User login
Survey quantifies COVID-19’s impact on oncology
An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.
The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).
Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.
The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.
The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.
The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).
The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
Impact on treatment
The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).
Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).
Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.
On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.
Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.
“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.
“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.
Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.
Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
Telehealth, meetings, and trials
The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).
Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).
While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.
Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.
Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.
He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”
This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.
SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.
An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.
The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).
Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.
The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.
The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.
The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).
The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
Impact on treatment
The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).
Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).
Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.
On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.
Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.
“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.
“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.
Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.
Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
Telehealth, meetings, and trials
The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).
Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).
While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.
Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.
Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.
He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”
This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.
SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.
An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.
The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).
Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.
The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.
The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.
The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).
The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
Impact on treatment
The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).
Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).
Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.
On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.
Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.
“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.
“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.
Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.
Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
Telehealth, meetings, and trials
The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).
Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).
While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.
Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.
Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.
He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”
This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.
SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.
FROM ESMO 2020
AI algorithm on par with radiologists as mammogram reader
The algorithm – from the company Lunit, which was not involved in the study – had an area under the curve of 0.956 for detection of pathologically confirmed breast cancer.
When operating at a specificity of 96.6%, the sensitivity was 81.9% for the algorithm, 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists. Combining the algorithm with first-reader radiologists identified more cases than combining first- and second-reader radiologists.
These findings were published in JAMA Oncology.
The study’s authors wrote that the algorithm results are a “considerable” achievement because, unlike the radiologists, the algorithm had no access to prior mammograms or information about hormonal medications or breast symptoms.
“We believe that the time has come to evaluate AI CAD [computer-aided detection] algorithms as independent readers in prospective clinical studies,” Mattie Salim, MD, of Karolinska Institute/Karolinska University Hospital in Stockholm, and colleagues wrote.
“The authors are to be commended for providing data that support this next critical phase of discovery,” Constance Dobbins Lehman, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, wrote in a related editorial. She added that “it is time to move beyond simulation and reader studies and enter the critical phase of rigorous, prospective clinical evaluation.”
Study rationale and details
Routine mammograms save lives, but the workload for radiologists is high, and the quality of assessments varies widely, Dr. Salim and colleagues wrote. There are also problems with access in areas with few radiologists.
To address these issues, academic and commercial researchers have worked hard to apply AI – specifically, deep neural networks – to computer programs that read mammograms.
For this study, the investigators conducted the first third-party external validation of three competing algorithms. The three algorithms were not named in the report, but Lunit announced that its algorithm was the best-performing algorithm after the study was published. The other two algorithms did not perform as well and remain anonymous.
The investigators compared the algorithms’ assessments with the original radiology reports for 739 women who were diagnosed with breast cancer within 12 months of their mammogram and 8,066 women with negative mammograms who remained cancer free at a 2-year follow-up.
The women, aged 40-74 years, had conventional two-dimensional imaging read by two radiologists at the Karolinska University Hospital during 2008-2015. The subjects’ median age at screening was 54.5 years.
The algorithms gave a prediction score between 0 and 1 for each breast, with 1 denoting the highest level of cancer suspicion. To enable a comparison with the binary decisions of the radiologists, the output of each algorithm was dichotomized (normal or abnormal) at a cut point defined by the mean specificity of the first-reader radiologists, 96.6%.
At a specificity of 96.6%, the sensitivity was 81.9% for the Lunit algorithm, 67.0% for one anonymous algorithm (AI-2), 67.4% for the other anonymous algorithm (AI-3), 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists
The investigators also ran their analysis at a cut point of 88.9% specificity. The sensitivity was 88.6% for the Lunit algorithm, 80.0% for AI-2, and 80.2% for AI-3.
“This can be compared with the Breast Cancer Surveillance Consortium benchmarks of 86.9% sensitivity at 88.9% specificity,” the authors wrote.
The most potent screening strategy was combining the Lunit algorithm with the first reader, which increased cancer detection by 8% but came at the cost of a 77% increase in abnormal assessments.
“More true-positive cases would likely be found, but a much larger proportion of false-positive examinations would have to be handled in the ensuing consensus discussion,” the authors wrote. “[A] cost-benefit analysis is required ... to determine the economic implications of adding a human reader at all.”
The team noted that the Lunit algorithm was trained on images of South Korean women from GE equipment.
“Although we do not have ethnic descriptors of our study population, the vast majority of women in Stockholm are White, and all images in our study were acquired on Hologic equipment,” the authors wrote. “In training AI algorithms for mammographic cancer detection, matching ethnic and equipment distributions between the training population and the clinical test population may not be of highest importance.”
As for why the Lunit algorithm outperformed the other two algorithms, one explanation may be that the Lunit algorithm was trained on more mammograms – 72,000 cancer and 680,000 normal images (vs. 10,000 cancer and 229,000 normal images for AI-2; 6,000 cancer and 106,000 normal images for AI-3).
As for next steps, the investigators are planning a prospective clinical study to see how AI works as an independent reviewer of mammograms in a day-to-day clinical environment, both as a third reviewer and to help select women for follow-up MRI.
The current study was funded by the Stockholm County Council. The investigators disclosed financial relationships with the Swedish Research Council, the Swedish Cancer Society, Stockholm City Council, Collective Minds Radiology, and Pfizer. Dr Lehman’s institution receives grants from GE Healthcare.
SOURCE: Salim M et al. JAMA Oncol. 2020 Aug 27. doi: 10.1001/jamaoncol.2020.3321.
The algorithm – from the company Lunit, which was not involved in the study – had an area under the curve of 0.956 for detection of pathologically confirmed breast cancer.
When operating at a specificity of 96.6%, the sensitivity was 81.9% for the algorithm, 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists. Combining the algorithm with first-reader radiologists identified more cases than combining first- and second-reader radiologists.
These findings were published in JAMA Oncology.
The study’s authors wrote that the algorithm results are a “considerable” achievement because, unlike the radiologists, the algorithm had no access to prior mammograms or information about hormonal medications or breast symptoms.
“We believe that the time has come to evaluate AI CAD [computer-aided detection] algorithms as independent readers in prospective clinical studies,” Mattie Salim, MD, of Karolinska Institute/Karolinska University Hospital in Stockholm, and colleagues wrote.
“The authors are to be commended for providing data that support this next critical phase of discovery,” Constance Dobbins Lehman, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, wrote in a related editorial. She added that “it is time to move beyond simulation and reader studies and enter the critical phase of rigorous, prospective clinical evaluation.”
Study rationale and details
Routine mammograms save lives, but the workload for radiologists is high, and the quality of assessments varies widely, Dr. Salim and colleagues wrote. There are also problems with access in areas with few radiologists.
To address these issues, academic and commercial researchers have worked hard to apply AI – specifically, deep neural networks – to computer programs that read mammograms.
For this study, the investigators conducted the first third-party external validation of three competing algorithms. The three algorithms were not named in the report, but Lunit announced that its algorithm was the best-performing algorithm after the study was published. The other two algorithms did not perform as well and remain anonymous.
The investigators compared the algorithms’ assessments with the original radiology reports for 739 women who were diagnosed with breast cancer within 12 months of their mammogram and 8,066 women with negative mammograms who remained cancer free at a 2-year follow-up.
The women, aged 40-74 years, had conventional two-dimensional imaging read by two radiologists at the Karolinska University Hospital during 2008-2015. The subjects’ median age at screening was 54.5 years.
The algorithms gave a prediction score between 0 and 1 for each breast, with 1 denoting the highest level of cancer suspicion. To enable a comparison with the binary decisions of the radiologists, the output of each algorithm was dichotomized (normal or abnormal) at a cut point defined by the mean specificity of the first-reader radiologists, 96.6%.
At a specificity of 96.6%, the sensitivity was 81.9% for the Lunit algorithm, 67.0% for one anonymous algorithm (AI-2), 67.4% for the other anonymous algorithm (AI-3), 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists
The investigators also ran their analysis at a cut point of 88.9% specificity. The sensitivity was 88.6% for the Lunit algorithm, 80.0% for AI-2, and 80.2% for AI-3.
“This can be compared with the Breast Cancer Surveillance Consortium benchmarks of 86.9% sensitivity at 88.9% specificity,” the authors wrote.
The most potent screening strategy was combining the Lunit algorithm with the first reader, which increased cancer detection by 8% but came at the cost of a 77% increase in abnormal assessments.
“More true-positive cases would likely be found, but a much larger proportion of false-positive examinations would have to be handled in the ensuing consensus discussion,” the authors wrote. “[A] cost-benefit analysis is required ... to determine the economic implications of adding a human reader at all.”
The team noted that the Lunit algorithm was trained on images of South Korean women from GE equipment.
“Although we do not have ethnic descriptors of our study population, the vast majority of women in Stockholm are White, and all images in our study were acquired on Hologic equipment,” the authors wrote. “In training AI algorithms for mammographic cancer detection, matching ethnic and equipment distributions between the training population and the clinical test population may not be of highest importance.”
As for why the Lunit algorithm outperformed the other two algorithms, one explanation may be that the Lunit algorithm was trained on more mammograms – 72,000 cancer and 680,000 normal images (vs. 10,000 cancer and 229,000 normal images for AI-2; 6,000 cancer and 106,000 normal images for AI-3).
As for next steps, the investigators are planning a prospective clinical study to see how AI works as an independent reviewer of mammograms in a day-to-day clinical environment, both as a third reviewer and to help select women for follow-up MRI.
The current study was funded by the Stockholm County Council. The investigators disclosed financial relationships with the Swedish Research Council, the Swedish Cancer Society, Stockholm City Council, Collective Minds Radiology, and Pfizer. Dr Lehman’s institution receives grants from GE Healthcare.
SOURCE: Salim M et al. JAMA Oncol. 2020 Aug 27. doi: 10.1001/jamaoncol.2020.3321.
The algorithm – from the company Lunit, which was not involved in the study – had an area under the curve of 0.956 for detection of pathologically confirmed breast cancer.
When operating at a specificity of 96.6%, the sensitivity was 81.9% for the algorithm, 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists. Combining the algorithm with first-reader radiologists identified more cases than combining first- and second-reader radiologists.
These findings were published in JAMA Oncology.
The study’s authors wrote that the algorithm results are a “considerable” achievement because, unlike the radiologists, the algorithm had no access to prior mammograms or information about hormonal medications or breast symptoms.
“We believe that the time has come to evaluate AI CAD [computer-aided detection] algorithms as independent readers in prospective clinical studies,” Mattie Salim, MD, of Karolinska Institute/Karolinska University Hospital in Stockholm, and colleagues wrote.
“The authors are to be commended for providing data that support this next critical phase of discovery,” Constance Dobbins Lehman, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, wrote in a related editorial. She added that “it is time to move beyond simulation and reader studies and enter the critical phase of rigorous, prospective clinical evaluation.”
Study rationale and details
Routine mammograms save lives, but the workload for radiologists is high, and the quality of assessments varies widely, Dr. Salim and colleagues wrote. There are also problems with access in areas with few radiologists.
To address these issues, academic and commercial researchers have worked hard to apply AI – specifically, deep neural networks – to computer programs that read mammograms.
For this study, the investigators conducted the first third-party external validation of three competing algorithms. The three algorithms were not named in the report, but Lunit announced that its algorithm was the best-performing algorithm after the study was published. The other two algorithms did not perform as well and remain anonymous.
The investigators compared the algorithms’ assessments with the original radiology reports for 739 women who were diagnosed with breast cancer within 12 months of their mammogram and 8,066 women with negative mammograms who remained cancer free at a 2-year follow-up.
The women, aged 40-74 years, had conventional two-dimensional imaging read by two radiologists at the Karolinska University Hospital during 2008-2015. The subjects’ median age at screening was 54.5 years.
The algorithms gave a prediction score between 0 and 1 for each breast, with 1 denoting the highest level of cancer suspicion. To enable a comparison with the binary decisions of the radiologists, the output of each algorithm was dichotomized (normal or abnormal) at a cut point defined by the mean specificity of the first-reader radiologists, 96.6%.
At a specificity of 96.6%, the sensitivity was 81.9% for the Lunit algorithm, 67.0% for one anonymous algorithm (AI-2), 67.4% for the other anonymous algorithm (AI-3), 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists
The investigators also ran their analysis at a cut point of 88.9% specificity. The sensitivity was 88.6% for the Lunit algorithm, 80.0% for AI-2, and 80.2% for AI-3.
