforce is an important consideration.”
Another issue is that new board certification will be limited to fellowship-trained physicians after the first 5 years. “We wanted to compare these numbers with the fellowship numbers,” she said. “Although fellowship numbers are something that the college potentially has the power to change.”
Dr. Ahn and colleagues used the Centers for Medicare & Medicaid Services database to evaluate the use of the Current Procedural Terminology (CPT) code 17311, which is one of the most common billing codes for Mohs micrographic technique. Looking at data from 2015-2020, they found that there was an annual increase in the number of unique national provider identifiers (NPIs) billing for 17311, at an average rate of 75.6 per year.
The total number of times that 17311 was billed also increased from 2015 to 2019 at an average rate of 4.7% per year but declined in 2020 by 8.4%. “Overall, there was an average of 135 new NPIs that appeared and an average of 59.4 NPIs that stopped billing for 17311,” thus, an attrition rate of 59 surgeons, Dr. Ahn explained.
She emphasized that notably, the number of approved MSDO fellowship spots has remained stable since 2016 and is about 92 to 93 per year. “There are about 135 new surgeons and about two-thirds are new fellowship graduates,” she said.
The researchers were also interested in seeing how saturated each surgeon was and looked at the approximate number of cases that they were handling.
Of the physicians who billed 17311 through CMS, over 26% billed less than 100 times and more than 45% billed less than 200 times, and over 80% billed less than 500 times.
“One might be able to conclude that there might be some potential flexibility depending on the future need for surgeons,” she said.
The study was limited by several factors, one being that the researchers looked only at CPT code 17311 and not other designated codes for Mohs surgery. Other factors such as staff and space limitations were not accounted for since only billing data were used.
Dr. Ahn and her team are going to continue their work, and the next steps are to look at geographic trends and monitor for insurance network eligibility changes. “We are currently doing a workforce survey so we can better understand our current workforce rather than just historical data,” she concluded.
Asked to comment on the results, Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who was not involved with the study, noted that the increase in the “billing rates of the first stage of Mohs micrographic surgery highlights not only the growing skin cancer epidemic, but also the number of providers who are providing these services. This underscores the importance of standardized training guidelines and board certifications of Mohs micrographic surgeons to assure high levels of patient care and the appropriate use of Mohs micrographic surgery,” he said.
No external funding of the study was reported. Dr. Ahn reported no relevant financial relationships. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
A version of this article originally appeared on Medscape.com.
SEATTLE – At least for now, and that has been the case for the past 5 years.
Using CMS billing codes as a surrogate, the researchers found that there was a steady increase in the number of physicians who billed from 2015 to 2020. With the exception of 2020, which was the height of the COVID-19 pandemic, the number of times that a specific code was billed for increased on average by 4.7% annually.
“Thus, if the attrition rate remains stable, even with changes in board certification and potential payer eligibility restrictions, the number of physicians will continue to increase,” study author Ji Won Ahn, MD, who specializes in dermatology and Mohs surgery at University of Pittsburgh Medical Center, said at the annual meeting of the American College of Mohs Surgery, where she presented the results.
The growth in the number of Mohs surgeons has been fueled by several factors, including a rising incidence of skin cancer as well as the superior cure rates and cosmetic outcomes with the procedure. Reimbursement has been favorable and training pathways have expanded. A 2019 retrospective study reported that there were 2,240 dermatologists who performed Mohs surgery in the United States, with nearly all of them (94.6%) residing in metropolitan areas.
Dr. Ahn explained that it was important to define the workforce because of several new factors that will be affecting it in the future. “With the establishment of Micrographic Surgery and Dermatologic Oncology [MSDO] board certification that went into effect 2 years ago, potential future payer eligibility restrictions may be coming,” she said. “The adequacy of the Mohs surgery workforce is an important consideration.”
Another issue is that new board certification will be limited to fellowship-trained physicians after the first 5 years. “We wanted to compare these numbers with the fellowship numbers,” she said. “Although fellowship numbers are something that the college potentially has the power to change.”
Dr. Ahn and colleagues used the Centers for Medicare & Medicaid Services database to evaluate the use of the Current Procedural Terminology (CPT) code 17311, which is one of the most common billing codes for Mohs micrographic technique. Looking at data from 2015-2020, they found that there was an annual increase in the number of unique national provider identifiers (NPIs) billing for 17311, at an average rate of 75.6 per year.
The total number of times that 17311 was billed also increased from 2015 to 2019 at an average rate of 4.7% per year but declined in 2020 by 8.4%. “Overall, there was an average of 135 new NPIs that appeared and an average of 59.4 NPIs that stopped billing for 17311,” thus, an attrition rate of 59 surgeons, Dr. Ahn explained.
She emphasized that notably, the number of approved MSDO fellowship spots has remained stable since 2016 and is about 92 to 93 per year. “There are about 135 new surgeons and about two-thirds are new fellowship graduates,” she said.
The researchers were also interested in seeing how saturated each surgeon was and looked at the approximate number of cases that they were handling.
Of the physicians who billed 17311 through CMS, over 26% billed less than 100 times and more than 45% billed less than 200 times, and over 80% billed less than 500 times.
“One might be able to conclude that there might be some potential flexibility depending on the future need for surgeons,” she said.
The study was limited by several factors, one being that the researchers looked only at CPT code 17311 and not other designated codes for Mohs surgery. Other factors such as staff and space limitations were not accounted for since only billing data were used.
Dr. Ahn and her team are going to continue their work, and the next steps are to look at geographic trends and monitor for insurance network eligibility changes. “We are currently doing a workforce survey so we can better understand our current workforce rather than just historical data,” she concluded.
Asked to comment on the results, Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who was not involved with the study, noted that the increase in the “billing rates of the first stage of Mohs micrographic surgery highlights not only the growing skin cancer epidemic, but also the number of providers who are providing these services. This underscores the importance of standardized training guidelines and board certifications of Mohs micrographic surgeons to assure high levels of patient care and the appropriate use of Mohs micrographic surgery,” he said.
No external funding of the study was reported. Dr. Ahn reported no relevant financial relationships. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
A version of this article originally appeared on Medscape.com.
AT ACMS 2023
Atezolizumab is associated with enhanced response in triple-negative breast cancer
based on final data from a randomized trial.
The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.
Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.
In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m2 once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).
The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.
Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.
The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.
In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.
Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.
As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.
In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.
Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.
More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”
In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.
“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.
“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients
In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.
For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.
In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.
“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.
At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.
A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.
The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.
In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.
“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.
No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.
The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.
“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.
During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.
Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.
Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
Defining response is key to de-escalation
In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.
Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”
Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.
For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.
With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.
There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.
Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.
IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.
based on final data from a randomized trial.
The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.
Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.
In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m2 once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).
The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.
Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.
The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.
In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.
Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.
As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.
In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.
Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.
More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”
In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.
“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.
“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients
In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.
For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.
In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.
“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.
At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.
A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.
The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.
In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.
“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.
No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.
The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.
“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.
During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.
Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.
Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
Defining response is key to de-escalation
In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.
Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”
Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.
For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.
With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.
There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.
Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.
IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.
based on final data from a randomized trial.
The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.
Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.
In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m2 once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).
The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.
Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.
The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.
In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.
Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.
As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.
In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.
Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.
More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”
In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.
“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.
“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients
In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.
For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.
In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.
“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.
At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.
A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.
The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.
In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.
“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.
No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.
The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.
“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.
During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.
Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.
Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
Defining response is key to de-escalation
In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.
Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”
Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.
For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.
With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.
There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.
Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.
IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.
FROM ESMO BREAST CANCER 2023
CDC: Drug-resistant ringworm reported in New York
BY ALICIA AULT
The in New York.
Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.
Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.
The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.
After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.
The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.
In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.
The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.
Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.
The authors report no relevant financial relationships.
BY ALICIA AULT
The in New York.
Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.
Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.
The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.
After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.
The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.
In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.
The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.
Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.
The authors report no relevant financial relationships.
BY ALICIA AULT
The in New York.
Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.
Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.
The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.
After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.
The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.
In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.
The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.
Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.
The authors report no relevant financial relationships.
What’s Causing Cancers at Air Force Bases?
It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).
In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.
So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.
In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.
Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.