“This can be compared with the Breast Cancer Surveillance Consortium benchmarks of 86.9% sensitivity at 88.9% specificity,” the authors wrote.
The most potent screening strategy was combining the Lunit algorithm with the first reader, which increased cancer detection by 8% but came at the cost of a 77% increase in abnormal assessments.
“More true-positive cases would likely be found, but a much larger proportion of false-positive examinations would have to be handled in the ensuing consensus discussion,” the authors wrote. “[A] cost-benefit analysis is required ... to determine the economic implications of adding a human reader at all.”
The team noted that the Lunit algorithm was trained on images of South Korean women from GE equipment.
“Although we do not have ethnic descriptors of our study population, the vast majority of women in Stockholm are White, and all images in our study were acquired on Hologic equipment,” the authors wrote. “In training AI algorithms for mammographic cancer detection, matching ethnic and equipment distributions between the training population and the clinical test population may not be of highest importance.”
As for why the Lunit algorithm outperformed the other two algorithms, one explanation may be that the Lunit algorithm was trained on more mammograms – 72,000 cancer and 680,000 normal images (vs. 10,000 cancer and 229,000 normal images for AI-2; 6,000 cancer and 106,000 normal images for AI-3).
As for next steps, the investigators are planning a prospective clinical study to see how AI works as an independent reviewer of mammograms in a day-to-day clinical environment, both as a third reviewer and to help select women for follow-up MRI.
The current study was funded by the Stockholm County Council. The investigators disclosed financial relationships with the Swedish Research Council, the Swedish Cancer Society, Stockholm City Council, Collective Minds Radiology, and Pfizer. Dr Lehman’s institution receives grants from GE Healthcare.
SOURCE: Salim M et al. JAMA Oncol. 2020 Aug 27. doi: 10.1001/jamaoncol.2020.3321.
FROM JAMA ONCOLOGY
In MS, serious adverse effects are more common in rituximab versus ocrelizumab
, a new postmarketing analysis finds, and AE-related deaths were not unusual. Serious AEs, and those linked to death, were more common in the rituximab group, although the reported infection rate was higher in the ocrelizumab group.
The analysis, published Aug. 21 in the Multiple Sclerosis Journal, highlights the importance of monitoring patients for infections and encouraging them to do the same, the authors said.
“This report points out the impact of treatments in terms of unrecognized or underappreciated complications,” said Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y., who reviewed the study findings. “These medications have a significant downside.”
Lead author Natalia Gonzalez Caldito, MD, of the University of Texas Southwestern Medical Center, Dallas, and colleagues analyzed AEs for the drugs in the Food and Drug Administration’s Adverse Event Reporting System. They only included cases in which the drugs were solely used to treat MS and were indicated as the cause of the AEs.
Rituximab (Rituxan) and ocrelizumab (Ocrevus) are both monoclonal antibodies. Rituximab is not FDA approved for MS but is used off label; ocrelizumab is approved for the relapsing forms of MS and primary progressive MS.
The researchers found 623 AE reports and 1,466 total AEs for rituximab and 7,948 and 23,613, respectively, for ocrelizumab. The average ages for the groups were 48.76 versus 43.89, respectively, (P < .001), and 71% in each group were women.
Among total AEs, serious AEs were more common in the rituximab group versus the ocrelizumab group (64.8% vs. 56.3%, respectively, P < .001). Adverse events that caused death were also more common in the rituximab group versus the ocrelizumab group (5.75% vs. 2.11%, P < .001).
Infections and infestations were more common in the ocrelizumab group than the rituximab group (21.93% vs. 11.05%, respectively, P < .001). However, certain AEs were more common in the rituximab group than the ocrelizumab group: Those in the blood and lymphatic system category (2.86% vs. 0.91%, respectively, P < .001), and those in the neoplasms category (4.02% vs. 1.28%, P < .001, respectively).
Researchers found a highly strong association between rituximab and a rare side effects – ear pruritus (itching, 0.8%). They also identified signals for infusion-related reaction (4.82%), throat irritation (4.01%) and throat tightness (1.44%), malignant melanoma (0.8%), breast cancer (1.77%) and neutropenia (2.57%).
Among the ocrelizumab AEs, researchers found the strongest association with oral herpes (2.21%), and they found other signals for herpes zoster (2.89%), urinary tract infection (10.52%), nasopharyngitis (9.79%), infusion-related reaction (4.76%), throat irritation (3.08%), and notably MS relapses (4.1%).
“Additional pharmacovigilance studies are needed to explore and further characterize these findings,” the researchers wrote. “Furthermore, these observations suggest that the AE profile of other second-generation anti-CD20 [monoclonal antibodies] may also differ from those of rituximab and ocrelizumab.”
Dr. Gudesblatt praised the analysis and said the findings make sense. “Use of B-cell–depleting agents lead to accumulative immune deficiency in routine care, which leads to higher rates of infection,” he said. He added that, “in the clinical trials for ocrelizumab, patients with IgG and IgM deficiency were excluded, but there is no advisement to exclude such patients in real care. The rates of infection in those patients with MS who have preexisting immune deficiencies and who are treated with these agents are unknown.”
The prospect of AEs is especially worrisome, he said, since “this information is only short term. Who knows what effect the prolonged use of unopposed B-cell depletion will have on infections in the long run?”
Neurologist Mitchell Wallin, MD, MPH, of George Washington University, Washington, and the University of Maryland, Baltimore County, said in an interview that the analysis is rigorous and especially useful because it includes a wider array of subjects – including those who are older and sicker – than took part in earlier clinical trials. “It’s really important to look at this real-world evidence,” he said, “and basically put this in the back of your head when you follow up with your patients.”
No study funding was reported. The corresponding author reported various disclosures. Dr. Gudesblatt and Dr. Wallin reported no disclosures.
SOURCE: Gonzalez Caldito N et al. Mult Scler J. 2020 Aug 21. doi: 10.1177/1352458520949986.
, a new postmarketing analysis finds, and AE-related deaths were not unusual. Serious AEs, and those linked to death, were more common in the rituximab group, although the reported infection rate was higher in the ocrelizumab group.
The analysis, published Aug. 21 in the Multiple Sclerosis Journal, highlights the importance of monitoring patients for infections and encouraging them to do the same, the authors said.
“This report points out the impact of treatments in terms of unrecognized or underappreciated complications,” said Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y., who reviewed the study findings. “These medications have a significant downside.”
Lead author Natalia Gonzalez Caldito, MD, of the University of Texas Southwestern Medical Center, Dallas, and colleagues analyzed AEs for the drugs in the Food and Drug Administration’s Adverse Event Reporting System. They only included cases in which the drugs were solely used to treat MS and were indicated as the cause of the AEs.
Rituximab (Rituxan) and ocrelizumab (Ocrevus) are both monoclonal antibodies. Rituximab is not FDA approved for MS but is used off label; ocrelizumab is approved for the relapsing forms of MS and primary progressive MS.
The researchers found 623 AE reports and 1,466 total AEs for rituximab and 7,948 and 23,613, respectively, for ocrelizumab. The average ages for the groups were 48.76 versus 43.89, respectively, (P < .001), and 71% in each group were women.
Among total AEs, serious AEs were more common in the rituximab group versus the ocrelizumab group (64.8% vs. 56.3%, respectively, P < .001). Adverse events that caused death were also more common in the rituximab group versus the ocrelizumab group (5.75% vs. 2.11%, P < .001).
Infections and infestations were more common in the ocrelizumab group than the rituximab group (21.93% vs. 11.05%, respectively, P < .001). However, certain AEs were more common in the rituximab group than the ocrelizumab group: Those in the blood and lymphatic system category (2.86% vs. 0.91%, respectively, P < .001), and those in the neoplasms category (4.02% vs. 1.28%, P < .001, respectively).
Researchers found a highly strong association between rituximab and a rare side effects – ear pruritus (itching, 0.8%). They also identified signals for infusion-related reaction (4.82%), throat irritation (4.01%) and throat tightness (1.44%), malignant melanoma (0.8%), breast cancer (1.77%) and neutropenia (2.57%).
Among the ocrelizumab AEs, researchers found the strongest association with oral herpes (2.21%), and they found other signals for herpes zoster (2.89%), urinary tract infection (10.52%), nasopharyngitis (9.79%), infusion-related reaction (4.76%), throat irritation (3.08%), and notably MS relapses (4.1%).
“Additional pharmacovigilance studies are needed to explore and further characterize these findings,” the researchers wrote. “Furthermore, these observations suggest that the AE profile of other second-generation anti-CD20 [monoclonal antibodies] may also differ from those of rituximab and ocrelizumab.”
Dr. Gudesblatt praised the analysis and said the findings make sense. “Use of B-cell–depleting agents lead to accumulative immune deficiency in routine care, which leads to higher rates of infection,” he said. He added that, “in the clinical trials for ocrelizumab, patients with IgG and IgM deficiency were excluded, but there is no advisement to exclude such patients in real care. The rates of infection in those patients with MS who have preexisting immune deficiencies and who are treated with these agents are unknown.”
The prospect of AEs is especially worrisome, he said, since “this information is only short term. Who knows what effect the prolonged use of unopposed B-cell depletion will have on infections in the long run?”
Neurologist Mitchell Wallin, MD, MPH, of George Washington University, Washington, and the University of Maryland, Baltimore County, said in an interview that the analysis is rigorous and especially useful because it includes a wider array of subjects – including those who are older and sicker – than took part in earlier clinical trials. “It’s really important to look at this real-world evidence,” he said, “and basically put this in the back of your head when you follow up with your patients.”
No study funding was reported. The corresponding author reported various disclosures. Dr. Gudesblatt and Dr. Wallin reported no disclosures.
SOURCE: Gonzalez Caldito N et al. Mult Scler J. 2020 Aug 21. doi: 10.1177/1352458520949986.
, a new postmarketing analysis finds, and AE-related deaths were not unusual. Serious AEs, and those linked to death, were more common in the rituximab group, although the reported infection rate was higher in the ocrelizumab group.
The analysis, published Aug. 21 in the Multiple Sclerosis Journal, highlights the importance of monitoring patients for infections and encouraging them to do the same, the authors said.
“This report points out the impact of treatments in terms of unrecognized or underappreciated complications,” said Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y., who reviewed the study findings. “These medications have a significant downside.”
Lead author Natalia Gonzalez Caldito, MD, of the University of Texas Southwestern Medical Center, Dallas, and colleagues analyzed AEs for the drugs in the Food and Drug Administration’s Adverse Event Reporting System. They only included cases in which the drugs were solely used to treat MS and were indicated as the cause of the AEs.
Rituximab (Rituxan) and ocrelizumab (Ocrevus) are both monoclonal antibodies. Rituximab is not FDA approved for MS but is used off label; ocrelizumab is approved for the relapsing forms of MS and primary progressive MS.
The researchers found 623 AE reports and 1,466 total AEs for rituximab and 7,948 and 23,613, respectively, for ocrelizumab. The average ages for the groups were 48.76 versus 43.89, respectively, (P < .001), and 71% in each group were women.
Among total AEs, serious AEs were more common in the rituximab group versus the ocrelizumab group (64.8% vs. 56.3%, respectively, P < .001). Adverse events that caused death were also more common in the rituximab group versus the ocrelizumab group (5.75% vs. 2.11%, P < .001).
Infections and infestations were more common in the ocrelizumab group than the rituximab group (21.93% vs. 11.05%, respectively, P < .001). However, certain AEs were more common in the rituximab group than the ocrelizumab group: Those in the blood and lymphatic system category (2.86% vs. 0.91%, respectively, P < .001), and those in the neoplasms category (4.02% vs. 1.28%, P < .001, respectively).
Researchers found a highly strong association between rituximab and a rare side effects – ear pruritus (itching, 0.8%). They also identified signals for infusion-related reaction (4.82%), throat irritation (4.01%) and throat tightness (1.44%), malignant melanoma (0.8%), breast cancer (1.77%) and neutropenia (2.57%).
Among the ocrelizumab AEs, researchers found the strongest association with oral herpes (2.21%), and they found other signals for herpes zoster (2.89%), urinary tract infection (10.52%), nasopharyngitis (9.79%), infusion-related reaction (4.76%), throat irritation (3.08%), and notably MS relapses (4.1%).
“Additional pharmacovigilance studies are needed to explore and further characterize these findings,” the researchers wrote. “Furthermore, these observations suggest that the AE profile of other second-generation anti-CD20 [monoclonal antibodies] may also differ from those of rituximab and ocrelizumab.”
Dr. Gudesblatt praised the analysis and said the findings make sense. “Use of B-cell–depleting agents lead to accumulative immune deficiency in routine care, which leads to higher rates of infection,” he said. He added that, “in the clinical trials for ocrelizumab, patients with IgG and IgM deficiency were excluded, but there is no advisement to exclude such patients in real care. The rates of infection in those patients with MS who have preexisting immune deficiencies and who are treated with these agents are unknown.”
The prospect of AEs is especially worrisome, he said, since “this information is only short term. Who knows what effect the prolonged use of unopposed B-cell depletion will have on infections in the long run?”
Neurologist Mitchell Wallin, MD, MPH, of George Washington University, Washington, and the University of Maryland, Baltimore County, said in an interview that the analysis is rigorous and especially useful because it includes a wider array of subjects – including those who are older and sicker – than took part in earlier clinical trials. “It’s really important to look at this real-world evidence,” he said, “and basically put this in the back of your head when you follow up with your patients.”
No study funding was reported. The corresponding author reported various disclosures. Dr. Gudesblatt and Dr. Wallin reported no disclosures.
SOURCE: Gonzalez Caldito N et al. Mult Scler J. 2020 Aug 21. doi: 10.1177/1352458520949986.
FROM MULTIPLE SCLEROSIS JOURNAL
Blood biomarker may predict Parkinson’s disease progression
Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.
Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.
That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
A potential biomarker?
To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.
The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.
In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.
Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).
Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
More specific markers needed
The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”
The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”
The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.
SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.
Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.
Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.
That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
A potential biomarker?
To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.
The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.
In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.
Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).
Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
More specific markers needed
The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”
The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”
The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.
SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.
Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.
Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.
That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
A potential biomarker?
To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.
The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.
In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.
Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).
Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
More specific markers needed
The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”
The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”
The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.
SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.
FROM MOVEMENT DISORDERS
Study supports multigene panel testing for all breast cancer patients with second primary cancers
according to a paper published in JCO Precision Oncology.
The authors noted that women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. However, it hasn’t been clear if mutations in genes other than BRCA1/2 are enriched in patients with multiple primary cancers.
“Surprisingly few papers have focused on genetic evaluation of patients with multiple primary cancers,” senior author Katherine L. Nathanson, MD, of the University of Pennsylvania in Philadelphia, said in an interview.
“Ours is one of the first studies to look closely at this issue. We know from clinical experience that these patients are more likely to have more than one genetic mutation,” she added.
For their study, Dr. Nathanson and colleagues identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in two cohorts.
Cohort 1 consisted of 1,000 high-risk breast cancer patients – 551 with multiple primary cancers and 449 with a single breast cancer.
Cohort 2 included 1,804 familial breast cancer patients – 340 with multiple primaries and 1,464 with a single breast cancer.
The researchers assessed mutations in these cohorts and compared them with mutations in a control data set.
Mutation rates and age
Pathogenic mutation rates were higher in both cohorts in patients with multiple primaries as compared with patients with single primaries.
In cohort 1, the overall panel positive rate was 8.53% in the multiple-primaries group and 4.90% in the single-primary group (P = .024).
In cohort 2, the overall panel positive rate was 7.06% in the multiple-primaries group and 4.23% in the single-primary group (P = .034).
In both cohorts, younger age at first breast cancer was associated with higher mutation rates. However, the age at onset of cancers other than breast cancer was not related to mutation rate.
“Regardless of age, mutations in genes other than BRCA1/2 are found in at least 5% of patients with breast cancer and another primary cancer, with up to 25% in patients with their first breast cancer at age 30 years,” Dr. Nathanson said. “This supports the need for multigene panel testing in all patients with breast cancer and another primary cancer.”
“Once a woman has multiple primaries with breast cancer, it doesn’t matter what her family history is, she is more likely to be at risk,” Dr. Nathanson added.
Genetic susceptibility
The researchers also identified genes associated with multiple primary cancers. TP53 and MSH6 mutations were significantly enriched in patients with multiple primaries but not single primaries. ATM and PALB2 mutations were significantly enriched in both groups when compared with controls.
The researchers noted that high-penetrance cancer genes were responsible for higher mutation rates in the cohort enriched for early-onset breast cancer and non–breast cancer second primaries. Moderate-penetrance cancer genes were responsible for the higher mutation rates in the cohort enriched for familial breast cancer and second breast cancer primaries.
“In multiple primary cancers, we found additional genes with moderate penetrance and some genes with high penetrance associated with TP53 and Lynch syndrome,” Dr. Nathanson said.
Cancer prevention and screening
The results of this study could lead to better implementation of cancer prevention and screening strategies, according to the researchers.
“As we look at guidelines in development and NCCN recommendations, our data suggest that age should not be part of the criteria for genetic testing in patients who have more than one primary cancer. These patients are at high risk and should be recommended for screening,” Dr. Nathanson said.
“If you see a patient with multiple primary cancers, refer for genetic testing. Age does not matter,” she reiterated.
Future research will look at potentially missing mutations.
“With targeted sequencing, structurally rearranged genes might be missed for those at risk. We will try to identify cancer susceptibility genes and define the true risk of penetrance of these genes in the general population,” Dr. Nathanson said.
This research was supported by grants from government agencies and foundations as well as the University of Pennsylvania. Dr. Nathanson disclosed no conflicts of interest. Other authors disclosed relationships with a range of companies, all listed in the paper.
SOURCE: Maxwell KN et al. JCO Precis Oncol. 2020. doi: 10.1200/PO.19.00301.
according to a paper published in JCO Precision Oncology.
The authors noted that women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. However, it hasn’t been clear if mutations in genes other than BRCA1/2 are enriched in patients with multiple primary cancers.
“Surprisingly few papers have focused on genetic evaluation of patients with multiple primary cancers,” senior author Katherine L. Nathanson, MD, of the University of Pennsylvania in Philadelphia, said in an interview.
“Ours is one of the first studies to look closely at this issue. We know from clinical experience that these patients are more likely to have more than one genetic mutation,” she added.
For their study, Dr. Nathanson and colleagues identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in two cohorts.
Cohort 1 consisted of 1,000 high-risk breast cancer patients – 551 with multiple primary cancers and 449 with a single breast cancer.
Cohort 2 included 1,804 familial breast cancer patients – 340 with multiple primaries and 1,464 with a single breast cancer.
The researchers assessed mutations in these cohorts and compared them with mutations in a control data set.
Mutation rates and age
Pathogenic mutation rates were higher in both cohorts in patients with multiple primaries as compared with patients with single primaries.
In cohort 1, the overall panel positive rate was 8.53% in the multiple-primaries group and 4.90% in the single-primary group (P = .024).
In cohort 2, the overall panel positive rate was 7.06% in the multiple-primaries group and 4.23% in the single-primary group (P = .034).
In both cohorts, younger age at first breast cancer was associated with higher mutation rates. However, the age at onset of cancers other than breast cancer was not related to mutation rate.
“Regardless of age, mutations in genes other than BRCA1/2 are found in at least 5% of patients with breast cancer and another primary cancer, with up to 25% in patients with their first breast cancer at age 30 years,” Dr. Nathanson said. “This supports the need for multigene panel testing in all patients with breast cancer and another primary cancer.”
“Once a woman has multiple primaries with breast cancer, it doesn’t matter what her family history is, she is more likely to be at risk,” Dr. Nathanson added.
Genetic susceptibility
The researchers also identified genes associated with multiple primary cancers. TP53 and MSH6 mutations were significantly enriched in patients with multiple primaries but not single primaries. ATM and PALB2 mutations were significantly enriched in both groups when compared with controls.
The researchers noted that high-penetrance cancer genes were responsible for higher mutation rates in the cohort enriched for early-onset breast cancer and non–breast cancer second primaries. Moderate-penetrance cancer genes were responsible for the higher mutation rates in the cohort enriched for familial breast cancer and second breast cancer primaries.
“In multiple primary cancers, we found additional genes with moderate penetrance and some genes with high penetrance associated with TP53 and Lynch syndrome,” Dr. Nathanson said.
Cancer prevention and screening
The results of this study could lead to better implementation of cancer prevention and screening strategies, according to the researchers.
“As we look at guidelines in development and NCCN recommendations, our data suggest that age should not be part of the criteria for genetic testing in patients who have more than one primary cancer. These patients are at high risk and should be recommended for screening,” Dr. Nathanson said.
“If you see a patient with multiple primary cancers, refer for genetic testing. Age does not matter,” she reiterated.
Future research will look at potentially missing mutations.
“With targeted sequencing, structurally rearranged genes might be missed for those at risk. We will try to identify cancer susceptibility genes and define the true risk of penetrance of these genes in the general population,” Dr. Nathanson said.
This research was supported by grants from government agencies and foundations as well as the University of Pennsylvania. Dr. Nathanson disclosed no conflicts of interest. Other authors disclosed relationships with a range of companies, all listed in the paper.
SOURCE: Maxwell KN et al. JCO Precis Oncol. 2020. doi: 10.1200/PO.19.00301.
according to a paper published in JCO Precision Oncology.
The authors noted that women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. However, it hasn’t been clear if mutations in genes other than BRCA1/2 are enriched in patients with multiple primary cancers.
“Surprisingly few papers have focused on genetic evaluation of patients with multiple primary cancers,” senior author Katherine L. Nathanson, MD, of the University of Pennsylvania in Philadelphia, said in an interview.
“Ours is one of the first studies to look closely at this issue. We know from clinical experience that these patients are more likely to have more than one genetic mutation,” she added.
For their study, Dr. Nathanson and colleagues identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in two cohorts.
Cohort 1 consisted of 1,000 high-risk breast cancer patients – 551 with multiple primary cancers and 449 with a single breast cancer.
Cohort 2 included 1,804 familial breast cancer patients – 340 with multiple primaries and 1,464 with a single breast cancer.
The researchers assessed mutations in these cohorts and compared them with mutations in a control data set.
Mutation rates and age
Pathogenic mutation rates were higher in both cohorts in patients with multiple primaries as compared with patients with single primaries.
In cohort 1, the overall panel positive rate was 8.53% in the multiple-primaries group and 4.90% in the single-primary group (P = .024).
In cohort 2, the overall panel positive rate was 7.06% in the multiple-primaries group and 4.23% in the single-primary group (P = .034).
In both cohorts, younger age at first breast cancer was associated with higher mutation rates. However, the age at onset of cancers other than breast cancer was not related to mutation rate.
“Regardless of age, mutations in genes other than BRCA1/2 are found in at least 5% of patients with breast cancer and another primary cancer, with up to 25% in patients with their first breast cancer at age 30 years,” Dr. Nathanson said. “This supports the need for multigene panel testing in all patients with breast cancer and another primary cancer.”
“Once a woman has multiple primaries with breast cancer, it doesn’t matter what her family history is, she is more likely to be at risk,” Dr. Nathanson added.
Genetic susceptibility
The researchers also identified genes associated with multiple primary cancers. TP53 and MSH6 mutations were significantly enriched in patients with multiple primaries but not single primaries. ATM and PALB2 mutations were significantly enriched in both groups when compared with controls.
The researchers noted that high-penetrance cancer genes were responsible for higher mutation rates in the cohort enriched for early-onset breast cancer and non–breast cancer second primaries. Moderate-penetrance cancer genes were responsible for the higher mutation rates in the cohort enriched for familial breast cancer and second breast cancer primaries.
“In multiple primary cancers, we found additional genes with moderate penetrance and some genes with high penetrance associated with TP53 and Lynch syndrome,” Dr. Nathanson said.
Cancer prevention and screening
The results of this study could lead to better implementation of cancer prevention and screening strategies, according to the researchers.
“As we look at guidelines in development and NCCN recommendations, our data suggest that age should not be part of the criteria for genetic testing in patients who have more than one primary cancer. These patients are at high risk and should be recommended for screening,” Dr. Nathanson said.
“If you see a patient with multiple primary cancers, refer for genetic testing. Age does not matter,” she reiterated.
Future research will look at potentially missing mutations.