The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711th Human Performance Wing, obtained by the Associated Press.
This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.
In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”
On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.
The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.
Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”
The USAF has also established a website to address the missileer community’s concerns.
It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).
In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.
So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.
In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.
Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.
The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711th Human Performance Wing, obtained by the Associated Press.
This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.
In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”
On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.
The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.
Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”
The USAF has also established a website to address the missileer community’s concerns.
It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).
In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.
So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.
In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.
Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.
The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711th Human Performance Wing, obtained by the Associated Press.
This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.
In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”
On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.
The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.
Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”
The USAF has also established a website to address the missileer community’s concerns.
Metabolic abnormalities boost obesity-related cancer risk
, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.
Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.
“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”
“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.
“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.
Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”
The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
Metabolically unhealthy obesity worst for cancer risks
Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.
“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.
Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.
“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.
“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
Synergy between metabolic aberrations and obesity, and cancer risk
Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.
According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.
Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).
When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).
Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.
Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.
“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.
In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.
Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.
A version of this article first appeared on Medscape.com.
, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.
Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.
“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”
“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.
“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.
Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”
The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
Metabolically unhealthy obesity worst for cancer risks
Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.
“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.
Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.
“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.
“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
Synergy between metabolic aberrations and obesity, and cancer risk
Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.
According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.
Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).
When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).
Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.
Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.
“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.
In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.
Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.
A version of this article first appeared on Medscape.com.
, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.
Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.
“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”
“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.
“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.
Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”
The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
Metabolically unhealthy obesity worst for cancer risks
Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.
“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.
Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.
“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.
“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
Synergy between metabolic aberrations and obesity, and cancer risk
Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.
According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.
Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).
When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).
Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.
Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.
“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.
In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.
Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.
A version of this article first appeared on Medscape.com.
FROM ECO 2023
Risk for breast cancer reduced after bariatric surgery
In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.
The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”
The study was published online in JAMA Surgery.
Protective association
To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).
Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.
Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).
In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.
Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.
Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.
There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).
In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).
“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.
Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”
There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
A universal benefit?
“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.
“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.
“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”
Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”
The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”
At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”
The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.
The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”
The study was published online in JAMA Surgery.
Protective association
To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).
Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.
Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).
In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.
Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.
Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.
There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).
In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).
“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.
Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”
There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
A universal benefit?
“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.
“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.
“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”
Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”
The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”
At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”
The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.
The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”
The study was published online in JAMA Surgery.
Protective association
To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).
Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.
Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).
In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.
Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.
Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.
There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).
In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).
“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.
Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”
There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
A universal benefit?
“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.
“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.
“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”
Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”
The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”
At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”
The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA SURGERY
Patritumab deruxtecan shows promise for breast cancer patients
according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.
Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.
Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.
In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.
In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.
Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.
All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.
At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049).
In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).
Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.
HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.
A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.
To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.
During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
ICARUS-BREAST01
In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.
The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.
The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.
After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.
As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.
Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.
“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.
In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.
Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.
In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.
Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.
Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
Early results merit further exploration
Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.
“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.
In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.
“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.
The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.
“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”
In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.
The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.
according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.
Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.
Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.
In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.
In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.
Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.
All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.
At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049).
In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).
Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.
HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.
A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.
To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.
During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
ICARUS-BREAST01
In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.
The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.
The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.
After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.
As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.
Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.
“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.
In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.
Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.
In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.
Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.
Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
Early results merit further exploration
Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.
“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.
In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.
“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.
The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.
“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”
In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.
The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.
according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.
Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.
Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.
In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.
In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.
Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.
All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.
At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049).
In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).
Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.
HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.
A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.
To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.
During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
ICARUS-BREAST01
In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.
The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.
The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.
After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.
As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.
Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.
“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.
In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.
Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.
In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.
Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.
Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
Early results merit further exploration
Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.
“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.
In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.
“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.
The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.
“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”
In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.
The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.
FROM ESMO BREAST CANCER 2023
Common gut bacteria linked to Parkinson’s disease
, a small study suggests.
Environmental factors as well as genetics are also suspected to play a role in PD etiology, although the exact cause remains unknown.
“Our findings indicate that specific strains of Desulfovibrio bacteria are likely to cause Parkinson’s disease,” study investigator Per Erik Saris, PhD, from the University of Helsinki, Finland, says in a news release.