“With targeted sequencing, structurally rearranged genes might be missed for those at risk. We will try to identify cancer susceptibility genes and define the true risk of penetrance of these genes in the general population,” Dr. Nathanson said.
This research was supported by grants from government agencies and foundations as well as the University of Pennsylvania. Dr. Nathanson disclosed no conflicts of interest. Other authors disclosed relationships with a range of companies, all listed in the paper.
SOURCE: Maxwell KN et al. JCO Precis Oncol. 2020. doi: 10.1200/PO.19.00301.
FROM JCO PRECISION ONCOLOGY
Lowering rituximab dose in patients with MS proves safe and effective
“Given its favorable cost-effectiveness profile, [rituximab] remains a valuable treatment option in the current landscape of MS treatments, even at the reduced dose,” wrote Giulio Disanto, MD, PhD, of the Neurocenter of Southern Switzerland in Lugano, and coauthors. The study was published in Multiple Sclerosis Journal.
To determine the clinical and radiologic effectiveness of deescalating rituximab dosage – along with assessing any adverse outcomes – this observational, single-center study examined 59 patients with MS who had been treated with rituximab at 1,000 mg for at least 1 year before the study began. Roughly 63% (n = 37) of the patients had relapsing remitting MS (RRMS), while the rest (n = 22) had secondary progressive disease (SPD). Their median age was 51, and nearly 75% were women.
All patients underwent neurologic examinations at baseline and then every 3 months for 1 year, with new symptoms, infections, or adverse events being assessed via the Expanded Disability Status Scale (EDSS). They also underwent brain and spinal MRI at baseline and at 12 months while blood samples were taken at baseline and then every 3 months for 1 year, with previous data for both collected when available.
Study results
All 59 patients completed 12-month follow-up, and no relapses occurred in the year after lowering rituximab dosage to 500 mg. No significant differences were observed when comparing EDSS scores at the start of the 1,000-mg dose with the start of the 500-mg dose (Wilcoxon P = .131) as well as from the start of the 500-mg dose to the end of follow-up (Wilcoxon P = .284). Analyzing RRMS and SPD patients separately also led to no differences in EDSS scores from the start of the 500-mg dose to the end of follow-up (Wilcoxon P = .531; Wilcoxon P = .408).
During the 1,000-mg treatment period the number of patients who developed at least one new T2 lesion on their brain or spine was 9 and 4, respectively. During the 500-mg period, just one patient developed a new T2 brain lesion and two patients developed new T2 spine lesions. IgG and IgM levels did not change from the start of 500-mg treatment, although total dose of rituximab was inversely associated with IgG concentrations when previous treatment with 1,000 mg was factored in (coefficient, −0.439; P = 0.041).
A total of 33 patients reported at least one adverse event during the 500-mg treatment period, with only three events being classified as serious: one pancreatitis, one coronary stenting, and one neutropenia.
Validating clinical experience
“This randomized trial is an important step,” said Timothy Vollmer, MD, of the Rocky Mountain MS Center in Westminster, Colo., in an interview. “It clearly supports that you can lessen the dose, which will allow us to use this revolutionary drug for a longer period of time in patients.”
Dr. Vollmer noted that, at his center, they have been using 500 mg of rituximab over a 6-month period since 2010 without a formal clinical trial and with no notable difference in adverse outcomes on MRIs or disability scales. “This validates what we’ve been doing, which we appreciate,” he said.
“The next thing you have to do is determine whether you really have to give it every 6 months,” he added, “because the treatment effect in most patients will last, in terms of B-cell depletion, about a year or more. What we should be testing next is giving the 500 mg and waiting until patients begin to recover B cells before we give them the next cycle, to see if that helps decrease the major side effect, which is a drop in IgG levels.”
The authors acknowledged their study’s limitations, including a moderate sample size, a short follow-up period after 500-mg dosage, and an inability to confirm consistency among 1,000-mg dose administration among all patients, which “may well influence efficacy and safety measures.”
The study was supported by the Neurocenter of Southern Switzerland. One author declared numerous potential conflicts of interest, including receiving speaker fees, research fees, and travel support, and serving on advisory boards for various foundations, universities, and pharmaceutical companies.
SOURCE: Disanto G et al. Mult Scler J. 2020 Aug 25. doi: 10.1177/1352458520952036.
“Given its favorable cost-effectiveness profile, [rituximab] remains a valuable treatment option in the current landscape of MS treatments, even at the reduced dose,” wrote Giulio Disanto, MD, PhD, of the Neurocenter of Southern Switzerland in Lugano, and coauthors. The study was published in Multiple Sclerosis Journal.
To determine the clinical and radiologic effectiveness of deescalating rituximab dosage – along with assessing any adverse outcomes – this observational, single-center study examined 59 patients with MS who had been treated with rituximab at 1,000 mg for at least 1 year before the study began. Roughly 63% (n = 37) of the patients had relapsing remitting MS (RRMS), while the rest (n = 22) had secondary progressive disease (SPD). Their median age was 51, and nearly 75% were women.
All patients underwent neurologic examinations at baseline and then every 3 months for 1 year, with new symptoms, infections, or adverse events being assessed via the Expanded Disability Status Scale (EDSS). They also underwent brain and spinal MRI at baseline and at 12 months while blood samples were taken at baseline and then every 3 months for 1 year, with previous data for both collected when available.
Study results
All 59 patients completed 12-month follow-up, and no relapses occurred in the year after lowering rituximab dosage to 500 mg. No significant differences were observed when comparing EDSS scores at the start of the 1,000-mg dose with the start of the 500-mg dose (Wilcoxon P = .131) as well as from the start of the 500-mg dose to the end of follow-up (Wilcoxon P = .284). Analyzing RRMS and SPD patients separately also led to no differences in EDSS scores from the start of the 500-mg dose to the end of follow-up (Wilcoxon P = .531; Wilcoxon P = .408).
During the 1,000-mg treatment period the number of patients who developed at least one new T2 lesion on their brain or spine was 9 and 4, respectively. During the 500-mg period, just one patient developed a new T2 brain lesion and two patients developed new T2 spine lesions. IgG and IgM levels did not change from the start of 500-mg treatment, although total dose of rituximab was inversely associated with IgG concentrations when previous treatment with 1,000 mg was factored in (coefficient, −0.439; P = 0.041).
A total of 33 patients reported at least one adverse event during the 500-mg treatment period, with only three events being classified as serious: one pancreatitis, one coronary stenting, and one neutropenia.
Validating clinical experience
“This randomized trial is an important step,” said Timothy Vollmer, MD, of the Rocky Mountain MS Center in Westminster, Colo., in an interview. “It clearly supports that you can lessen the dose, which will allow us to use this revolutionary drug for a longer period of time in patients.”
Dr. Vollmer noted that, at his center, they have been using 500 mg of rituximab over a 6-month period since 2010 without a formal clinical trial and with no notable difference in adverse outcomes on MRIs or disability scales. “This validates what we’ve been doing, which we appreciate,” he said.
“The next thing you have to do is determine whether you really have to give it every 6 months,” he added, “because the treatment effect in most patients will last, in terms of B-cell depletion, about a year or more. What we should be testing next is giving the 500 mg and waiting until patients begin to recover B cells before we give them the next cycle, to see if that helps decrease the major side effect, which is a drop in IgG levels.”
The authors acknowledged their study’s limitations, including a moderate sample size, a short follow-up period after 500-mg dosage, and an inability to confirm consistency among 1,000-mg dose administration among all patients, which “may well influence efficacy and safety measures.”
The study was supported by the Neurocenter of Southern Switzerland. One author declared numerous potential conflicts of interest, including receiving speaker fees, research fees, and travel support, and serving on advisory boards for various foundations, universities, and pharmaceutical companies.
SOURCE: Disanto G et al. Mult Scler J. 2020 Aug 25. doi: 10.1177/1352458520952036.
“Given its favorable cost-effectiveness profile, [rituximab] remains a valuable treatment option in the current landscape of MS treatments, even at the reduced dose,” wrote Giulio Disanto, MD, PhD, of the Neurocenter of Southern Switzerland in Lugano, and coauthors. The study was published in Multiple Sclerosis Journal.
To determine the clinical and radiologic effectiveness of deescalating rituximab dosage – along with assessing any adverse outcomes – this observational, single-center study examined 59 patients with MS who had been treated with rituximab at 1,000 mg for at least 1 year before the study began. Roughly 63% (n = 37) of the patients had relapsing remitting MS (RRMS), while the rest (n = 22) had secondary progressive disease (SPD). Their median age was 51, and nearly 75% were women.
All patients underwent neurologic examinations at baseline and then every 3 months for 1 year, with new symptoms, infections, or adverse events being assessed via the Expanded Disability Status Scale (EDSS). They also underwent brain and spinal MRI at baseline and at 12 months while blood samples were taken at baseline and then every 3 months for 1 year, with previous data for both collected when available.
Study results
All 59 patients completed 12-month follow-up, and no relapses occurred in the year after lowering rituximab dosage to 500 mg. No significant differences were observed when comparing EDSS scores at the start of the 1,000-mg dose with the start of the 500-mg dose (Wilcoxon P = .131) as well as from the start of the 500-mg dose to the end of follow-up (Wilcoxon P = .284). Analyzing RRMS and SPD patients separately also led to no differences in EDSS scores from the start of the 500-mg dose to the end of follow-up (Wilcoxon P = .531; Wilcoxon P = .408).
During the 1,000-mg treatment period the number of patients who developed at least one new T2 lesion on their brain or spine was 9 and 4, respectively. During the 500-mg period, just one patient developed a new T2 brain lesion and two patients developed new T2 spine lesions. IgG and IgM levels did not change from the start of 500-mg treatment, although total dose of rituximab was inversely associated with IgG concentrations when previous treatment with 1,000 mg was factored in (coefficient, −0.439; P = 0.041).
A total of 33 patients reported at least one adverse event during the 500-mg treatment period, with only three events being classified as serious: one pancreatitis, one coronary stenting, and one neutropenia.
Validating clinical experience
“This randomized trial is an important step,” said Timothy Vollmer, MD, of the Rocky Mountain MS Center in Westminster, Colo., in an interview. “It clearly supports that you can lessen the dose, which will allow us to use this revolutionary drug for a longer period of time in patients.”
Dr. Vollmer noted that, at his center, they have been using 500 mg of rituximab over a 6-month period since 2010 without a formal clinical trial and with no notable difference in adverse outcomes on MRIs or disability scales. “This validates what we’ve been doing, which we appreciate,” he said.
“The next thing you have to do is determine whether you really have to give it every 6 months,” he added, “because the treatment effect in most patients will last, in terms of B-cell depletion, about a year or more. What we should be testing next is giving the 500 mg and waiting until patients begin to recover B cells before we give them the next cycle, to see if that helps decrease the major side effect, which is a drop in IgG levels.”
The authors acknowledged their study’s limitations, including a moderate sample size, a short follow-up period after 500-mg dosage, and an inability to confirm consistency among 1,000-mg dose administration among all patients, which “may well influence efficacy and safety measures.”
The study was supported by the Neurocenter of Southern Switzerland. One author declared numerous potential conflicts of interest, including receiving speaker fees, research fees, and travel support, and serving on advisory boards for various foundations, universities, and pharmaceutical companies.
SOURCE: Disanto G et al. Mult Scler J. 2020 Aug 25. doi: 10.1177/1352458520952036.
FROM MULTIPLE SCLEROSIS JOURNAL
Atezolizumab TNBC indication ‘in jeopardy’ because of phase 3 results
The FDA said the phase 3 IMpassion131 trial showed that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in programmed death-ligand 1 (PD-L1)–positive patients.
“Additionally, interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population,” the FDA noted.
As a result, “health care professionals should not replace paclitaxel protein-bound (Abraxane) with paclitaxel in clinical practice,” the FDA advised.
Atezolizumab is approved for use in combination with protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel (nab-paclitaxel), to treat patients with unresectable, locally advanced, or metastatic TNBC whose tumors express PD-L1, as detected by an FDA-approved test. The combination was granted accelerated approval for this indication last year.
Atezolizumab plus nab-paclitaxel is the combination most often used in PD-L1-positive TNBC, as opposed to atezolizumab and unbound paclitaxel, said Melinda L. Telli, MD, an associate professor of medicine and director of the Stanford Cancer Institute Breast Cancer Program at Stanford (Calif.) University.
However, as the FDA noted, “continued approval of atezolizumab in combination with [nab-paclitaxel] may be contingent on proven benefit of the treatment in additional trials.”
Dr. Telli explained that atezolizumab was granted accelerated approval for the treatment of PD-L1-positive TNBC based on results of the phase 3 IMpassion130 trial, which compared nab-paclitaxel plus atezolizumab with nab-paclitaxel plus placebo.
“Additional data from IMpassion131 was hoped to be used to support the conversion of the accelerated approval to a full approval. Since IMpassion131 was negative, it unfortunately places the status of atezolizumab in [TNBC] in jeopardy as the benefits were not corroborated. The FDA may move to revoke the approval of atezolizumab for [TNBC],” Dr. Telli said.
In its alert, the FDA stated that it “will review the findings of IMpassion131 and will communicate new information regarding the IMpassion131 results and any potential changes to prescribing information.”
“We need to wait for full presentation and publication of the study results, but, in my assessment, the negative results in IMpassion131 are most likely due to differences in patient selection [from IMpassion130],” Dr. Telli said.
Results from IMpassion131 are scheduled to be presented at the ESMO Virtual Congress 2020.
The IMpassion trials were funded by Roche, maker of atezolizumab. Dr. Telli disclosed relationships with AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro.
The FDA said the phase 3 IMpassion131 trial showed that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in programmed death-ligand 1 (PD-L1)–positive patients.
“Additionally, interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population,” the FDA noted.
As a result, “health care professionals should not replace paclitaxel protein-bound (Abraxane) with paclitaxel in clinical practice,” the FDA advised.
Atezolizumab is approved for use in combination with protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel (nab-paclitaxel), to treat patients with unresectable, locally advanced, or metastatic TNBC whose tumors express PD-L1, as detected by an FDA-approved test. The combination was granted accelerated approval for this indication last year.
Atezolizumab plus nab-paclitaxel is the combination most often used in PD-L1-positive TNBC, as opposed to atezolizumab and unbound paclitaxel, said Melinda L. Telli, MD, an associate professor of medicine and director of the Stanford Cancer Institute Breast Cancer Program at Stanford (Calif.) University.
However, as the FDA noted, “continued approval of atezolizumab in combination with [nab-paclitaxel] may be contingent on proven benefit of the treatment in additional trials.”
Dr. Telli explained that atezolizumab was granted accelerated approval for the treatment of PD-L1-positive TNBC based on results of the phase 3 IMpassion130 trial, which compared nab-paclitaxel plus atezolizumab with nab-paclitaxel plus placebo.
“Additional data from IMpassion131 was hoped to be used to support the conversion of the accelerated approval to a full approval. Since IMpassion131 was negative, it unfortunately places the status of atezolizumab in [TNBC] in jeopardy as the benefits were not corroborated. The FDA may move to revoke the approval of atezolizumab for [TNBC],” Dr. Telli said.
In its alert, the FDA stated that it “will review the findings of IMpassion131 and will communicate new information regarding the IMpassion131 results and any potential changes to prescribing information.”
“We need to wait for full presentation and publication of the study results, but, in my assessment, the negative results in IMpassion131 are most likely due to differences in patient selection [from IMpassion130],” Dr. Telli said.
Results from IMpassion131 are scheduled to be presented at the ESMO Virtual Congress 2020.
The IMpassion trials were funded by Roche, maker of atezolizumab. Dr. Telli disclosed relationships with AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro.
The FDA said the phase 3 IMpassion131 trial showed that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in programmed death-ligand 1 (PD-L1)–positive patients.
“Additionally, interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population,” the FDA noted.
As a result, “health care professionals should not replace paclitaxel protein-bound (Abraxane) with paclitaxel in clinical practice,” the FDA advised.
Atezolizumab is approved for use in combination with protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel (nab-paclitaxel), to treat patients with unresectable, locally advanced, or metastatic TNBC whose tumors express PD-L1, as detected by an FDA-approved test. The combination was granted accelerated approval for this indication last year.
Atezolizumab plus nab-paclitaxel is the combination most often used in PD-L1-positive TNBC, as opposed to atezolizumab and unbound paclitaxel, said Melinda L. Telli, MD, an associate professor of medicine and director of the Stanford Cancer Institute Breast Cancer Program at Stanford (Calif.) University.
However, as the FDA noted, “continued approval of atezolizumab in combination with [nab-paclitaxel] may be contingent on proven benefit of the treatment in additional trials.”
Dr. Telli explained that atezolizumab was granted accelerated approval for the treatment of PD-L1-positive TNBC based on results of the phase 3 IMpassion130 trial, which compared nab-paclitaxel plus atezolizumab with nab-paclitaxel plus placebo.
“Additional data from IMpassion131 was hoped to be used to support the conversion of the accelerated approval to a full approval. Since IMpassion131 was negative, it unfortunately places the status of atezolizumab in [TNBC] in jeopardy as the benefits were not corroborated. The FDA may move to revoke the approval of atezolizumab for [TNBC],” Dr. Telli said.
In its alert, the FDA stated that it “will review the findings of IMpassion131 and will communicate new information regarding the IMpassion131 results and any potential changes to prescribing information.”
“We need to wait for full presentation and publication of the study results, but, in my assessment, the negative results in IMpassion131 are most likely due to differences in patient selection [from IMpassion130],” Dr. Telli said.
Results from IMpassion131 are scheduled to be presented at the ESMO Virtual Congress 2020.
The IMpassion trials were funded by Roche, maker of atezolizumab. Dr. Telli disclosed relationships with AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro.
Drug combo slows functional decline in ALS
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
From New England Journal of Medicine
Hair dye and cancer study ‘offers some reassurance’
Findings limited to White women in United States
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Findings limited to White women in United States
Findings limited to White women in United States
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Chronicles of Cancer: A history of mammography, part 2
The push and pull of social forces
Science and technology emerge from and are shaped by social forces outside the laboratory and clinic. This is an essential fact of most new medical technology. In the Chronicles of Cancer series, part 1 of the story of mammography focused on the technological determinants of its development and use. Part 2 will focus on some of the social forces that shaped the development of mammography.
“Few medical issues have been as controversial – or as political, at least in the United States – as the role of mammographic screening for breast cancer,” according to Donald A. Berry, PhD, a biostatistician at the University of Texas MD Anderson Cancer Center, Houston.1
In fact, technology aside, the history of mammography has been and remains rife with controversy on the one side and vigorous promotion on the other, all enmeshed within the War on Cancer, corporate and professional interests, and the women’s rights movement’s growing issues with what was seen as a patriarchal medical establishment.
Today the issue of conflicts of interest are paramount in any discussion of new medical developments, from the early preclinical stages to ultimate deployment. Then, as now, professional and advocacy societies had a profound influence on government and social decision-making, but in that earlier, more trusting era, buoyed by the amazing changes that technology was bringing to everyday life and an unshakable commitment to and belief in “progress,” science and the medical community held a far more effective sway over the beliefs and behavior of the general population.
Women’s health observed
Although the main focus of the women’s movement with regard to breast cancer was a struggle against the common practice of routine radical mastectomies and a push toward breast-conserving surgeries, the issue of preventive care and screening with regard to women’s health was also a major concern.
Regarding mammography, early enthusiasm in the medical community and among the general public was profound. In 1969, Robert Egan described how mammography had a “certain magic appeal.” The patient, he continued, “feels something special is being done for her.” Women whose cancers had been discovered on a mammogram praised radiologists as heroes who had saved their lives.2
In that era, however, beyond the confines of the doctor’s office, mammography and breast cancer remained topics not discussed among the public at large, despite efforts by the American Cancer Society to change this.
ACS weighs in
Various groups had been promoting the benefits of breast self-examination since the 1930s, and in 1947, the American Cancer Society launched an awareness campaign, “Look for a Lump or Thickening in the Breast,” instructing women to perform a monthly breast self-exam. Between self-examination and clinical breast examinations in physicians’ offices, the ACS believed that smaller and more treatable breast cancers could be discovered.
In 1972, the ACS, working with the National Cancer Institute (NCI), inaugurated the Breast Cancer Detection Demonstration Project (BCDDP), which planned to screen over a quarter of a million American women for breast cancer. The initiative was a direct outgrowth of the National Cancer Act of 1971,3 the key legislation of the War on Cancer, promoted by President Richard Nixon in his State of the Union address in 1971 and responsible for the creation of the National Cancer Institute.
Arthur I. Holleb, MD, ACS senior vice president for medical affairs and research, announced that, “[T]he time has come for the American Cancer Society to mount a massive program on mammography just as we did with the Pap test,”2 according to Barron Lerner, MD, whose book “The Breast Cancer Wars” provides a history of the long-term controversies involved.4
The Pap test, widely promulgated in the 1950s and 1960s, had produced a decline in mortality from cervical cancer.
Regardless of the lack of data on effectiveness at earlier ages, the ACS chose to include women as young as 35 in the BCDDP in order “to inculcate them with ‘good health habits’ ” and “to make our screenee want to return periodically and to want to act as a missionary to bring other women into the screening process.”2
Celebrity status matters
All of the elements of a social revolution in the use of mammography were in place in the late 1960s, but the final triggers to raise social consciousness were the cases of several high-profile female celebrities. In 1973, beloved former child star Shirley Temple Black revealed her breast cancer diagnosis and mastectomy in an era when public discussion of cancer – especially breast cancer – was rare.4
But it wasn’t until 1974 that public awareness and media coverage exploded, sparked by the impact of First Lady Betty Ford’s outspokenness on her own experience of breast cancer. “In obituaries prior to the 1950s and 1960s, women who died from breast cancer were often listed as dying from ‘a prolonged disease’ or ‘a woman’s disease,’ ” according to Tasha Dubriwny, PhD, now an associate professor of communication and women’s and gender studies at Texas A&M University, College Station, when interviewed by the American Association for Cancer Research.5Betty Ford openly addressed her breast cancer diagnosis and treatment and became a prominent advocate for early screening, transforming the landscape of breast cancer awareness. And although Betty Ford’s diagnosis was based on clinical examination rather than mammography, its boost to overall screening was indisputable.
“Within weeks [after Betty Ford’s announcement] thousands of women who had been reluctant to examine their breasts inundated cancer screening centers,” according to a 1987 article in the New York Times.6 Among these women was Happy Rockefeller, the wife of Vice President Nelson A. Rockefeller. Happy Rockefeller also found that she had breast cancer upon screening, and with Betty Ford would become another icon thereafter for breast cancer screening.
“Ford’s lesson for other women was straightforward: Get a mammogram, which she had not done. The American Cancer Society and National Cancer Institute had recently mounted a demonstration project to promote the detection of breast cancer as early as possible, when it was presumed to be more curable. The degree to which women embraced Ford’s message became clear through the famous ‘Betty Ford blip.’ So many women got breast examinations and mammograms for the first time after Ford’s announcement that the actual incidence of breast cancer in the United States went up by 15 percent.”4
In a 1975 address to the American Cancer Society, Betty Ford said: “One day I appeared to be fine and the next day I was in the hospital for a mastectomy. It made me realize how many women in the country could be in the same situation. That realization made me decide to discuss my breast cancer operation openly, because I thought of all the lives in jeopardy. My experience and frank discussion of breast cancer did prompt many women to learn about self-examination, regular checkups, and such detection techniques as mammography. These are so important. I just cannot stress enough how necessary it is for women to take an active interest in their own health and body.”7
ACS guidelines evolve
It wasn’t until 1976 that the ACS issued its first major guidelines for mammography screening. The ACS suggested mammograms may be called for in women aged 35-39 if there was a personal history of breast cancer, and between ages 40 and 49 if their mother or sisters had a history of breast cancer. Women aged 50 years and older could have yearly screening. Thereafter, the use of mammography was encouraged more and more with each new set of recommendations.8
Between 1980 and 1982, these guidelines expanded to advising a baseline mammogram for women aged 35-39 years; that women consult with their physician between ages 40 and 49; and that women over 50 have a yearly mammogram.
Between 1983 and 1991, the recommendations were for a baseline mammogram for women aged 35-39 years; a mammogram every 1-2 years for women aged 40-49; and yearly mammograms for women aged 50 and up. The baseline mammogram recommendation was dropped in 1992.
Between 1997 and 2015, the stakes were upped, and women aged 40-49 years were now recommended to have yearly mammograms, as were still all women aged 50 years and older.
In October 2015, the ACS changed their recommendation to say that women aged 40-44 years should have the choice of initiating mammogram screening, and that the risks and benefits of doing so should be discussed with their physicians. Women aged 45 years and older were still recommended for yearly mammogram screening. That recommendation stands today.
Controversies arise over risk/benefit
The technology was not, however, universally embraced. “By the late 1970s, mammography had diffused much more widely but had become a source of tremendous controversy. On the one hand, advocates of the technology enthusiastically touted its ability to detect smaller, more curable cancers. On the other hand, critics asked whether breast x-rays, particularly for women aged 50 and younger, actually caused more harm than benefit.”2
In addition, meta-analyses of the nine major screening trials conducted between 1965 and 1991 indicated that the reduced breast cancer mortality with screening was dependent on age. In particular, the results for women aged 40-49 years and 50-59 years showed only borderline statistical significance, and they varied depending on how cases were accrued in individual trials.
“Assuming that differences actually exist, the absolute breast cancer mortality reduction per 10,000 women screened for 10 years ranged from 3 for age 39-49 years; 5-8 for age 50-59 years; and 12-21 for age 60=69 years,” according to a review by the U.S. Preventive Services Task Force.9
The estimates for the group aged 70-74 years were limited by low numbers of events in trials that had smaller numbers of women in this age group.
Age has continued to be a major factor in determining the cost/benefit of routine mammography screening, with the American College of Physicians stating in its 2019 guidelines, “The potential harms outweigh the benefits in most women aged 40 to 49 years,” and adding, “In average-risk women aged 75 years or older or in women with a life expectancy of 10 years or less, clinicians should discontinue screening for breast cancer.”10
A Cochrane Report from 2013 was equally critical: “If we assume that screening reduces breast cancer mortality by 15% after 13 years of follow-up and that overdiagnosis and overtreatment is at 30%, it means that for every 2,000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings.”11
Conflicting voices exist
These reports advising a more nuanced evaluation of the benefits of mammography, however, were received with skepticism from doctors committed to the vision of breast cancer screening and convinced by anecdotal evidence in their own practices.
These reports were also in direct contradiction to recommendations made in 1997 by the National Cancer Institute, which recommended screening mammograms every 3 years for women aged 40-49 years at average risk of breast cancer.
Such scientific vacillation has contributed to a love/hate relationship with mammography in the mainstream media, fueling new controversies with regard to breast cancer screening, sometimes as much driven by public suspicion and political advocacy as by scientific evolution.
Vocal opponents of universal mammography screening arose throughout the years, and even the cases of Betty Ford and Happy Rockefeller have been called into question as iconic demonstrations of the effectiveness of screening. And although not directly linked to the issue of screening, the rebellion against the routine use of radical mastectomies, a technique pioneered by Halsted in 1894 and in continuing use into the modern era, sparked outrage in women’s rights activists who saw it as evidence of a patriarchal medical establishment making arbitrary decisions concerning women’s bodies. For example, feminist and breast cancer activist Rose Kushner argued against the unnecessary disfigurement of women’s bodies and urged the use and development of less drastic techniques, including partial mastectomies and lumpectomies as viable choices. And these choices were increasingly supported by the medical community as safe and effective alternatives for many patients.12
A 2015 paper in the Journal of the Royal Society of Medicine was bluntly titled “Mammography screening is harmful and should be abandoned.”13 According to the author, who was the editor of the 2013 Cochrane Report, “I believe that if screening had been a drug, it would have been withdrawn from the market long ago.” And the popular press has not been shy at weighing in on the controversy, driven, in part, by the lack of consensus and continually changing guidelines, with major publications such as U.S. News and World Report, the Washington Post, and others addressing the issue over the years. And even public advocacy groups such as the Susan G. Komen organization14 are supporting the more modern professional guidelines in taking a more nuanced approach to the discussion of risks and benefits for individual women.
In 2014, the Swiss Medical Board, a nationally appointed body, recommended that new mammography screening programs should not be instituted in that country and that limits be placed on current programs because of the imbalance between risks and benefits of mammography screening.15 And a study done in Australia in 2020 agreed, stating, “Using data of 30% overdiagnosis of women aged 50 to 69 years in the NSW [New South Wales] BreastScreen program in 2012, we calculated an Australian ratio of harm of overdiagnosis to benefit (breast cancer deaths avoided) of 15:1 and recommended stopping the invitation to screening.”16
Conclusion
If nothing else, the history of mammography shows that the interconnection of social factors with the rise of a medical technology can have profound impacts on patient care. Technology developed by men for women became a touchstone of resentment in a world ever more aware of sex and gender biases in everything from the conduct of clinical trials to the care (or lack thereof) of women with heart disease. Tied for so many years to a radically disfiguring and drastic form of surgery that affected what many felt to be a hallmark and representation of womanhood1,17 mammography also carried the weight of both the real and imaginary fears of radiation exposure.
Well into its development, the technology still found itself under intense public scrutiny, and was enmeshed in a continual media circus, with ping-ponging discussions of risk/benefit in the scientific literature fueling complaints by many of the dominance of a patriarchal medical community over women’s bodies.
With guidelines for mammography still evolving, questions still remaining, and new technologies such as digital imaging falling short in their hoped-for promise, the story remains unfinished, and the future still uncertain. One thing remains clear, however: In the right circumstances, with the right patient population, and properly executed, mammography has saved lives when tied to effective, early treatment, whatever its flaws and failings. This truth goes hand in hand with another reality: It may have also contributed to considerable unanticipated harm through overdiagnosis and overtreatment.
Overall, the history of mammography is a cautionary tale for the entire medical community and for the development of new medical technologies. The push-pull of the demand for progress to save lives and the slowness and often inconclusiveness of scientific studies that validate new technologies create gray areas, where social determinants and professional interests vie in an information vacuum for control of the narrative of risks vs. benefits.
The story of mammography is not yet concluded, and may never be, especially given the unlikelihood of conducting the massive randomized clinical trials that would be needed to settle the issue. It is more likely to remain controversial, at least until the technology of mammography becomes obsolete, replaced by something new and different, which will likely start the push-pull cycle all over again.
And regardless of the risks and benefits of mammography screening, the issue of treatment once breast cancer is identified is perhaps one of more overwhelming import.
References
1. Berry, DA. The Breast. 2013;22[Supplement 2]:S73-S76.
2. Lerner, BH. “To See Today With the Eyes of Tomorrow: A History of Screening Mammography.” Background paper for the Institute of Medicine report Mammography and Beyond: Developing Technologies for the Early Detection of Breast Cancer. 2001.
3. NCI website. The National Cancer Act of 1971. www.cancer.gov/about-nci/overview/history/national-cancer-act-1971.
4. Lerner BH. The Huffington Post, Sep. 26, 2014.
5. Wu C. Cancer Today. 2012;2(3): Sep. 27.
6. “”The New York Times. Oct. 17, 1987.
7. Ford B. Remarks to the American Cancer Society. 1975.
8. The American Cancer Society website. History of ACS Recommendations for the Early Detection of Cancer in People Without Symptoms.
9. Nelson HD et al. Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. 2016; Evidence Syntheses, No. 124; pp.29-49.
10. Qasseem A et al. Annals of Internal Medicine. 2019;170(8):547-60.
11. Gotzsche PC et al. Cochrane Report 2013.
12. Lerner, BH. West J Med. May 2001;174(5):362-5.
13. Gotzsche PC. J R Soc Med. 2015;108(9): 341-5.
14. Susan G. Komen website. Weighing the Benefits and Risks of Mammography.
15. Biller-Andorno N et al. N Engl J Med 2014;370:1965-7.
16. Burton R et al. JAMA Netw Open. 2020;3(6):e208249.
17. Webb C et al. Plast Surg. 2019;27(1):49-53.
Mark Lesney is the editor of Hematology News and the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has worked as a writer/editor for the American Chemical Society, and has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.
The push and pull of social forces
The push and pull of social forces
Science and technology emerge from and are shaped by social forces outside the laboratory and clinic. This is an essential fact of most new medical technology. In the Chronicles of Cancer series, part 1 of the story of mammography focused on the technological determinants of its development and use. Part 2 will focus on some of the social forces that shaped the development of mammography.
“Few medical issues have been as controversial – or as political, at least in the United States – as the role of mammographic screening for breast cancer,” according to Donald A. Berry, PhD, a biostatistician at the University of Texas MD Anderson Cancer Center, Houston.1
In fact, technology aside, the history of mammography has been and remains rife with controversy on the one side and vigorous promotion on the other, all enmeshed within the War on Cancer, corporate and professional interests, and the women’s rights movement’s growing issues with what was seen as a patriarchal medical establishment.
Today the issue of conflicts of interest are paramount in any discussion of new medical developments, from the early preclinical stages to ultimate deployment. Then, as now, professional and advocacy societies had a profound influence on government and social decision-making, but in that earlier, more trusting era, buoyed by the amazing changes that technology was bringing to everyday life and an unshakable commitment to and belief in “progress,” science and the medical community held a far more effective sway over the beliefs and behavior of the general population.
Women’s health observed
Although the main focus of the women’s movement with regard to breast cancer was a struggle against the common practice of routine radical mastectomies and a push toward breast-conserving surgeries, the issue of preventive care and screening with regard to women’s health was also a major concern.
Regarding mammography, early enthusiasm in the medical community and among the general public was profound. In 1969, Robert Egan described how mammography had a “certain magic appeal.” The patient, he continued, “feels something special is being done for her.” Women whose cancers had been discovered on a mammogram praised radiologists as heroes who had saved their lives.2
In that era, however, beyond the confines of the doctor’s office, mammography and breast cancer remained topics not discussed among the public at large, despite efforts by the American Cancer Society to change this.
ACS weighs in
Various groups had been promoting the benefits of breast self-examination since the 1930s, and in 1947, the American Cancer Society launched an awareness campaign, “Look for a Lump or Thickening in the Breast,” instructing women to perform a monthly breast self-exam. Between self-examination and clinical breast examinations in physicians’ offices, the ACS believed that smaller and more treatable breast cancers could be discovered.
In 1972, the ACS, working with the National Cancer Institute (NCI), inaugurated the Breast Cancer Detection Demonstration Project (BCDDP), which planned to screen over a quarter of a million American women for breast cancer. The initiative was a direct outgrowth of the National Cancer Act of 1971,3 the key legislation of the War on Cancer, promoted by President Richard Nixon in his State of the Union address in 1971 and responsible for the creation of the National Cancer Institute.
Arthur I. Holleb, MD, ACS senior vice president for medical affairs and research, announced that, “[T]he time has come for the American Cancer Society to mount a massive program on mammography just as we did with the Pap test,”2 according to Barron Lerner, MD, whose book “The Breast Cancer Wars” provides a history of the long-term controversies involved.4
The Pap test, widely promulgated in the 1950s and 1960s, had produced a decline in mortality from cervical cancer.
Regardless of the lack of data on effectiveness at earlier ages, the ACS chose to include women as young as 35 in the BCDDP in order “to inculcate them with ‘good health habits’ ” and “to make our screenee want to return periodically and to want to act as a missionary to bring other women into the screening process.”2
Celebrity status matters
All of the elements of a social revolution in the use of mammography were in place in the late 1960s, but the final triggers to raise social consciousness were the cases of several high-profile female celebrities. In 1973, beloved former child star Shirley Temple Black revealed her breast cancer diagnosis and mastectomy in an era when public discussion of cancer – especially breast cancer – was rare.4
But it wasn’t until 1974 that public awareness and media coverage exploded, sparked by the impact of First Lady Betty Ford’s outspokenness on her own experience of breast cancer. “In obituaries prior to the 1950s and 1960s, women who died from breast cancer were often listed as dying from ‘a prolonged disease’ or ‘a woman’s disease,’ ” according to Tasha Dubriwny, PhD, now an associate professor of communication and women’s and gender studies at Texas A&M University, College Station, when interviewed by the American Association for Cancer Research.5Betty Ford openly addressed her breast cancer diagnosis and treatment and became a prominent advocate for early screening, transforming the landscape of breast cancer awareness. And although Betty Ford’s diagnosis was based on clinical examination rather than mammography, its boost to overall screening was indisputable.
“Within weeks [after Betty Ford’s announcement] thousands of women who had been reluctant to examine their breasts inundated cancer screening centers,” according to a 1987 article in the New York Times.6 Among these women was Happy Rockefeller, the wife of Vice President Nelson A. Rockefeller. Happy Rockefeller also found that she had breast cancer upon screening, and with Betty Ford would become another icon thereafter for breast cancer screening.
“Ford’s lesson for other women was straightforward: Get a mammogram, which she had not done. The American Cancer Society and National Cancer Institute had recently mounted a demonstration project to promote the detection of breast cancer as early as possible, when it was presumed to be more curable. The degree to which women embraced Ford’s message became clear through the famous ‘Betty Ford blip.’ So many women got breast examinations and mammograms for the first time after Ford’s announcement that the actual incidence of breast cancer in the United States went up by 15 percent.”4
In a 1975 address to the American Cancer Society, Betty Ford said: “One day I appeared to be fine and the next day I was in the hospital for a mastectomy. It made me realize how many women in the country could be in the same situation. That realization made me decide to discuss my breast cancer operation openly, because I thought of all the lives in jeopardy. My experience and frank discussion of breast cancer did prompt many women to learn about self-examination, regular checkups, and such detection techniques as mammography. These are so important. I just cannot stress enough how necessary it is for women to take an active interest in their own health and body.”7
ACS guidelines evolve
It wasn’t until 1976 that the ACS issued its first major guidelines for mammography screening. The ACS suggested mammograms may be called for in women aged 35-39 if there was a personal history of breast cancer, and between ages 40 and 49 if their mother or sisters had a history of breast cancer. Women aged 50 years and older could have yearly screening. Thereafter, the use of mammography was encouraged more and more with each new set of recommendations.8
Between 1980 and 1982, these guidelines expanded to advising a baseline mammogram for women aged 35-39 years; that women consult with their physician between ages 40 and 49; and that women over 50 have a yearly mammogram.
Between 1983 and 1991, the recommendations were for a baseline mammogram for women aged 35-39 years; a mammogram every 1-2 years for women aged 40-49; and yearly mammograms for women aged 50 and up. The baseline mammogram recommendation was dropped in 1992.
Between 1997 and 2015, the stakes were upped, and women aged 40-49 years were now recommended to have yearly mammograms, as were still all women aged 50 years and older.
In October 2015, the ACS changed their recommendation to say that women aged 40-44 years should have the choice of initiating mammogram screening, and that the risks and benefits of doing so should be discussed with their physicians. Women aged 45 years and older were still recommended for yearly mammogram screening. That recommendation stands today.
Controversies arise over risk/benefit
The technology was not, however, universally embraced. “By the late 1970s, mammography had diffused much more widely but had become a source of tremendous controversy. On the one hand, advocates of the technology enthusiastically touted its ability to detect smaller, more curable cancers. On the other hand, critics asked whether breast x-rays, particularly for women aged 50 and younger, actually caused more harm than benefit.”2
In addition, meta-analyses of the nine major screening trials conducted between 1965 and 1991 indicated that the reduced breast cancer mortality with screening was dependent on age. In particular, the results for women aged 40-49 years and 50-59 years showed only borderline statistical significance, and they varied depending on how cases were accrued in individual trials.
“Assuming that differences actually exist, the absolute breast cancer mortality reduction per 10,000 women screened for 10 years ranged from 3 for age 39-49 years; 5-8 for age 50-59 years; and 12-21 for age 60=69 years,” according to a review by the U.S. Preventive Services Task Force.9
The estimates for the group aged 70-74 years were limited by low numbers of events in trials that had smaller numbers of women in this age group.
Age has continued to be a major factor in determining the cost/benefit of routine mammography screening, with the American College of Physicians stating in its 2019 guidelines, “The potential harms outweigh the benefits in most women aged 40 to 49 years,” and adding, “In average-risk women aged 75 years or older or in women with a life expectancy of 10 years or less, clinicians should discontinue screening for breast cancer.”10
A Cochrane Report from 2013 was equally critical: “If we assume that screening reduces breast cancer mortality by 15% after 13 years of follow-up and that overdiagnosis and overtreatment is at 30%, it means that for every 2,000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings.”11
Conflicting voices exist
These reports advising a more nuanced evaluation of the benefits of mammography, however, were received with skepticism from doctors committed to the vision of breast cancer screening and convinced by anecdotal evidence in their own practices.
These reports were also in direct contradiction to recommendations made in 1997 by the National Cancer Institute, which recommended screening mammograms every 3 years for women aged 40-49 years at average risk of breast cancer.
Such scientific vacillation has contributed to a love/hate relationship with mammography in the mainstream media, fueling new controversies with regard to breast cancer screening, sometimes as much driven by public suspicion and political advocacy as by scientific evolution.
Vocal opponents of universal mammography screening arose throughout the years, and even the cases of Betty Ford and Happy Rockefeller have been called into question as iconic demonstrations of the effectiveness of screening. And although not directly linked to the issue of screening, the rebellion against the routine use of radical mastectomies, a technique pioneered by Halsted in 1894 and in continuing use into the modern era, sparked outrage in women’s rights activists who saw it as evidence of a patriarchal medical establishment making arbitrary decisions concerning women’s bodies. For example, feminist and breast cancer activist Rose Kushner argued against the unnecessary disfigurement of women’s bodies and urged the use and development of less drastic techniques, including partial mastectomies and lumpectomies as viable choices. And these choices were increasingly supported by the medical community as safe and effective alternatives for many patients.12
A 2015 paper in the Journal of the Royal Society of Medicine was bluntly titled “Mammography screening is harmful and should be abandoned.”13 According to the author, who was the editor of the 2013 Cochrane Report, “I believe that if screening had been a drug, it would have been withdrawn from the market long ago.” And the popular press has not been shy at weighing in on the controversy, driven, in part, by the lack of consensus and continually changing guidelines, with major publications such as U.S. News and World Report, the Washington Post, and others addressing the issue over the years. And even public advocacy groups such as the Susan G. Komen organization14 are supporting the more modern professional guidelines in taking a more nuanced approach to the discussion of risks and benefits for individual women.
In 2014, the Swiss Medical Board, a nationally appointed body, recommended that new mammography screening programs should not be instituted in that country and that limits be placed on current programs because of the imbalance between risks and benefits of mammography screening.15 And a study done in Australia in 2020 agreed, stating, “Using data of 30% overdiagnosis of women aged 50 to 69 years in the NSW [New South Wales] BreastScreen program in 2012, we calculated an Australian ratio of harm of overdiagnosis to benefit (breast cancer deaths avoided) of 15:1 and recommended stopping the invitation to screening.”16
Conclusion
If nothing else, the history of mammography shows that the interconnection of social factors with the rise of a medical technology can have profound impacts on patient care. Technology developed by men for women became a touchstone of resentment in a world ever more aware of sex and gender biases in everything from the conduct of clinical trials to the care (or lack thereof) of women with heart disease. Tied for so many years to a radically disfiguring and drastic form of surgery that affected what many felt to be a hallmark and representation of womanhood1,17 mammography also carried the weight of both the real and imaginary fears of radiation exposure.
Well into its development, the technology still found itself under intense public scrutiny, and was enmeshed in a continual media circus, with ping-ponging discussions of risk/benefit in the scientific literature fueling complaints by many of the dominance of a patriarchal medical community over women’s bodies.
With guidelines for mammography still evolving, questions still remaining, and new technologies such as digital imaging falling short in their hoped-for promise, the story remains unfinished, and the future still uncertain. One thing remains clear, however: In the right circumstances, with the right patient population, and properly executed, mammography has saved lives when tied to effective, early treatment, whatever its flaws and failings. This truth goes hand in hand with another reality: It may have also contributed to considerable unanticipated harm through overdiagnosis and overtreatment.
Overall, the history of mammography is a cautionary tale for the entire medical community and for the development of new medical technologies. The push-pull of the demand for progress to save lives and the slowness and often inconclusiveness of scientific studies that validate new technologies create gray areas, where social determinants and professional interests vie in an information vacuum for control of the narrative of risks vs. benefits.
The story of mammography is not yet concluded, and may never be, especially given the unlikelihood of conducting the massive randomized clinical trials that would be needed to settle the issue. It is more likely to remain controversial, at least until the technology of mammography becomes obsolete, replaced by something new and different, which will likely start the push-pull cycle all over again.
And regardless of the risks and benefits of mammography screening, the issue of treatment once breast cancer is identified is perhaps one of more overwhelming import.
References
1. Berry, DA. The Breast. 2013;22[Supplement 2]:S73-S76.
2. Lerner, BH. “To See Today With the Eyes of Tomorrow: A History of Screening Mammography.” Background paper for the Institute of Medicine report Mammography and Beyond: Developing Technologies for the Early Detection of Breast Cancer. 2001.
3. NCI website. The National Cancer Act of 1971. www.cancer.gov/about-nci/overview/history/national-cancer-act-1971.
4. Lerner BH. The Huffington Post, Sep. 26, 2014.
5. Wu C. Cancer Today. 2012;2(3): Sep. 27.
6. “”The New York Times. Oct. 17, 1987.
7. Ford B. Remarks to the American Cancer Society. 1975.
8. The American Cancer Society website. History of ACS Recommendations for the Early Detection of Cancer in People Without Symptoms.
9. Nelson HD et al. Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. 2016; Evidence Syntheses, No. 124; pp.29-49.
10. Qasseem A et al. Annals of Internal Medicine. 2019;170(8):547-60.
11. Gotzsche PC et al. Cochrane Report 2013.
12. Lerner, BH. West J Med. May 2001;174(5):362-5.
13. Gotzsche PC. J R Soc Med. 2015;108(9): 341-5.
14. Susan G. Komen website. Weighing the Benefits and Risks of Mammography.
15. Biller-Andorno N et al. N Engl J Med 2014;370:1965-7.
16. Burton R et al. JAMA Netw Open. 2020;3(6):e208249.
17. Webb C et al. Plast Surg. 2019;27(1):49-53.
Mark Lesney is the editor of Hematology News and the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has worked as a writer/editor for the American Chemical Society, and has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.
Science and technology emerge from and are shaped by social forces outside the laboratory and clinic. This is an essential fact of most new medical technology. In the Chronicles of Cancer series, part 1 of the story of mammography focused on the technological determinants of its development and use. Part 2 will focus on some of the social forces that shaped the development of mammography.
“Few medical issues have been as controversial – or as political, at least in the United States – as the role of mammographic screening for breast cancer,” according to Donald A. Berry, PhD, a biostatistician at the University of Texas MD Anderson Cancer Center, Houston.1
In fact, technology aside, the history of mammography has been and remains rife with controversy on the one side and vigorous promotion on the other, all enmeshed within the War on Cancer, corporate and professional interests, and the women’s rights movement’s growing issues with what was seen as a patriarchal medical establishment.
Today the issue of conflicts of interest are paramount in any discussion of new medical developments, from the early preclinical stages to ultimate deployment. Then, as now, professional and advocacy societies had a profound influence on government and social decision-making, but in that earlier, more trusting era, buoyed by the amazing changes that technology was bringing to everyday life and an unshakable commitment to and belief in “progress,” science and the medical community held a far more effective sway over the beliefs and behavior of the general population.
Women’s health observed
Although the main focus of the women’s movement with regard to breast cancer was a struggle against the common practice of routine radical mastectomies and a push toward breast-conserving surgeries, the issue of preventive care and screening with regard to women’s health was also a major concern.
Regarding mammography, early enthusiasm in the medical community and among the general public was profound. In 1969, Robert Egan described how mammography had a “certain magic appeal.” The patient, he continued, “feels something special is being done for her.” Women whose cancers had been discovered on a mammogram praised radiologists as heroes who had saved their lives.2
In that era, however, beyond the confines of the doctor’s office, mammography and breast cancer remained topics not discussed among the public at large, despite efforts by the American Cancer Society to change this.
ACS weighs in
Various groups had been promoting the benefits of breast self-examination since the 1930s, and in 1947, the American Cancer Society launched an awareness campaign, “Look for a Lump or Thickening in the Breast,” instructing women to perform a monthly breast self-exam. Between self-examination and clinical breast examinations in physicians’ offices, the ACS believed that smaller and more treatable breast cancers could be discovered.