The study was published online in Frontiers in Cellular and Infection Microbiology.
Screen and treat?
It builds on earlier work by the researchers that showed that Desulfovibrio bacteria were more prevalent and more abundant in quantity in patients with PD, especially patients with more severe disease, than in healthy individuals.
Desulfovibrio is a genus of gram-negative bacteria commonly found in aquatic environments in which levels of organic material are elevated, as well as in waterlogged soils.
In their latest study, Dr. Saris and colleagues looked for Desulfovibrio species in fecal samples from 10 patients with PD and their healthy spouses. Isolated Desulfovibrio strains were fed to a strain of Caenorhabditis elegans roundworms that expressed human alpha-syn fused with yellow fluorescent protein.
They found that worms fed Desulfovibrio bacteria from patients with PD harbored significantly more (P < .001) and larger alpha-syn aggregates (P < .001) than worms fed Desulfovibrio bacteria from healthy individuals or worms fed Escherichia coli strains.
In addition, worms fed Desulfovibrio strains from patients with PD died in significantly higher quantities than worms fed E. coli bacteria (P < .01).
Desulfovibrio strains isolated from patients with PD and strains isolated from healthy individuals appear to have different traits. Comparative genomics studies are needed to identify genetic differences and pathogenic genes from Desulfovibrio strains from patients with PD, the researchers note.
“Taking into account that aggregation of alpha-syn is a hallmark of PD, the ability of Desulfovibrio bacteria to induce alpha-syn aggregation in large numbers and sizes, as demonstrated in the present study, provides further evidence for the pathogenic role of Desulfovibrio bacteria in PD, as previously suggested,” they add.
The findings highlight the potential for screening and targeted removal of harmful Desulfovibrio bacteria, Dr. Saris suggests in the news release.
No clinical implications
In a comment, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, cautioned that “this research is in a very early stage, uses a nonvertebrate animal model, and the number of participants is small.
“Understanding the role of the gut microbiome in influencing PD is in its infancy. These are important steps to determining what – if any – link may be between gut bacteria and PD,” Dr. Beck said.
“Right now, there are no implications for the screening/treatment of carriers,” Dr. Beck said.
“It seems that a lot of people, whether with PD or not, harbor Desulfovibrio bacteria in their gut. More research is needed to understand what is different between the Desulfovibrio bacteria of people with PD vs. those who do not have PD,” Dr. Beck added.
The study was supported by the Magnus Ehrnrooth Foundation and the Jane and Aatos Erkko Foundation. Dr. Saris and Dr. Beck have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, a small study suggests.
Environmental factors as well as genetics are also suspected to play a role in PD etiology, although the exact cause remains unknown.
“Our findings indicate that specific strains of Desulfovibrio bacteria are likely to cause Parkinson’s disease,” study investigator Per Erik Saris, PhD, from the University of Helsinki, Finland, says in a news release.
The study was published online in Frontiers in Cellular and Infection Microbiology.
Screen and treat?
It builds on earlier work by the researchers that showed that Desulfovibrio bacteria were more prevalent and more abundant in quantity in patients with PD, especially patients with more severe disease, than in healthy individuals.
Desulfovibrio is a genus of gram-negative bacteria commonly found in aquatic environments in which levels of organic material are elevated, as well as in waterlogged soils.
In their latest study, Dr. Saris and colleagues looked for Desulfovibrio species in fecal samples from 10 patients with PD and their healthy spouses. Isolated Desulfovibrio strains were fed to a strain of Caenorhabditis elegans roundworms that expressed human alpha-syn fused with yellow fluorescent protein.
They found that worms fed Desulfovibrio bacteria from patients with PD harbored significantly more (P < .001) and larger alpha-syn aggregates (P < .001) than worms fed Desulfovibrio bacteria from healthy individuals or worms fed Escherichia coli strains.
In addition, worms fed Desulfovibrio strains from patients with PD died in significantly higher quantities than worms fed E. coli bacteria (P < .01).
Desulfovibrio strains isolated from patients with PD and strains isolated from healthy individuals appear to have different traits. Comparative genomics studies are needed to identify genetic differences and pathogenic genes from Desulfovibrio strains from patients with PD, the researchers note.