In 1972, the ACS, working with the National Cancer Institute (NCI), inaugurated the Breast Cancer Detection Demonstration Project (BCDDP), which planned to screen over a quarter of a million American women for breast cancer. The initiative was a direct outgrowth of the National Cancer Act of 1971,3 the key legislation of the War on Cancer, promoted by President Richard Nixon in his State of the Union address in 1971 and responsible for the creation of the National Cancer Institute.
Arthur I. Holleb, MD, ACS senior vice president for medical affairs and research, announced that, “[T]he time has come for the American Cancer Society to mount a massive program on mammography just as we did with the Pap test,”2 according to Barron Lerner, MD, whose book “The Breast Cancer Wars” provides a history of the long-term controversies involved.4
The Pap test, widely promulgated in the 1950s and 1960s, had produced a decline in mortality from cervical cancer.
Regardless of the lack of data on effectiveness at earlier ages, the ACS chose to include women as young as 35 in the BCDDP in order “to inculcate them with ‘good health habits’ ” and “to make our screenee want to return periodically and to want to act as a missionary to bring other women into the screening process.”2
Celebrity status matters
All of the elements of a social revolution in the use of mammography were in place in the late 1960s, but the final triggers to raise social consciousness were the cases of several high-profile female celebrities. In 1973, beloved former child star Shirley Temple Black revealed her breast cancer diagnosis and mastectomy in an era when public discussion of cancer – especially breast cancer – was rare.4
But it wasn’t until 1974 that public awareness and media coverage exploded, sparked by the impact of First Lady Betty Ford’s outspokenness on her own experience of breast cancer. “In obituaries prior to the 1950s and 1960s, women who died from breast cancer were often listed as dying from ‘a prolonged disease’ or ‘a woman’s disease,’ ” according to Tasha Dubriwny, PhD, now an associate professor of communication and women’s and gender studies at Texas A&M University, College Station, when interviewed by the American Association for Cancer Research.5Betty Ford openly addressed her breast cancer diagnosis and treatment and became a prominent advocate for early screening, transforming the landscape of breast cancer awareness. And although Betty Ford’s diagnosis was based on clinical examination rather than mammography, its boost to overall screening was indisputable.
“Within weeks [after Betty Ford’s announcement] thousands of women who had been reluctant to examine their breasts inundated cancer screening centers,” according to a 1987 article in the New York Times.6 Among these women was Happy Rockefeller, the wife of Vice President Nelson A. Rockefeller. Happy Rockefeller also found that she had breast cancer upon screening, and with Betty Ford would become another icon thereafter for breast cancer screening.
“Ford’s lesson for other women was straightforward: Get a mammogram, which she had not done. The American Cancer Society and National Cancer Institute had recently mounted a demonstration project to promote the detection of breast cancer as early as possible, when it was presumed to be more curable. The degree to which women embraced Ford’s message became clear through the famous ‘Betty Ford blip.’ So many women got breast examinations and mammograms for the first time after Ford’s announcement that the actual incidence of breast cancer in the United States went up by 15 percent.”4
In a 1975 address to the American Cancer Society, Betty Ford said: “One day I appeared to be fine and the next day I was in the hospital for a mastectomy. It made me realize how many women in the country could be in the same situation. That realization made me decide to discuss my breast cancer operation openly, because I thought of all the lives in jeopardy. My experience and frank discussion of breast cancer did prompt many women to learn about self-examination, regular checkups, and such detection techniques as mammography. These are so important. I just cannot stress enough how necessary it is for women to take an active interest in their own health and body.”7
ACS guidelines evolve
It wasn’t until 1976 that the ACS issued its first major guidelines for mammography screening. The ACS suggested mammograms may be called for in women aged 35-39 if there was a personal history of breast cancer, and between ages 40 and 49 if their mother or sisters had a history of breast cancer. Women aged 50 years and older could have yearly screening. Thereafter, the use of mammography was encouraged more and more with each new set of recommendations.8
Between 1980 and 1982, these guidelines expanded to advising a baseline mammogram for women aged 35-39 years; that women consult with their physician between ages 40 and 49; and that women over 50 have a yearly mammogram.
Between 1983 and 1991, the recommendations were for a baseline mammogram for women aged 35-39 years; a mammogram every 1-2 years for women aged 40-49; and yearly mammograms for women aged 50 and up. The baseline mammogram recommendation was dropped in 1992.
Between 1997 and 2015, the stakes were upped, and women aged 40-49 years were now recommended to have yearly mammograms, as were still all women aged 50 years and older.
In October 2015, the ACS changed their recommendation to say that women aged 40-44 years should have the choice of initiating mammogram screening, and that the risks and benefits of doing so should be discussed with their physicians. Women aged 45 years and older were still recommended for yearly mammogram screening. That recommendation stands today.
Controversies arise over risk/benefit
The technology was not, however, universally embraced. “By the late 1970s, mammography had diffused much more widely but had become a source of tremendous controversy. On the one hand, advocates of the technology enthusiastically touted its ability to detect smaller, more curable cancers. On the other hand, critics asked whether breast x-rays, particularly for women aged 50 and younger, actually caused more harm than benefit.”2
In addition, meta-analyses of the nine major screening trials conducted between 1965 and 1991 indicated that the reduced breast cancer mortality with screening was dependent on age. In particular, the results for women aged 40-49 years and 50-59 years showed only borderline statistical significance, and they varied depending on how cases were accrued in individual trials.
“Assuming that differences actually exist, the absolute breast cancer mortality reduction per 10,000 women screened for 10 years ranged from 3 for age 39-49 years; 5-8 for age 50-59 years; and 12-21 for age 60=69 years,” according to a review by the U.S. Preventive Services Task Force.9
The estimates for the group aged 70-74 years were limited by low numbers of events in trials that had smaller numbers of women in this age group.
Age has continued to be a major factor in determining the cost/benefit of routine mammography screening, with the American College of Physicians stating in its 2019 guidelines, “The potential harms outweigh the benefits in most women aged 40 to 49 years,” and adding, “In average-risk women aged 75 years or older or in women with a life expectancy of 10 years or less, clinicians should discontinue screening for breast cancer.”10
A Cochrane Report from 2013 was equally critical: “If we assume that screening reduces breast cancer mortality by 15% after 13 years of follow-up and that overdiagnosis and overtreatment is at 30%, it means that for every 2,000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings.”11
Conflicting voices exist
These reports advising a more nuanced evaluation of the benefits of mammography, however, were received with skepticism from doctors committed to the vision of breast cancer screening and convinced by anecdotal evidence in their own practices.
These reports were also in direct contradiction to recommendations made in 1997 by the National Cancer Institute, which recommended screening mammograms every 3 years for women aged 40-49 years at average risk of breast cancer.
Such scientific vacillation has contributed to a love/hate relationship with mammography in the mainstream media, fueling new controversies with regard to breast cancer screening, sometimes as much driven by public suspicion and political advocacy as by scientific evolution.
Vocal opponents of universal mammography screening arose throughout the years, and even the cases of Betty Ford and Happy Rockefeller have been called into question as iconic demonstrations of the effectiveness of screening. And although not directly linked to the issue of screening, the rebellion against the routine use of radical mastectomies, a technique pioneered by Halsted in 1894 and in continuing use into the modern era, sparked outrage in women’s rights activists who saw it as evidence of a patriarchal medical establishment making arbitrary decisions concerning women’s bodies. For example, feminist and breast cancer activist Rose Kushner argued against the unnecessary disfigurement of women’s bodies and urged the use and development of less drastic techniques, including partial mastectomies and lumpectomies as viable choices. And these choices were increasingly supported by the medical community as safe and effective alternatives for many patients.12
A 2015 paper in the Journal of the Royal Society of Medicine was bluntly titled “Mammography screening is harmful and should be abandoned.”13 According to the author, who was the editor of the 2013 Cochrane Report, “I believe that if screening had been a drug, it would have been withdrawn from the market long ago.” And the popular press has not been shy at weighing in on the controversy, driven, in part, by the lack of consensus and continually changing guidelines, with major publications such as U.S. News and World Report, the Washington Post, and others addressing the issue over the years. And even public advocacy groups such as the Susan G. Komen organization14 are supporting the more modern professional guidelines in taking a more nuanced approach to the discussion of risks and benefits for individual women.
In 2014, the Swiss Medical Board, a nationally appointed body, recommended that new mammography screening programs should not be instituted in that country and that limits be placed on current programs because of the imbalance between risks and benefits of mammography screening.15 And a study done in Australia in 2020 agreed, stating, “Using data of 30% overdiagnosis of women aged 50 to 69 years in the NSW [New South Wales] BreastScreen program in 2012, we calculated an Australian ratio of harm of overdiagnosis to benefit (breast cancer deaths avoided) of 15:1 and recommended stopping the invitation to screening.”16
Conclusion
If nothing else, the history of mammography shows that the interconnection of social factors with the rise of a medical technology can have profound impacts on patient care. Technology developed by men for women became a touchstone of resentment in a world ever more aware of sex and gender biases in everything from the conduct of clinical trials to the care (or lack thereof) of women with heart disease. Tied for so many years to a radically disfiguring and drastic form of surgery that affected what many felt to be a hallmark and representation of womanhood1,17 mammography also carried the weight of both the real and imaginary fears of radiation exposure.
Well into its development, the technology still found itself under intense public scrutiny, and was enmeshed in a continual media circus, with ping-ponging discussions of risk/benefit in the scientific literature fueling complaints by many of the dominance of a patriarchal medical community over women’s bodies.
With guidelines for mammography still evolving, questions still remaining, and new technologies such as digital imaging falling short in their hoped-for promise, the story remains unfinished, and the future still uncertain. One thing remains clear, however: In the right circumstances, with the right patient population, and properly executed, mammography has saved lives when tied to effective, early treatment, whatever its flaws and failings. This truth goes hand in hand with another reality: It may have also contributed to considerable unanticipated harm through overdiagnosis and overtreatment.
Overall, the history of mammography is a cautionary tale for the entire medical community and for the development of new medical technologies. The push-pull of the demand for progress to save lives and the slowness and often inconclusiveness of scientific studies that validate new technologies create gray areas, where social determinants and professional interests vie in an information vacuum for control of the narrative of risks vs. benefits.
The story of mammography is not yet concluded, and may never be, especially given the unlikelihood of conducting the massive randomized clinical trials that would be needed to settle the issue. It is more likely to remain controversial, at least until the technology of mammography becomes obsolete, replaced by something new and different, which will likely start the push-pull cycle all over again.
And regardless of the risks and benefits of mammography screening, the issue of treatment once breast cancer is identified is perhaps one of more overwhelming import.
References
1. Berry, DA. The Breast. 2013;22[Supplement 2]:S73-S76.
2. Lerner, BH. “To See Today With the Eyes of Tomorrow: A History of Screening Mammography.” Background paper for the Institute of Medicine report Mammography and Beyond: Developing Technologies for the Early Detection of Breast Cancer. 2001.
3. NCI website. The National Cancer Act of 1971. www.cancer.gov/about-nci/overview/history/national-cancer-act-1971.
4. Lerner BH. The Huffington Post, Sep. 26, 2014.
5. Wu C. Cancer Today. 2012;2(3): Sep. 27.
6. “”The New York Times. Oct. 17, 1987.
7. Ford B. Remarks to the American Cancer Society. 1975.
8. The American Cancer Society website. History of ACS Recommendations for the Early Detection of Cancer in People Without Symptoms.
9. Nelson HD et al. Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. 2016; Evidence Syntheses, No. 124; pp.29-49.
10. Qasseem A et al. Annals of Internal Medicine. 2019;170(8):547-60.
11. Gotzsche PC et al. Cochrane Report 2013.
12. Lerner, BH. West J Med. May 2001;174(5):362-5.
13. Gotzsche PC. J R Soc Med. 2015;108(9): 341-5.
14. Susan G. Komen website. Weighing the Benefits and Risks of Mammography.
15. Biller-Andorno N et al. N Engl J Med 2014;370:1965-7.
16. Burton R et al. JAMA Netw Open. 2020;3(6):e208249.
17. Webb C et al. Plast Surg. 2019;27(1):49-53.
Mark Lesney is the editor of Hematology News and the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has worked as a writer/editor for the American Chemical Society, and has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.