“Taking into account that aggregation of alpha-syn is a hallmark of PD, the ability of Desulfovibrio bacteria to induce alpha-syn aggregation in large numbers and sizes, as demonstrated in the present study, provides further evidence for the pathogenic role of Desulfovibrio bacteria in PD, as previously suggested,” they add.
The findings highlight the potential for screening and targeted removal of harmful Desulfovibrio bacteria, Dr. Saris suggests in the news release.
No clinical implications
In a comment, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, cautioned that “this research is in a very early stage, uses a nonvertebrate animal model, and the number of participants is small.
“Understanding the role of the gut microbiome in influencing PD is in its infancy. These are important steps to determining what – if any – link may be between gut bacteria and PD,” Dr. Beck said.
“Right now, there are no implications for the screening/treatment of carriers,” Dr. Beck said.
“It seems that a lot of people, whether with PD or not, harbor Desulfovibrio bacteria in their gut. More research is needed to understand what is different between the Desulfovibrio bacteria of people with PD vs. those who do not have PD,” Dr. Beck added.
The study was supported by the Magnus Ehrnrooth Foundation and the Jane and Aatos Erkko Foundation. Dr. Saris and Dr. Beck have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, a small study suggests.
Environmental factors as well as genetics are also suspected to play a role in PD etiology, although the exact cause remains unknown.
“Our findings indicate that specific strains of Desulfovibrio bacteria are likely to cause Parkinson’s disease,” study investigator Per Erik Saris, PhD, from the University of Helsinki, Finland, says in a news release.
The study was published online in Frontiers in Cellular and Infection Microbiology.
Screen and treat?
It builds on earlier work by the researchers that showed that Desulfovibrio bacteria were more prevalent and more abundant in quantity in patients with PD, especially patients with more severe disease, than in healthy individuals.
Desulfovibrio is a genus of gram-negative bacteria commonly found in aquatic environments in which levels of organic material are elevated, as well as in waterlogged soils.
In their latest study, Dr. Saris and colleagues looked for Desulfovibrio species in fecal samples from 10 patients with PD and their healthy spouses. Isolated Desulfovibrio strains were fed to a strain of Caenorhabditis elegans roundworms that expressed human alpha-syn fused with yellow fluorescent protein.
They found that worms fed Desulfovibrio bacteria from patients with PD harbored significantly more (P < .001) and larger alpha-syn aggregates (P < .001) than worms fed Desulfovibrio bacteria from healthy individuals or worms fed Escherichia coli strains.
In addition, worms fed Desulfovibrio strains from patients with PD died in significantly higher quantities than worms fed E. coli bacteria (P < .01).
Desulfovibrio strains isolated from patients with PD and strains isolated from healthy individuals appear to have different traits. Comparative genomics studies are needed to identify genetic differences and pathogenic genes from Desulfovibrio strains from patients with PD, the researchers note.
“Taking into account that aggregation of alpha-syn is a hallmark of PD, the ability of Desulfovibrio bacteria to induce alpha-syn aggregation in large numbers and sizes, as demonstrated in the present study, provides further evidence for the pathogenic role of Desulfovibrio bacteria in PD, as previously suggested,” they add.
The findings highlight the potential for screening and targeted removal of harmful Desulfovibrio bacteria, Dr. Saris suggests in the news release.
No clinical implications
In a comment, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, cautioned that “this research is in a very early stage, uses a nonvertebrate animal model, and the number of participants is small.
“Understanding the role of the gut microbiome in influencing PD is in its infancy. These are important steps to determining what – if any – link may be between gut bacteria and PD,” Dr. Beck said.
“Right now, there are no implications for the screening/treatment of carriers,” Dr. Beck said.
“It seems that a lot of people, whether with PD or not, harbor Desulfovibrio bacteria in their gut. More research is needed to understand what is different between the Desulfovibrio bacteria of people with PD vs. those who do not have PD,” Dr. Beck added.
The study was supported by the Magnus Ehrnrooth Foundation and the Jane and Aatos Erkko Foundation. Dr. Saris and Dr. Beck have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY