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Mental disorders in early life are associated with a significantly increased risk of dementia in later years.

Results of a large, longitudinal, population-based study show that individuals hospitalized for a mental health disorder had a fourfold increased relative risk (RR) for developing dementia, compared with those who were not hospitalized with a mental illness.

In addition, those with dementia plus a mental disorder developed dementia almost 6 years earlier than those without a mental illness.

The findings were consistent among men and women, in patients with early- and late-onset dementia, in those with Alzheimer’s and non-Alzheimer’s dementia, and across all mental health disorders – and remained so after accounting for pre-existing physical illness and socioeconomic factors.

“Dementia is not typically treated until later in life, but our study suggests that we need to be thinking about dementia prevention much earlier in the life course,” study investigator Leah Richmond-Rakerd, PhD, assistant professor, department of psychology, University of Michigan, said in an interview.

“Supporting young people’s mental health could be a window of opportunity to help reduce the burden of dementia in older adults,” she said.

The findings were published online Feb. 16.
 

Underappreciated risk factor

“Recognition of the outsized influence of dementia on later-life functioning has fueled research into modifiable risk factors and prevention targets,” the investigators write.

Previous research suggests mental disorders may “comprise an underappreciated category of modifiable risk factors.” However, those studies focused primarily on midlife and older individuals, not on capturing mental disorders during young adulthood, which is the time of “peak prevalence,” they add. In addition, most studies have not explored the full range of mental disorders.

Dr. Richmond-Rakerd noted that it is well known that mental health disorders peak in adolescence and young adulthood – and are treatable.

“If the same people who have mental disorders when they are young tend to develop dementia when they are older, that would mean that preventing mental health problems in younger people might reduce or delay the burden of dementia in older people,” she said.

The investigators assessed records from the New Zealand Integrated Data Infrastructure, which is a de-identified register that includes the entire New Zealand population. They also examined information about hospitalizations and diagnoses from records kept by the New Zealand Ministry of Health.

The researchers followed 1,711,386 individuals born between 1928 and 1967 (50.6% men, aged 21 to 60 years at baseline) for 30 years. The population was subdivided into age groups based on birth years: 1928-1937 (14.8%), 1938-1947 (20.85%), 1948-1957 (29.35%), and 1958-1967 (35.1%).
 

Earlier onset

During the study period, 3.8% of individuals were identified as having a mental disorder, and 2% were identified as having dementia. Similar percentages of men and women had a mental disorder, and similar percentages had dementia.

Dementia was “over-represented” among participants with versus without a mental disorder (6.1% vs. 1.8%). This finding held across all age groups.

Those diagnosed with a mental disorder were also more likely to develop dementia, compared with their peers without a mental disorder (RR, 3.51; 95% confidence interval, 3.39-3.64), which is a larger association than that between physical diseases and dementia (RR, 1.19; 95% CI, 1.16-1.21).

These associations were present in both sexes and in all age groups, although the associations were stronger in more recently born cohorts.

A sixfold higher risk for dementia remained even after adjusting for pre-existing physical illnesses (HR, 6.49; 95% CI, 6.25-6.73); and the elevated risk was evident across different lengths of follow-up from the index mental disorder.

When the researchers focused specifically on individuals diagnosed with dementia, they found that those diagnosed with a mental disorder developed dementia a mean of 5.60 years earlier than those without a mental disorder diagnosis – an association observed across both sexes and all age groups.

“Individuals diagnosed with psychotic, substance use, mood, neurotic, and all other mental disorders and who engaged in self-harm were all more likely than those without a mental disorder to be diagnosed with subsequent dementia, even after accounting for their physical disease histories,” the investigators write.

Although there was a link between mental disorders in both Alzheimer’s and non-Alzheimer’s dementias, the association was larger in non-Alzheimer’s.

The researchers note that the study has several limitations, including the fact that it was conducted in New Zealand and therefore the results may not be generalizable to other regions. In addition, inpatient hospital records do not capture less severe mental disorder cases treated in the outpatient setting.

Dr. Richmond-Rakerd suggested several potential mechanisms that could account for the link between mental illness and dementia, including poor lifestyle choices and metabolic side effects associated with some psychiatric medications.

“There could also be shared risk factors for both mental disorders and dementia, such as shared genetics, or individuals may experience a lifelong brain vulnerability that shows up as mental health problems earlier in life and shows up as dementia later in life,” she said.
 

An important risk factor

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness, said a major strength of the study was its longitudinal scope and large population size.

He described the study as allowing clinicians to “watch the movie,” as opposed to looking at a “snapshot” of data.

“Although you can learn things from snapshots, a large, comprehensive public health system looking at 30 years of claims – something not possible in the U.S. because of our more fragmented health care system – offers more insight,” said Dr. Duckworth, who was not involved with the research.

The investigators are “painting a picture of a correlation of risk, and to me, that’s the beginning of further inquiry,” he added. “Would preventive efforts targeting dementia, such as exercise and socialization, be helpful? It’s a great study that raises these interesting questions.”

Also commenting in an interview, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, said the study “adds a wealth of data to our understanding” of mental disorders as a dementia risk factor.

However, the study was observational, so “the findings cannot imply causation, [and just] because someone has depression, that does not mean they will go on to develop Alzheimer’s,” said Dr. Sexton, who also was not involved with the research.

Still, “these data support the idea that taking care of one’s mental health is incredibly important for overall wellbeing. For providers, it’s important to have mental health evaluation be a part of your patient’s regular checkups,” she added.

Dr. Richmond-Rakerd noted that even if mental health conditions are not a causal risk factor for dementia, “the presence of a mental health problem is still an important indicator of risk. Mental health providers may wish to target other risk factors for dementia that are more common in individuals with mental health conditions, such as social disconnection.”

The study was funded by grants from the National Institute on Aging, the U.K. Medical Research Council, the National Institute of Child Health and Development through the Duke Population Research Center, and the National Institute on Aging through the Center for Advancing Sociodemographic and Economic Study of Alzheimer’s Disease and Related Dementias. Dr. Richmond-Rakerd reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Sexton and Dr. Duckworth report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Mental disorders in early life are associated with a significantly increased risk of dementia in later years.

Results of a large, longitudinal, population-based study show that individuals hospitalized for a mental health disorder had a fourfold increased relative risk (RR) for developing dementia, compared with those who were not hospitalized with a mental illness.

In addition, those with dementia plus a mental disorder developed dementia almost 6 years earlier than those without a mental illness.

The findings were consistent among men and women, in patients with early- and late-onset dementia, in those with Alzheimer’s and non-Alzheimer’s dementia, and across all mental health disorders – and remained so after accounting for pre-existing physical illness and socioeconomic factors.

“Dementia is not typically treated until later in life, but our study suggests that we need to be thinking about dementia prevention much earlier in the life course,” study investigator Leah Richmond-Rakerd, PhD, assistant professor, department of psychology, University of Michigan, said in an interview.

“Supporting young people’s mental health could be a window of opportunity to help reduce the burden of dementia in older adults,” she said.

The findings were published online Feb. 16.
 

Underappreciated risk factor

“Recognition of the outsized influence of dementia on later-life functioning has fueled research into modifiable risk factors and prevention targets,” the investigators write.

Previous research suggests mental disorders may “comprise an underappreciated category of modifiable risk factors.” However, those studies focused primarily on midlife and older individuals, not on capturing mental disorders during young adulthood, which is the time of “peak prevalence,” they add. In addition, most studies have not explored the full range of mental disorders.

Dr. Richmond-Rakerd noted that it is well known that mental health disorders peak in adolescence and young adulthood – and are treatable.

“If the same people who have mental disorders when they are young tend to develop dementia when they are older, that would mean that preventing mental health problems in younger people might reduce or delay the burden of dementia in older people,” she said.

The investigators assessed records from the New Zealand Integrated Data Infrastructure, which is a de-identified register that includes the entire New Zealand population. They also examined information about hospitalizations and diagnoses from records kept by the New Zealand Ministry of Health.

The researchers followed 1,711,386 individuals born between 1928 and 1967 (50.6% men, aged 21 to 60 years at baseline) for 30 years. The population was subdivided into age groups based on birth years: 1928-1937 (14.8%), 1938-1947 (20.85%), 1948-1957 (29.35%), and 1958-1967 (35.1%).
 

Earlier onset

During the study period, 3.8% of individuals were identified as having a mental disorder, and 2% were identified as having dementia. Similar percentages of men and women had a mental disorder, and similar percentages had dementia.

Dementia was “over-represented” among participants with versus without a mental disorder (6.1% vs. 1.8%). This finding held across all age groups.

Those diagnosed with a mental disorder were also more likely to develop dementia, compared with their peers without a mental disorder (RR, 3.51; 95% confidence interval, 3.39-3.64), which is a larger association than that between physical diseases and dementia (RR, 1.19; 95% CI, 1.16-1.21).

These associations were present in both sexes and in all age groups, although the associations were stronger in more recently born cohorts.

A sixfold higher risk for dementia remained even after adjusting for pre-existing physical illnesses (HR, 6.49; 95% CI, 6.25-6.73); and the elevated risk was evident across different lengths of follow-up from the index mental disorder.

When the researchers focused specifically on individuals diagnosed with dementia, they found that those diagnosed with a mental disorder developed dementia a mean of 5.60 years earlier than those without a mental disorder diagnosis – an association observed across both sexes and all age groups.

“Individuals diagnosed with psychotic, substance use, mood, neurotic, and all other mental disorders and who engaged in self-harm were all more likely than those without a mental disorder to be diagnosed with subsequent dementia, even after accounting for their physical disease histories,” the investigators write.

Although there was a link between mental disorders in both Alzheimer’s and non-Alzheimer’s dementias, the association was larger in non-Alzheimer’s.

The researchers note that the study has several limitations, including the fact that it was conducted in New Zealand and therefore the results may not be generalizable to other regions. In addition, inpatient hospital records do not capture less severe mental disorder cases treated in the outpatient setting.

Dr. Richmond-Rakerd suggested several potential mechanisms that could account for the link between mental illness and dementia, including poor lifestyle choices and metabolic side effects associated with some psychiatric medications.

“There could also be shared risk factors for both mental disorders and dementia, such as shared genetics, or individuals may experience a lifelong brain vulnerability that shows up as mental health problems earlier in life and shows up as dementia later in life,” she said.
 

An important risk factor

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness, said a major strength of the study was its longitudinal scope and large population size.

He described the study as allowing clinicians to “watch the movie,” as opposed to looking at a “snapshot” of data.

“Although you can learn things from snapshots, a large, comprehensive public health system looking at 30 years of claims – something not possible in the U.S. because of our more fragmented health care system – offers more insight,” said Dr. Duckworth, who was not involved with the research.

The investigators are “painting a picture of a correlation of risk, and to me, that’s the beginning of further inquiry,” he added. “Would preventive efforts targeting dementia, such as exercise and socialization, be helpful? It’s a great study that raises these interesting questions.”

Also commenting in an interview, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, said the study “adds a wealth of data to our understanding” of mental disorders as a dementia risk factor.

However, the study was observational, so “the findings cannot imply causation, [and just] because someone has depression, that does not mean they will go on to develop Alzheimer’s,” said Dr. Sexton, who also was not involved with the research.

Still, “these data support the idea that taking care of one’s mental health is incredibly important for overall wellbeing. For providers, it’s important to have mental health evaluation be a part of your patient’s regular checkups,” she added.

Dr. Richmond-Rakerd noted that even if mental health conditions are not a causal risk factor for dementia, “the presence of a mental health problem is still an important indicator of risk. Mental health providers may wish to target other risk factors for dementia that are more common in individuals with mental health conditions, such as social disconnection.”

The study was funded by grants from the National Institute on Aging, the U.K. Medical Research Council, the National Institute of Child Health and Development through the Duke Population Research Center, and the National Institute on Aging through the Center for Advancing Sociodemographic and Economic Study of Alzheimer’s Disease and Related Dementias. Dr. Richmond-Rakerd reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Sexton and Dr. Duckworth report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Mental disorders in early life are associated with a significantly increased risk of dementia in later years.

Results of a large, longitudinal, population-based study show that individuals hospitalized for a mental health disorder had a fourfold increased relative risk (RR) for developing dementia, compared with those who were not hospitalized with a mental illness.

In addition, those with dementia plus a mental disorder developed dementia almost 6 years earlier than those without a mental illness.

The findings were consistent among men and women, in patients with early- and late-onset dementia, in those with Alzheimer’s and non-Alzheimer’s dementia, and across all mental health disorders – and remained so after accounting for pre-existing physical illness and socioeconomic factors.

“Dementia is not typically treated until later in life, but our study suggests that we need to be thinking about dementia prevention much earlier in the life course,” study investigator Leah Richmond-Rakerd, PhD, assistant professor, department of psychology, University of Michigan, said in an interview.

“Supporting young people’s mental health could be a window of opportunity to help reduce the burden of dementia in older adults,” she said.

The findings were published online Feb. 16.
 

Underappreciated risk factor

“Recognition of the outsized influence of dementia on later-life functioning has fueled research into modifiable risk factors and prevention targets,” the investigators write.

Previous research suggests mental disorders may “comprise an underappreciated category of modifiable risk factors.” However, those studies focused primarily on midlife and older individuals, not on capturing mental disorders during young adulthood, which is the time of “peak prevalence,” they add. In addition, most studies have not explored the full range of mental disorders.

Dr. Richmond-Rakerd noted that it is well known that mental health disorders peak in adolescence and young adulthood – and are treatable.

“If the same people who have mental disorders when they are young tend to develop dementia when they are older, that would mean that preventing mental health problems in younger people might reduce or delay the burden of dementia in older people,” she said.

The investigators assessed records from the New Zealand Integrated Data Infrastructure, which is a de-identified register that includes the entire New Zealand population. They also examined information about hospitalizations and diagnoses from records kept by the New Zealand Ministry of Health.

The researchers followed 1,711,386 individuals born between 1928 and 1967 (50.6% men, aged 21 to 60 years at baseline) for 30 years. The population was subdivided into age groups based on birth years: 1928-1937 (14.8%), 1938-1947 (20.85%), 1948-1957 (29.35%), and 1958-1967 (35.1%).
 

Earlier onset

During the study period, 3.8% of individuals were identified as having a mental disorder, and 2% were identified as having dementia. Similar percentages of men and women had a mental disorder, and similar percentages had dementia.

Dementia was “over-represented” among participants with versus without a mental disorder (6.1% vs. 1.8%). This finding held across all age groups.

Those diagnosed with a mental disorder were also more likely to develop dementia, compared with their peers without a mental disorder (RR, 3.51; 95% confidence interval, 3.39-3.64), which is a larger association than that between physical diseases and dementia (RR, 1.19; 95% CI, 1.16-1.21).

These associations were present in both sexes and in all age groups, although the associations were stronger in more recently born cohorts.

A sixfold higher risk for dementia remained even after adjusting for pre-existing physical illnesses (HR, 6.49; 95% CI, 6.25-6.73); and the elevated risk was evident across different lengths of follow-up from the index mental disorder.

When the researchers focused specifically on individuals diagnosed with dementia, they found that those diagnosed with a mental disorder developed dementia a mean of 5.60 years earlier than those without a mental disorder diagnosis – an association observed across both sexes and all age groups.

“Individuals diagnosed with psychotic, substance use, mood, neurotic, and all other mental disorders and who engaged in self-harm were all more likely than those without a mental disorder to be diagnosed with subsequent dementia, even after accounting for their physical disease histories,” the investigators write.

Although there was a link between mental disorders in both Alzheimer’s and non-Alzheimer’s dementias, the association was larger in non-Alzheimer’s.

The researchers note that the study has several limitations, including the fact that it was conducted in New Zealand and therefore the results may not be generalizable to other regions. In addition, inpatient hospital records do not capture less severe mental disorder cases treated in the outpatient setting.

Dr. Richmond-Rakerd suggested several potential mechanisms that could account for the link between mental illness and dementia, including poor lifestyle choices and metabolic side effects associated with some psychiatric medications.

“There could also be shared risk factors for both mental disorders and dementia, such as shared genetics, or individuals may experience a lifelong brain vulnerability that shows up as mental health problems earlier in life and shows up as dementia later in life,” she said.
 

An important risk factor

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness, said a major strength of the study was its longitudinal scope and large population size.

He described the study as allowing clinicians to “watch the movie,” as opposed to looking at a “snapshot” of data.

“Although you can learn things from snapshots, a large, comprehensive public health system looking at 30 years of claims – something not possible in the U.S. because of our more fragmented health care system – offers more insight,” said Dr. Duckworth, who was not involved with the research.

The investigators are “painting a picture of a correlation of risk, and to me, that’s the beginning of further inquiry,” he added. “Would preventive efforts targeting dementia, such as exercise and socialization, be helpful? It’s a great study that raises these interesting questions.”

Also commenting in an interview, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, said the study “adds a wealth of data to our understanding” of mental disorders as a dementia risk factor.

However, the study was observational, so “the findings cannot imply causation, [and just] because someone has depression, that does not mean they will go on to develop Alzheimer’s,” said Dr. Sexton, who also was not involved with the research.

Still, “these data support the idea that taking care of one’s mental health is incredibly important for overall wellbeing. For providers, it’s important to have mental health evaluation be a part of your patient’s regular checkups,” she added.

Dr. Richmond-Rakerd noted that even if mental health conditions are not a causal risk factor for dementia, “the presence of a mental health problem is still an important indicator of risk. Mental health providers may wish to target other risk factors for dementia that are more common in individuals with mental health conditions, such as social disconnection.”

The study was funded by grants from the National Institute on Aging, the U.K. Medical Research Council, the National Institute of Child Health and Development through the Duke Population Research Center, and the National Institute on Aging through the Center for Advancing Sociodemographic and Economic Study of Alzheimer’s Disease and Related Dementias. Dr. Richmond-Rakerd reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Sexton and Dr. Duckworth report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The U.S. Preventive Services Task Force (USPSTF) criteria for lung cancer screening should be expanded to include more women, especially those with a history of breast cancer, according to a new study published in BJS Open.

The 2021 screening guidelines include adults aged between 50 and 80 years who have a 20–pack-year smoking history and currently smoke or have quit within the past 15 years, but the guidelines do not include nonsmokers or patients with a history of previous malignancies, such as breast cancer.

Led by Daniela Molena, MD, a thoracic surgeon and director of esophageal surgery at Memorial Sloan Kettering Cancer Center, New York, researchers conducted an analysis of 2,192 women with first-time lung cancer who underwent lung resections at Memorial Sloan Kettering between January 2000 and December 2017. The study’s objective was to determine stage at diagnosis, survival, and eligibility for lung cancer screening among patients with lung cancer who had a previous breast cancer diagnosis and those who did not have a history of breast cancer.

Only 331 (15.1%) patients were previously diagnosed with breast cancer, which was not statistically significant. “Overall, there were no statistically significant differences in genomic or oncogenic pathway alterations between the two groups, which suggests that lung cancer in patients who previously had breast cancer may not be affected at the genomic level by the previous breast cancer,” the authors wrote.

However, at 58.4%, more than half of patients in the study (1,281 patients) were prior smokers and only 33.3% met the USPSTF criteria for lung cancer screening, which the authors said was concerning.

“The most important finding of the study was that a high percentage of women with lung cancer, regardless of breast cancer history, did not meet the current USPSTF criteria for lung cancer screening. This is very important given the observation that nearly half of the women included in the study did not have a history of smoking. As such, the role of imaging for other causes, such as cancer surveillance, becomes especially important for early cancer diagnosis,” Dr. Molena and colleagues wrote. “To reduce late-stage cancer diagnoses, further assessment of guidelines for lung cancer screening for all women may be needed.”

Instead, for almost half of women in the study group with a history of breast cancer, the lung cancer was detected on a routine follow-up imaging scan.

USPSTF guidelines for lung cancer screening do not include previous malignancy as a high-risk feature requiring evaluation, which may explain why so few women in this study were screened for lung cancer, even though lung cancer is more common in breast cancer survivors than the general population. Approximately 10% of women who have had breast cancer will develop a second malignancy within 10 years and in most cases, it will be lung cancer. Plus, according to the National Cancer Institute, breast, lung, and colorectal cancers are the three most common cancers in women and account for approximately 50% of all new cancer diagnoses in women in 2020.

A 2018 analysis published in Frontiers in Oncology found that, of more than 6,000 women with secondary primary lung cancer after having had breast cancer, 42% had distant-stage disease at the time of diagnosis which, Dr. Molena and colleagues said, suggests an ongoing need to update screening recommendations.

“Given that lung cancer has a 5-year overall survival rate of less than 20% (highlighting the benefits of early-stage diagnosis), a better understanding of lung cancer in women with a history of breast cancer could have important implications for screening and surveillance,” the authors wrote.

Estrogen is known to play a role in the development of lung cancer by activating the epidermal growth factor receptor (EGFR). Previous research has shown an increased risk of lung cancer in patients with estrogen receptor–negative, progesterone receptor–negative, HER2-negative, or triple-negative breast cancer.

“Antiestrogen treatment has been demonstrated to decrease the incidence of lung cancer and has been associated with improved long-term survival in patients with lung cancer after breast cancer. Future studies should seek to identify high-risk populations on the basis of hormone receptor status and antiestrogen therapy use,” the authors wrote.

The authors noted a number of limitations to the study, including the single hospital as the sole source of data, plus, the analysis did not account for the length of time since patients quit smoking and a lung cancer diagnosis. Nor did it consider other risk factors, such as radiation, chemotherapy, or antiestrogen therapies.

The authors did not disclose any study-related conflicts of interests.

This article was updated 3/2/22.

The U.S. Preventive Services Task Force (USPSTF) criteria for lung cancer screening should be expanded to include more women, especially those with a history of breast cancer, according to a new study published in BJS Open.

The 2021 screening guidelines include adults aged between 50 and 80 years who have a 20–pack-year smoking history and currently smoke or have quit within the past 15 years, but the guidelines do not include nonsmokers or patients with a history of previous malignancies, such as breast cancer.

Led by Daniela Molena, MD, a thoracic surgeon and director of esophageal surgery at Memorial Sloan Kettering Cancer Center, New York, researchers conducted an analysis of 2,192 women with first-time lung cancer who underwent lung resections at Memorial Sloan Kettering between January 2000 and December 2017. The study’s objective was to determine stage at diagnosis, survival, and eligibility for lung cancer screening among patients with lung cancer who had a previous breast cancer diagnosis and those who did not have a history of breast cancer.

Only 331 (15.1%) patients were previously diagnosed with breast cancer, which was not statistically significant. “Overall, there were no statistically significant differences in genomic or oncogenic pathway alterations between the two groups, which suggests that lung cancer in patients who previously had breast cancer may not be affected at the genomic level by the previous breast cancer,” the authors wrote.

However, at 58.4%, more than half of patients in the study (1,281 patients) were prior smokers and only 33.3% met the USPSTF criteria for lung cancer screening, which the authors said was concerning.

“The most important finding of the study was that a high percentage of women with lung cancer, regardless of breast cancer history, did not meet the current USPSTF criteria for lung cancer screening. This is very important given the observation that nearly half of the women included in the study did not have a history of smoking. As such, the role of imaging for other causes, such as cancer surveillance, becomes especially important for early cancer diagnosis,” Dr. Molena and colleagues wrote. “To reduce late-stage cancer diagnoses, further assessment of guidelines for lung cancer screening for all women may be needed.”

Instead, for almost half of women in the study group with a history of breast cancer, the lung cancer was detected on a routine follow-up imaging scan.

USPSTF guidelines for lung cancer screening do not include previous malignancy as a high-risk feature requiring evaluation, which may explain why so few women in this study were screened for lung cancer, even though lung cancer is more common in breast cancer survivors than the general population. Approximately 10% of women who have had breast cancer will develop a second malignancy within 10 years and in most cases, it will be lung cancer. Plus, according to the National Cancer Institute, breast, lung, and colorectal cancers are the three most common cancers in women and account for approximately 50% of all new cancer diagnoses in women in 2020.

A 2018 analysis published in Frontiers in Oncology found that, of more than 6,000 women with secondary primary lung cancer after having had breast cancer, 42% had distant-stage disease at the time of diagnosis which, Dr. Molena and colleagues said, suggests an ongoing need to update screening recommendations.

“Given that lung cancer has a 5-year overall survival rate of less than 20% (highlighting the benefits of early-stage diagnosis), a better understanding of lung cancer in women with a history of breast cancer could have important implications for screening and surveillance,” the authors wrote.

Estrogen is known to play a role in the development of lung cancer by activating the epidermal growth factor receptor (EGFR). Previous research has shown an increased risk of lung cancer in patients with estrogen receptor–negative, progesterone receptor–negative, HER2-negative, or triple-negative breast cancer.

“Antiestrogen treatment has been demonstrated to decrease the incidence of lung cancer and has been associated with improved long-term survival in patients with lung cancer after breast cancer. Future studies should seek to identify high-risk populations on the basis of hormone receptor status and antiestrogen therapy use,” the authors wrote.

The authors noted a number of limitations to the study, including the single hospital as the sole source of data, plus, the analysis did not account for the length of time since patients quit smoking and a lung cancer diagnosis. Nor did it consider other risk factors, such as radiation, chemotherapy, or antiestrogen therapies.

The authors did not disclose any study-related conflicts of interests.

This article was updated 3/2/22.

The U.S. Preventive Services Task Force (USPSTF) criteria for lung cancer screening should be expanded to include more women, especially those with a history of breast cancer, according to a new study published in BJS Open.

The 2021 screening guidelines include adults aged between 50 and 80 years who have a 20–pack-year smoking history and currently smoke or have quit within the past 15 years, but the guidelines do not include nonsmokers or patients with a history of previous malignancies, such as breast cancer.

Led by Daniela Molena, MD, a thoracic surgeon and director of esophageal surgery at Memorial Sloan Kettering Cancer Center, New York, researchers conducted an analysis of 2,192 women with first-time lung cancer who underwent lung resections at Memorial Sloan Kettering between January 2000 and December 2017. The study’s objective was to determine stage at diagnosis, survival, and eligibility for lung cancer screening among patients with lung cancer who had a previous breast cancer diagnosis and those who did not have a history of breast cancer.

Only 331 (15.1%) patients were previously diagnosed with breast cancer, which was not statistically significant. “Overall, there were no statistically significant differences in genomic or oncogenic pathway alterations between the two groups, which suggests that lung cancer in patients who previously had breast cancer may not be affected at the genomic level by the previous breast cancer,” the authors wrote.

However, at 58.4%, more than half of patients in the study (1,281 patients) were prior smokers and only 33.3% met the USPSTF criteria for lung cancer screening, which the authors said was concerning.

“The most important finding of the study was that a high percentage of women with lung cancer, regardless of breast cancer history, did not meet the current USPSTF criteria for lung cancer screening. This is very important given the observation that nearly half of the women included in the study did not have a history of smoking. As such, the role of imaging for other causes, such as cancer surveillance, becomes especially important for early cancer diagnosis,” Dr. Molena and colleagues wrote. “To reduce late-stage cancer diagnoses, further assessment of guidelines for lung cancer screening for all women may be needed.”

Instead, for almost half of women in the study group with a history of breast cancer, the lung cancer was detected on a routine follow-up imaging scan.

USPSTF guidelines for lung cancer screening do not include previous malignancy as a high-risk feature requiring evaluation, which may explain why so few women in this study were screened for lung cancer, even though lung cancer is more common in breast cancer survivors than the general population. Approximately 10% of women who have had breast cancer will develop a second malignancy within 10 years and in most cases, it will be lung cancer. Plus, according to the National Cancer Institute, breast, lung, and colorectal cancers are the three most common cancers in women and account for approximately 50% of all new cancer diagnoses in women in 2020.

A 2018 analysis published in Frontiers in Oncology found that, of more than 6,000 women with secondary primary lung cancer after having had breast cancer, 42% had distant-stage disease at the time of diagnosis which, Dr. Molena and colleagues said, suggests an ongoing need to update screening recommendations.

“Given that lung cancer has a 5-year overall survival rate of less than 20% (highlighting the benefits of early-stage diagnosis), a better understanding of lung cancer in women with a history of breast cancer could have important implications for screening and surveillance,” the authors wrote.

Estrogen is known to play a role in the development of lung cancer by activating the epidermal growth factor receptor (EGFR). Previous research has shown an increased risk of lung cancer in patients with estrogen receptor–negative, progesterone receptor–negative, HER2-negative, or triple-negative breast cancer.

“Antiestrogen treatment has been demonstrated to decrease the incidence of lung cancer and has been associated with improved long-term survival in patients with lung cancer after breast cancer. Future studies should seek to identify high-risk populations on the basis of hormone receptor status and antiestrogen therapy use,” the authors wrote.

The authors noted a number of limitations to the study, including the single hospital as the sole source of data, plus, the analysis did not account for the length of time since patients quit smoking and a lung cancer diagnosis. Nor did it consider other risk factors, such as radiation, chemotherapy, or antiestrogen therapies.

The authors did not disclose any study-related conflicts of interests.

This article was updated 3/2/22.

A New York state radiation oncologist accused of gross negligence and incompetence back in 2018 has now lost his medical license.

The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.

“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.

Dr. Yi’s lawyer said that he is appealing the decision.

Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.

In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.

Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.

However, whistleblower claims from a former CSS Oncology employee were dismissed.
 

Troubled history

CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.

Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.

However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.

The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.

The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
 

Medical misconduct

The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.

In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.

The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.

Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.

“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”

A version of this article first appeared on Medscape.com.

A New York state radiation oncologist accused of gross negligence and incompetence back in 2018 has now lost his medical license.

The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.

“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.

Dr. Yi’s lawyer said that he is appealing the decision.

Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.

In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.

Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.

However, whistleblower claims from a former CSS Oncology employee were dismissed.
 

Troubled history

CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.

Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.

However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.

The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.

The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
 

Medical misconduct

The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.

In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.

The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.

Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.

“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”

A version of this article first appeared on Medscape.com.

A New York state radiation oncologist accused of gross negligence and incompetence back in 2018 has now lost his medical license.

The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.

“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.

Dr. Yi’s lawyer said that he is appealing the decision.

Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.

In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.

Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.

However, whistleblower claims from a former CSS Oncology employee were dismissed.
 

Troubled history

CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.

Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.

However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.

The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.

The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
 

Medical misconduct

The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.

In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.

The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.

Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.

“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”

A version of this article first appeared on Medscape.com.

Kia Slade was 7 months pregnant, unvaccinated, and fighting for breath, her oxygen levels plummeting, when her son came into the world last May.

A severe case of COVID-19 pneumonia had left Ms. Slade delirious. When the intensive care team tried to place an oxygen mask on her face, she snatched it away, she recalled. Her baby’s heart rate began to drop.

Ms. Slade’s doctor performed an emergency cesarean section at her bedside in the intensive care unit, delivering baby Tristan 10 weeks early. He weighed just 2 pounds, 14 ounces, about half the size of small full-term baby.

But Ms. Slade wouldn’t meet him until July. She was on a ventilator in a medically-induced coma for 8 weeks, and she developed a serious infection and blood clot while unconscious. It was only after a perilous 2½ months in the hospital, during which her heart stopped twice, that Ms. Slade was vaccinated against COVID-19.

“I wish I had gotten the vaccine earlier,” said Ms. Slade, 42, who remains too sick to return to work as a special education teacher in Baltimore. Doctors “kept pushing me to get vaccinated, but there just wasn’t enough information out there for me to do it.”

A year ago, there was little to no vaccine safety data for pregnant people like Ms. Slade, because they had been excluded from clinical trials run by Pfizer, Moderna, and other vaccine makers.

Lacking data, health experts were unsure and divided about how to advise expectant parents. Although U.S. health officials permitted pregnant people to be vaccinated, the World Health Organization in January 2021 actually discouraged them from doing so; it later reversed that recommendation.

The uncertainty led many women to delay vaccination, and only about two-thirds of the pregnant people who have been tracked by the Centers for Disease Control and Prevention were fully vaccinated as of Feb. 5, 2022, leaving many expectant moms at a high risk of infection and life-threatening complications.

More than 29,000 pregnant people have been hospitalized with COVID-19 and 274 have died, according to the CDC.

“There were surely women who were hospitalized because there wasn’t information available to them,” said Paul A. Offit, MD, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.

Vaccine developers say that pregnant people – who have special health needs and risks – were excluded from clinical trials to protect them from potential side effects of novel technologies, including the Pfizer and Moderna mRNA vaccines and formulations made with cold viruses, such as the Johnson & Johnson vaccine.

But a KHN analysis also shows that pregnant people were left behind because including them in vaccine studies would have complicated and potentially delayed the delivery of COVID-19 vaccines to the broader population.

A growing number of women’s health researchers and advocates say that excluding pregnant people – and the months-long delay in recommending that they be immunized – helped fuel widespread vaccine hesitancy in this vulnerable group.

“Women and their unborn fetuses are dying of COVID infection,” said Jane Van Dis, MD, an ob.gyn. at the University of Rochester (N.Y.) Medical Center who has treated many patients like Ms. Slade. “Our failure as a society to vaccinate women in pregnancy will be remembered by the children and families who lost their mothers to this disease.”
 

New technology, uncertain risks

At the time COVID-19 vaccines were being developed, scientists had very little experience using mRNA vaccines in pregnant women, said Jacqueline Miller, MD, a senior vice president involved in vaccine research at Moderna.

“When you study anything in pregnant women, you have two patients, the mom and the unborn child,” Dr. Miller said. “Until we had more safety data on the platform, it wasn’t something we wanted to undertake.”

But Dr. Offit noted that vaccines have a strong record of safety in pregnancy and he sees no reason to have excluded pregnant people. None of the vaccines currently in use – including the chickenpox and rubella vaccines, which contain live viruses – have been shown to harm fetuses, he said. Doctors routinely recommend that pregnant people receive pertussis and flu vaccinations.

Dr. Offit, the coinventor of a rotavirus vaccine, said that some concerns about vaccines stem from commercial, not medical, interests. Drug makers don’t want to risk that their product will be blamed for any problems occurring in pregnant people, even if coincidental, he said.

“These companies don’t want bad news,” Dr. Offit said.

In the United States, health officials typically would have told expectant mothers not to take a vaccine that was untested during pregnancy, said Dr. Offit, a member of a committee that advises the Food and Drug Administration on vaccines.

Due to the urgency of the pandemic, health agencies instead permitted pregnant people to make up their own minds about vaccines without recommending them.

Women’s medical associations were also hampered by the lack of data. Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine actively encouraged pregnant people to be vaccinated until July 30, 2021, after the first real-world vaccine studies had been published. The CDC followed suit in August of 2021.

“If we had had this data in the beginning, we would have been able to vaccinate more women,” said Kelli Burroughs, MD, the department chair of obstetrics and gynecology at Memorial Hermann Sugar Land Hospital near Houston.

Yet anti-vaccine groups wasted no time in scaring pregnant people, flooding social media with misinformation about impaired fertility and harm to the fetus.

In the first few months after the COVID-19 vaccines were approved, some doctors were ambivalent about recommending them, and some still advise pregnant patients against vaccination.

An estimated 67% of pregnant people today are fully vaccinated, compared with about 89% of people 65 and older, another high-risk group, and 65% of Americans overall. Vaccination rates are lower among minorities, with 65% of expectant Hispanic mothers and 53% of pregnant African Americans fully vaccinated, according to the CDC.

Vaccination is especially important during pregnancy, because of increased risks of hospitalization, ICU admission, and mechanical ventilation, Dr. Burroughs said. A study released in February from the National Institutes of Health found that pregnant people with a moderate to severe COVID-19 infection also were more likely to have a C-section, deliver preterm, or develop a postpartum hemorrhage.

Black moms such as Ms. Slade were already at higher risk of maternal and infant mortality before the pandemic, because of higher underlying risks, unequal access to health care, and other factors. COVID-19 has magnified those risks, said Dr. Burroughs, who has persuaded reluctant patients by revealing that she had a healthy pregnancy and child after being vaccinated.

Ms. Slade said she has never opposed vaccines and had no hesitation about receiving other vaccines while pregnant. But she said she “just wasn’t comfortable” with COVID-19 shots.

“If there had been data out there saying the COVID shot was safe, and that nothing would happen to my baby and there was no risk of birth defects, I would have taken it,” said Ms. Slade, who has had type 2 diabetes for 12 years.
 

Working at warp speed

Government scientists at the NIH were concerned about the risk of COVID-19 to pregnant people from the very beginning and knew that expectant moms needed vaccines as much or more than anyone else, said Larry Corey, MD, a leader of the COVID-19 Prevention Network, which coordinated COVID-19 vaccine trials for the federal government.

But including pregnant volunteers in the larger vaccine trials could have led to interruptions and delays, Dr. Corey said. Researchers would have had to enroll thousands of pregnant volunteers to achieve statistically robust results that weren’t due to chance, he said.

Pregnancy can bring on a wide range of complications: gestational diabetes, hypertension, anemia, bleeding, blood clots, or problems with the placenta, for example. Up to 20% of people who know they’re pregnant miscarry. Because researchers would have been obliged to investigate any medical problem to make sure it wasn’t caused by one of the COVID-19 vaccines, including pregnant people might have meant having to hit pause on those trials, Dr. Corey said.

With death tolls from the pandemic mounting, “we had a mission to do this as quickly and as thoroughly as possible,” Dr. Corey said. Making COVID-19 vaccines available within a year “saved hundreds of thousands of lives.”

The first data on COVID-19 vaccine safety in pregnancy was published in April of 2021 when the CDC released an analysis of nearly 36,000 vaccinated pregnant people who had enrolled in a registry called V-safe, which allows users to log the dates of their vaccinations and any subsequent symptoms.

Later research showed that COVID-19 vaccines weren’t associated with increased risk of miscarriage or premature delivery.

Brenna Hughes, MD, a maternal-fetal medicine specialist and member of the American College of Obstetricians and Gynecologists’ COVID-19 expert group, agrees that adding pregnant people to large-scale COVID-19 vaccine and drug trials may have been impractical. But researchers could have launched parallel trials of pregnant women, once early studies showed the vaccines were safe in humans, she said.

“Would it have been hard? Everything with COVID is hard,” Dr. Hughes said. “But it would have been feasible.”

The FDA requires that researchers perform additional animal studies – called developmental and reproductive toxicity studies – before testing vaccines in pregnant people. Although these studies are essential, they take 5-6 months, and weren’t completed until late 2020, around the time the first COVID-19 vaccines were authorized for adults, said Emily Erbelding, MD, director of microbiology and infectious diseases at the National Institute of Allergy and Infectious Diseases, part of the NIH.

Pregnancy studies “were an afterthought,” said Irina Burd, MD, director of Johns Hopkins’ Integrated Research Center for Fetal Medicine and a professor of gynecology and obstetrics. “They should have been done sooner.”

The NIH is conducting a study of pregnant and postpartum people who decided on their own to be vaccinated, Dr. Erbelding said. The study is due to be completed by July 2023.

Janssen and Moderna are also conducting studies in pregnant people, both due to be completed in 2024.

Pfizer scientists encountered problems when they initiated a clinical trial, which would have randomly assigned pregnant people to receive either a vaccine or placebo. Once vaccines were widely available, many patients weren’t willing to take a chance on being unvaccinated until after delivery.

Pfizer has stopped recruiting patients and has not said whether it will publicly report any data from the trial.

Dr. Hughes said vaccine developers need to include pregnant people from the very beginning.

“There is this notion of protecting pregnant people from research,” Dr. Hughes said. “But we should be protecting patients through research, not from research.”
 

Recovering physically and emotionally

Ms. Slade still regrets being deprived of time with her children while she fought the disease.

Being on a ventilator kept her from spending those early weeks with her newborn, or from seeing her 9-year-old daughter, Zoe.

Even when Ms. Slade was finally able to see her son, she wasn’t able to tell him she loved him or sing a lullaby, or even talk at all, because of a breathing tube in her throat.

Today, Ms. Slade is a strong advocate of COVID-19 vaccinations, urging her friends and family to get their shots to avoid suffering the way she has.

Ms. Slade had to relearn to walk after being bedridden for weeks. Her many weeks on a ventilator may have contributed to her stomach paralysis, which often causes intense pain, nausea, and even vomiting when she eats or drinks. Ms. Slade weighs 50 pounds less today than before she became pregnant and has resorted to going to the emergency department when the pain is unbearable. “Most days, I’m just miserable,” she said.

Her family suffered as well. Like many babies born prematurely, Tristan, now nearly 9 months old and crawling, receives physical therapy to strengthen his muscles. At 15 pounds, Tristan is largely healthy, although his doctor said he has symptoms of asthma.

Ms. Slade said she would like to attend family counseling with Zoe, who rarely complains and tends to keep her feelings to herself. Ms. Slade said she knows her illness must have been terrifying for her little girl.

“The other day she was talking to me,” Ms. Slade said, “and she said, ‘You know, I almost had to bury you.’ ”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Kia Slade was 7 months pregnant, unvaccinated, and fighting for breath, her oxygen levels plummeting, when her son came into the world last May.

A severe case of COVID-19 pneumonia had left Ms. Slade delirious. When the intensive care team tried to place an oxygen mask on her face, she snatched it away, she recalled. Her baby’s heart rate began to drop.

Ms. Slade’s doctor performed an emergency cesarean section at her bedside in the intensive care unit, delivering baby Tristan 10 weeks early. He weighed just 2 pounds, 14 ounces, about half the size of small full-term baby.

But Ms. Slade wouldn’t meet him until July. She was on a ventilator in a medically-induced coma for 8 weeks, and she developed a serious infection and blood clot while unconscious. It was only after a perilous 2½ months in the hospital, during which her heart stopped twice, that Ms. Slade was vaccinated against COVID-19.

“I wish I had gotten the vaccine earlier,” said Ms. Slade, 42, who remains too sick to return to work as a special education teacher in Baltimore. Doctors “kept pushing me to get vaccinated, but there just wasn’t enough information out there for me to do it.”

A year ago, there was little to no vaccine safety data for pregnant people like Ms. Slade, because they had been excluded from clinical trials run by Pfizer, Moderna, and other vaccine makers.

Lacking data, health experts were unsure and divided about how to advise expectant parents. Although U.S. health officials permitted pregnant people to be vaccinated, the World Health Organization in January 2021 actually discouraged them from doing so; it later reversed that recommendation.

The uncertainty led many women to delay vaccination, and only about two-thirds of the pregnant people who have been tracked by the Centers for Disease Control and Prevention were fully vaccinated as of Feb. 5, 2022, leaving many expectant moms at a high risk of infection and life-threatening complications.

More than 29,000 pregnant people have been hospitalized with COVID-19 and 274 have died, according to the CDC.

“There were surely women who were hospitalized because there wasn’t information available to them,” said Paul A. Offit, MD, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.

Vaccine developers say that pregnant people – who have special health needs and risks – were excluded from clinical trials to protect them from potential side effects of novel technologies, including the Pfizer and Moderna mRNA vaccines and formulations made with cold viruses, such as the Johnson & Johnson vaccine.

But a KHN analysis also shows that pregnant people were left behind because including them in vaccine studies would have complicated and potentially delayed the delivery of COVID-19 vaccines to the broader population.

A growing number of women’s health researchers and advocates say that excluding pregnant people – and the months-long delay in recommending that they be immunized – helped fuel widespread vaccine hesitancy in this vulnerable group.

“Women and their unborn fetuses are dying of COVID infection,” said Jane Van Dis, MD, an ob.gyn. at the University of Rochester (N.Y.) Medical Center who has treated many patients like Ms. Slade. “Our failure as a society to vaccinate women in pregnancy will be remembered by the children and families who lost their mothers to this disease.”
 

New technology, uncertain risks

At the time COVID-19 vaccines were being developed, scientists had very little experience using mRNA vaccines in pregnant women, said Jacqueline Miller, MD, a senior vice president involved in vaccine research at Moderna.

“When you study anything in pregnant women, you have two patients, the mom and the unborn child,” Dr. Miller said. “Until we had more safety data on the platform, it wasn’t something we wanted to undertake.”

But Dr. Offit noted that vaccines have a strong record of safety in pregnancy and he sees no reason to have excluded pregnant people. None of the vaccines currently in use – including the chickenpox and rubella vaccines, which contain live viruses – have been shown to harm fetuses, he said. Doctors routinely recommend that pregnant people receive pertussis and flu vaccinations.

Dr. Offit, the coinventor of a rotavirus vaccine, said that some concerns about vaccines stem from commercial, not medical, interests. Drug makers don’t want to risk that their product will be blamed for any problems occurring in pregnant people, even if coincidental, he said.

“These companies don’t want bad news,” Dr. Offit said.

In the United States, health officials typically would have told expectant mothers not to take a vaccine that was untested during pregnancy, said Dr. Offit, a member of a committee that advises the Food and Drug Administration on vaccines.

Due to the urgency of the pandemic, health agencies instead permitted pregnant people to make up their own minds about vaccines without recommending them.

Women’s medical associations were also hampered by the lack of data. Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine actively encouraged pregnant people to be vaccinated until July 30, 2021, after the first real-world vaccine studies had been published. The CDC followed suit in August of 2021.

“If we had had this data in the beginning, we would have been able to vaccinate more women,” said Kelli Burroughs, MD, the department chair of obstetrics and gynecology at Memorial Hermann Sugar Land Hospital near Houston.

Yet anti-vaccine groups wasted no time in scaring pregnant people, flooding social media with misinformation about impaired fertility and harm to the fetus.

In the first few months after the COVID-19 vaccines were approved, some doctors were ambivalent about recommending them, and some still advise pregnant patients against vaccination.

An estimated 67% of pregnant people today are fully vaccinated, compared with about 89% of people 65 and older, another high-risk group, and 65% of Americans overall. Vaccination rates are lower among minorities, with 65% of expectant Hispanic mothers and 53% of pregnant African Americans fully vaccinated, according to the CDC.

Vaccination is especially important during pregnancy, because of increased risks of hospitalization, ICU admission, and mechanical ventilation, Dr. Burroughs said. A study released in February from the National Institutes of Health found that pregnant people with a moderate to severe COVID-19 infection also were more likely to have a C-section, deliver preterm, or develop a postpartum hemorrhage.

Black moms such as Ms. Slade were already at higher risk of maternal and infant mortality before the pandemic, because of higher underlying risks, unequal access to health care, and other factors. COVID-19 has magnified those risks, said Dr. Burroughs, who has persuaded reluctant patients by revealing that she had a healthy pregnancy and child after being vaccinated.

Ms. Slade said she has never opposed vaccines and had no hesitation about receiving other vaccines while pregnant. But she said she “just wasn’t comfortable” with COVID-19 shots.

“If there had been data out there saying the COVID shot was safe, and that nothing would happen to my baby and there was no risk of birth defects, I would have taken it,” said Ms. Slade, who has had type 2 diabetes for 12 years.
 

Working at warp speed

Government scientists at the NIH were concerned about the risk of COVID-19 to pregnant people from the very beginning and knew that expectant moms needed vaccines as much or more than anyone else, said Larry Corey, MD, a leader of the COVID-19 Prevention Network, which coordinated COVID-19 vaccine trials for the federal government.

But including pregnant volunteers in the larger vaccine trials could have led to interruptions and delays, Dr. Corey said. Researchers would have had to enroll thousands of pregnant volunteers to achieve statistically robust results that weren’t due to chance, he said.

Pregnancy can bring on a wide range of complications: gestational diabetes, hypertension, anemia, bleeding, blood clots, or problems with the placenta, for example. Up to 20% of people who know they’re pregnant miscarry. Because researchers would have been obliged to investigate any medical problem to make sure it wasn’t caused by one of the COVID-19 vaccines, including pregnant people might have meant having to hit pause on those trials, Dr. Corey said.

With death tolls from the pandemic mounting, “we had a mission to do this as quickly and as thoroughly as possible,” Dr. Corey said. Making COVID-19 vaccines available within a year “saved hundreds of thousands of lives.”

The first data on COVID-19 vaccine safety in pregnancy was published in April of 2021 when the CDC released an analysis of nearly 36,000 vaccinated pregnant people who had enrolled in a registry called V-safe, which allows users to log the dates of their vaccinations and any subsequent symptoms.

Later research showed that COVID-19 vaccines weren’t associated with increased risk of miscarriage or premature delivery.

Brenna Hughes, MD, a maternal-fetal medicine specialist and member of the American College of Obstetricians and Gynecologists’ COVID-19 expert group, agrees that adding pregnant people to large-scale COVID-19 vaccine and drug trials may have been impractical. But researchers could have launched parallel trials of pregnant women, once early studies showed the vaccines were safe in humans, she said.

“Would it have been hard? Everything with COVID is hard,” Dr. Hughes said. “But it would have been feasible.”

The FDA requires that researchers perform additional animal studies – called developmental and reproductive toxicity studies – before testing vaccines in pregnant people. Although these studies are essential, they take 5-6 months, and weren’t completed until late 2020, around the time the first COVID-19 vaccines were authorized for adults, said Emily Erbelding, MD, director of microbiology and infectious diseases at the National Institute of Allergy and Infectious Diseases, part of the NIH.

Pregnancy studies “were an afterthought,” said Irina Burd, MD, director of Johns Hopkins’ Integrated Research Center for Fetal Medicine and a professor of gynecology and obstetrics. “They should have been done sooner.”

The NIH is conducting a study of pregnant and postpartum people who decided on their own to be vaccinated, Dr. Erbelding said. The study is due to be completed by July 2023.

Janssen and Moderna are also conducting studies in pregnant people, both due to be completed in 2024.

Pfizer scientists encountered problems when they initiated a clinical trial, which would have randomly assigned pregnant people to receive either a vaccine or placebo. Once vaccines were widely available, many patients weren’t willing to take a chance on being unvaccinated until after delivery.

Pfizer has stopped recruiting patients and has not said whether it will publicly report any data from the trial.

Dr. Hughes said vaccine developers need to include pregnant people from the very beginning.

“There is this notion of protecting pregnant people from research,” Dr. Hughes said. “But we should be protecting patients through research, not from research.”
 

Recovering physically and emotionally

Ms. Slade still regrets being deprived of time with her children while she fought the disease.

Being on a ventilator kept her from spending those early weeks with her newborn, or from seeing her 9-year-old daughter, Zoe.

Even when Ms. Slade was finally able to see her son, she wasn’t able to tell him she loved him or sing a lullaby, or even talk at all, because of a breathing tube in her throat.

Today, Ms. Slade is a strong advocate of COVID-19 vaccinations, urging her friends and family to get their shots to avoid suffering the way she has.

Ms. Slade had to relearn to walk after being bedridden for weeks. Her many weeks on a ventilator may have contributed to her stomach paralysis, which often causes intense pain, nausea, and even vomiting when she eats or drinks. Ms. Slade weighs 50 pounds less today than before she became pregnant and has resorted to going to the emergency department when the pain is unbearable. “Most days, I’m just miserable,” she said.

Her family suffered as well. Like many babies born prematurely, Tristan, now nearly 9 months old and crawling, receives physical therapy to strengthen his muscles. At 15 pounds, Tristan is largely healthy, although his doctor said he has symptoms of asthma.

Ms. Slade said she would like to attend family counseling with Zoe, who rarely complains and tends to keep her feelings to herself. Ms. Slade said she knows her illness must have been terrifying for her little girl.

“The other day she was talking to me,” Ms. Slade said, “and she said, ‘You know, I almost had to bury you.’ ”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Kia Slade was 7 months pregnant, unvaccinated, and fighting for breath, her oxygen levels plummeting, when her son came into the world last May.

A severe case of COVID-19 pneumonia had left Ms. Slade delirious. When the intensive care team tried to place an oxygen mask on her face, she snatched it away, she recalled. Her baby’s heart rate began to drop.

Ms. Slade’s doctor performed an emergency cesarean section at her bedside in the intensive care unit, delivering baby Tristan 10 weeks early. He weighed just 2 pounds, 14 ounces, about half the size of small full-term baby.

But Ms. Slade wouldn’t meet him until July. She was on a ventilator in a medically-induced coma for 8 weeks, and she developed a serious infection and blood clot while unconscious. It was only after a perilous 2½ months in the hospital, during which her heart stopped twice, that Ms. Slade was vaccinated against COVID-19.

“I wish I had gotten the vaccine earlier,” said Ms. Slade, 42, who remains too sick to return to work as a special education teacher in Baltimore. Doctors “kept pushing me to get vaccinated, but there just wasn’t enough information out there for me to do it.”

A year ago, there was little to no vaccine safety data for pregnant people like Ms. Slade, because they had been excluded from clinical trials run by Pfizer, Moderna, and other vaccine makers.

Lacking data, health experts were unsure and divided about how to advise expectant parents. Although U.S. health officials permitted pregnant people to be vaccinated, the World Health Organization in January 2021 actually discouraged them from doing so; it later reversed that recommendation.

The uncertainty led many women to delay vaccination, and only about two-thirds of the pregnant people who have been tracked by the Centers for Disease Control and Prevention were fully vaccinated as of Feb. 5, 2022, leaving many expectant moms at a high risk of infection and life-threatening complications.

More than 29,000 pregnant people have been hospitalized with COVID-19 and 274 have died, according to the CDC.

“There were surely women who were hospitalized because there wasn’t information available to them,” said Paul A. Offit, MD, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.

Vaccine developers say that pregnant people – who have special health needs and risks – were excluded from clinical trials to protect them from potential side effects of novel technologies, including the Pfizer and Moderna mRNA vaccines and formulations made with cold viruses, such as the Johnson & Johnson vaccine.

But a KHN analysis also shows that pregnant people were left behind because including them in vaccine studies would have complicated and potentially delayed the delivery of COVID-19 vaccines to the broader population.

A growing number of women’s health researchers and advocates say that excluding pregnant people – and the months-long delay in recommending that they be immunized – helped fuel widespread vaccine hesitancy in this vulnerable group.

“Women and their unborn fetuses are dying of COVID infection,” said Jane Van Dis, MD, an ob.gyn. at the University of Rochester (N.Y.) Medical Center who has treated many patients like Ms. Slade. “Our failure as a society to vaccinate women in pregnancy will be remembered by the children and families who lost their mothers to this disease.”
 

New technology, uncertain risks

At the time COVID-19 vaccines were being developed, scientists had very little experience using mRNA vaccines in pregnant women, said Jacqueline Miller, MD, a senior vice president involved in vaccine research at Moderna.

“When you study anything in pregnant women, you have two patients, the mom and the unborn child,” Dr. Miller said. “Until we had more safety data on the platform, it wasn’t something we wanted to undertake.”

But Dr. Offit noted that vaccines have a strong record of safety in pregnancy and he sees no reason to have excluded pregnant people. None of the vaccines currently in use – including the chickenpox and rubella vaccines, which contain live viruses – have been shown to harm fetuses, he said. Doctors routinely recommend that pregnant people receive pertussis and flu vaccinations.

Dr. Offit, the coinventor of a rotavirus vaccine, said that some concerns about vaccines stem from commercial, not medical, interests. Drug makers don’t want to risk that their product will be blamed for any problems occurring in pregnant people, even if coincidental, he said.

“These companies don’t want bad news,” Dr. Offit said.

In the United States, health officials typically would have told expectant mothers not to take a vaccine that was untested during pregnancy, said Dr. Offit, a member of a committee that advises the Food and Drug Administration on vaccines.

Due to the urgency of the pandemic, health agencies instead permitted pregnant people to make up their own minds about vaccines without recommending them.

Women’s medical associations were also hampered by the lack of data. Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine actively encouraged pregnant people to be vaccinated until July 30, 2021, after the first real-world vaccine studies had been published. The CDC followed suit in August of 2021.

“If we had had this data in the beginning, we would have been able to vaccinate more women,” said Kelli Burroughs, MD, the department chair of obstetrics and gynecology at Memorial Hermann Sugar Land Hospital near Houston.

Yet anti-vaccine groups wasted no time in scaring pregnant people, flooding social media with misinformation about impaired fertility and harm to the fetus.

In the first few months after the COVID-19 vaccines were approved, some doctors were ambivalent about recommending them, and some still advise pregnant patients against vaccination.

An estimated 67% of pregnant people today are fully vaccinated, compared with about 89% of people 65 and older, another high-risk group, and 65% of Americans overall. Vaccination rates are lower among minorities, with 65% of expectant Hispanic mothers and 53% of pregnant African Americans fully vaccinated, according to the CDC.

Vaccination is especially important during pregnancy, because of increased risks of hospitalization, ICU admission, and mechanical ventilation, Dr. Burroughs said. A study released in February from the National Institutes of Health found that pregnant people with a moderate to severe COVID-19 infection also were more likely to have a C-section, deliver preterm, or develop a postpartum hemorrhage.

Black moms such as Ms. Slade were already at higher risk of maternal and infant mortality before the pandemic, because of higher underlying risks, unequal access to health care, and other factors. COVID-19 has magnified those risks, said Dr. Burroughs, who has persuaded reluctant patients by revealing that she had a healthy pregnancy and child after being vaccinated.

Ms. Slade said she has never opposed vaccines and had no hesitation about receiving other vaccines while pregnant. But she said she “just wasn’t comfortable” with COVID-19 shots.

“If there had been data out there saying the COVID shot was safe, and that nothing would happen to my baby and there was no risk of birth defects, I would have taken it,” said Ms. Slade, who has had type 2 diabetes for 12 years.
 

Working at warp speed

Government scientists at the NIH were concerned about the risk of COVID-19 to pregnant people from the very beginning and knew that expectant moms needed vaccines as much or more than anyone else, said Larry Corey, MD, a leader of the COVID-19 Prevention Network, which coordinated COVID-19 vaccine trials for the federal government.

But including pregnant volunteers in the larger vaccine trials could have led to interruptions and delays, Dr. Corey said. Researchers would have had to enroll thousands of pregnant volunteers to achieve statistically robust results that weren’t due to chance, he said.

Pregnancy can bring on a wide range of complications: gestational diabetes, hypertension, anemia, bleeding, blood clots, or problems with the placenta, for example. Up to 20% of people who know they’re pregnant miscarry. Because researchers would have been obliged to investigate any medical problem to make sure it wasn’t caused by one of the COVID-19 vaccines, including pregnant people might have meant having to hit pause on those trials, Dr. Corey said.

With death tolls from the pandemic mounting, “we had a mission to do this as quickly and as thoroughly as possible,” Dr. Corey said. Making COVID-19 vaccines available within a year “saved hundreds of thousands of lives.”

The first data on COVID-19 vaccine safety in pregnancy was published in April of 2021 when the CDC released an analysis of nearly 36,000 vaccinated pregnant people who had enrolled in a registry called V-safe, which allows users to log the dates of their vaccinations and any subsequent symptoms.

Later research showed that COVID-19 vaccines weren’t associated with increased risk of miscarriage or premature delivery.

Brenna Hughes, MD, a maternal-fetal medicine specialist and member of the American College of Obstetricians and Gynecologists’ COVID-19 expert group, agrees that adding pregnant people to large-scale COVID-19 vaccine and drug trials may have been impractical. But researchers could have launched parallel trials of pregnant women, once early studies showed the vaccines were safe in humans, she said.

“Would it have been hard? Everything with COVID is hard,” Dr. Hughes said. “But it would have been feasible.”

The FDA requires that researchers perform additional animal studies – called developmental and reproductive toxicity studies – before testing vaccines in pregnant people. Although these studies are essential, they take 5-6 months, and weren’t completed until late 2020, around the time the first COVID-19 vaccines were authorized for adults, said Emily Erbelding, MD, director of microbiology and infectious diseases at the National Institute of Allergy and Infectious Diseases, part of the NIH.

Pregnancy studies “were an afterthought,” said Irina Burd, MD, director of Johns Hopkins’ Integrated Research Center for Fetal Medicine and a professor of gynecology and obstetrics. “They should have been done sooner.”

The NIH is conducting a study of pregnant and postpartum people who decided on their own to be vaccinated, Dr. Erbelding said. The study is due to be completed by July 2023.

Janssen and Moderna are also conducting studies in pregnant people, both due to be completed in 2024.

Pfizer scientists encountered problems when they initiated a clinical trial, which would have randomly assigned pregnant people to receive either a vaccine or placebo. Once vaccines were widely available, many patients weren’t willing to take a chance on being unvaccinated until after delivery.

Pfizer has stopped recruiting patients and has not said whether it will publicly report any data from the trial.

Dr. Hughes said vaccine developers need to include pregnant people from the very beginning.

“There is this notion of protecting pregnant people from research,” Dr. Hughes said. “But we should be protecting patients through research, not from research.”
 

Recovering physically and emotionally

Ms. Slade still regrets being deprived of time with her children while she fought the disease.

Being on a ventilator kept her from spending those early weeks with her newborn, or from seeing her 9-year-old daughter, Zoe.

Even when Ms. Slade was finally able to see her son, she wasn’t able to tell him she loved him or sing a lullaby, or even talk at all, because of a breathing tube in her throat.

Today, Ms. Slade is a strong advocate of COVID-19 vaccinations, urging her friends and family to get their shots to avoid suffering the way she has.

Ms. Slade had to relearn to walk after being bedridden for weeks. Her many weeks on a ventilator may have contributed to her stomach paralysis, which often causes intense pain, nausea, and even vomiting when she eats or drinks. Ms. Slade weighs 50 pounds less today than before she became pregnant and has resorted to going to the emergency department when the pain is unbearable. “Most days, I’m just miserable,” she said.

Her family suffered as well. Like many babies born prematurely, Tristan, now nearly 9 months old and crawling, receives physical therapy to strengthen his muscles. At 15 pounds, Tristan is largely healthy, although his doctor said he has symptoms of asthma.

Ms. Slade said she would like to attend family counseling with Zoe, who rarely complains and tends to keep her feelings to herself. Ms. Slade said she knows her illness must have been terrifying for her little girl.

“The other day she was talking to me,” Ms. Slade said, “and she said, ‘You know, I almost had to bury you.’ ”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

For the first time, neuroscientists have recorded the brain activity of a dying person, revealing a brain wave pattern similar to that seen when memories are recalled. Although only a single case study, researchers say the recording raises the possibility that as we die, our lives really do flash before our eyes.

“The same neurophysiological activity patterns that occur in our brains when we dream, remember, meditate, concentrate – these same patterns also appear just before we die,” study investigator Ajmal Zemmar, MD, PhD, assistant professor of neurosurgery at the University of Louisville (Ky.), said in an interview.

The research was published online Feb. 22, 2022, in the Frontiers in Aging Neuroscience.
 

Accidental finding

The recording of brain activity was captured inadvertently in 2016 when neuroscientists used continuous EEG to detect and treat seizures in an 87-year-old man who had developed epilepsy after a traumatic brain injury, While undergoing the EEG, the patient had a cardiac arrest and died.

In the 30 seconds before and after blood flow to the brain stopped, the EEG showed an increase in gamma oscillations. These are brain waves known to be involved in high cognitive functions, including conscious perception and memory flashbacks.

Researchers also noted changes in alpha, theta, delta, and beta wave activity just before and just after cardiac arrest, and that changes in one type modulated changes in others. That suggests a coordinated rhythm, which further suggests the activity is more than just the firing of neurons as they die.

“When you observe this and you observe the rhythmic oscillation, you are inclined to think this may be a coordinated activity pattern of the brain rather than a mere discharge when the brain dies,” Dr. Zemmar said.

Although they’ve had the data since 2016, Dr. Zemmar and colleagues held off on publishing in the hopes of finding similar recordings in other individuals. That their 5-year search yielded no results illustrates just how difficult a study like this is to conduct, Dr. Zemmar noted. “We’re trying to figure out how to do this in a predictable way, but obtaining datasets like this is going to be challenging,” he said.

Although Dr. Zemmar was unable to find recordings of activity in the dying brains of other humans, he did find a similar study conducted with rats in 2013. In that research, investigators reported a surge of brain activity in rats just prior to and immediately after experimental cardiac arrest. Changes in high- and low-frequency brain waves mirrored those documented in the current case study.
 

Bringing a picture together

Commenting on the new study, George Mashour, MD, PhD, professor and chair of anesthesiology and professor of neurosurgery and pharmacology at the University of Michigan, Ann Arbor, said the results are eerily similar to a 2013 study that he coauthored.

Although the current research is just a single case study, Dr. Mashour said when taken with his team’s findings in rats and other work, the new findings are “starting to put a picture together of what might be going on in the dying brain.”

“They were able to record throughout the process of cardiac arrest and death and what they found was strikingly similar to what we found in our highly controlled animal study,” said Dr. Mashour, who is also the founding director of the Center for Consciousness Science at the University of Michigan.

“There was a surge of higher-frequency activity and there was coherence across different parts of the brain,” he added. “That suggests that what we found in the rigorous controlled setting of a laboratory actually translates to humans who are undergoing the clinical process of dying.”

What remains unclear is whether this brain activity explains the near-death experiences described in the literature, which include “life recall” of memories, Dr. Mashour said. “This higher-frequency surge that’s happening around the time of death, is that correlated with experiencing something like this near-death experience? Or is it just a neural feature that can just as easily happen in an unconscious brain?”

The study was funded by the Heidi Demetriades Foundation, the ETH Zürich Foundation, and the Henan Provincial People’s Hospital Outstanding Talents Founding Grant Project. Dr. Zemmar and Dr. Mashour disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For the first time, neuroscientists have recorded the brain activity of a dying person, revealing a brain wave pattern similar to that seen when memories are recalled. Although only a single case study, researchers say the recording raises the possibility that as we die, our lives really do flash before our eyes.

“The same neurophysiological activity patterns that occur in our brains when we dream, remember, meditate, concentrate – these same patterns also appear just before we die,” study investigator Ajmal Zemmar, MD, PhD, assistant professor of neurosurgery at the University of Louisville (Ky.), said in an interview.

The research was published online Feb. 22, 2022, in the Frontiers in Aging Neuroscience.
 

Accidental finding

The recording of brain activity was captured inadvertently in 2016 when neuroscientists used continuous EEG to detect and treat seizures in an 87-year-old man who had developed epilepsy after a traumatic brain injury, While undergoing the EEG, the patient had a cardiac arrest and died.

In the 30 seconds before and after blood flow to the brain stopped, the EEG showed an increase in gamma oscillations. These are brain waves known to be involved in high cognitive functions, including conscious perception and memory flashbacks.

Researchers also noted changes in alpha, theta, delta, and beta wave activity just before and just after cardiac arrest, and that changes in one type modulated changes in others. That suggests a coordinated rhythm, which further suggests the activity is more than just the firing of neurons as they die.

“When you observe this and you observe the rhythmic oscillation, you are inclined to think this may be a coordinated activity pattern of the brain rather than a mere discharge when the brain dies,” Dr. Zemmar said.

Although they’ve had the data since 2016, Dr. Zemmar and colleagues held off on publishing in the hopes of finding similar recordings in other individuals. That their 5-year search yielded no results illustrates just how difficult a study like this is to conduct, Dr. Zemmar noted. “We’re trying to figure out how to do this in a predictable way, but obtaining datasets like this is going to be challenging,” he said.

Although Dr. Zemmar was unable to find recordings of activity in the dying brains of other humans, he did find a similar study conducted with rats in 2013. In that research, investigators reported a surge of brain activity in rats just prior to and immediately after experimental cardiac arrest. Changes in high- and low-frequency brain waves mirrored those documented in the current case study.
 

Bringing a picture together

Commenting on the new study, George Mashour, MD, PhD, professor and chair of anesthesiology and professor of neurosurgery and pharmacology at the University of Michigan, Ann Arbor, said the results are eerily similar to a 2013 study that he coauthored.

Although the current research is just a single case study, Dr. Mashour said when taken with his team’s findings in rats and other work, the new findings are “starting to put a picture together of what might be going on in the dying brain.”

“They were able to record throughout the process of cardiac arrest and death and what they found was strikingly similar to what we found in our highly controlled animal study,” said Dr. Mashour, who is also the founding director of the Center for Consciousness Science at the University of Michigan.

“There was a surge of higher-frequency activity and there was coherence across different parts of the brain,” he added. “That suggests that what we found in the rigorous controlled setting of a laboratory actually translates to humans who are undergoing the clinical process of dying.”

What remains unclear is whether this brain activity explains the near-death experiences described in the literature, which include “life recall” of memories, Dr. Mashour said. “This higher-frequency surge that’s happening around the time of death, is that correlated with experiencing something like this near-death experience? Or is it just a neural feature that can just as easily happen in an unconscious brain?”

The study was funded by the Heidi Demetriades Foundation, the ETH Zürich Foundation, and the Henan Provincial People’s Hospital Outstanding Talents Founding Grant Project. Dr. Zemmar and Dr. Mashour disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For the first time, neuroscientists have recorded the brain activity of a dying person, revealing a brain wave pattern similar to that seen when memories are recalled. Although only a single case study, researchers say the recording raises the possibility that as we die, our lives really do flash before our eyes.

“The same neurophysiological activity patterns that occur in our brains when we dream, remember, meditate, concentrate – these same patterns also appear just before we die,” study investigator Ajmal Zemmar, MD, PhD, assistant professor of neurosurgery at the University of Louisville (Ky.), said in an interview.

The research was published online Feb. 22, 2022, in the Frontiers in Aging Neuroscience.
 

Accidental finding

The recording of brain activity was captured inadvertently in 2016 when neuroscientists used continuous EEG to detect and treat seizures in an 87-year-old man who had developed epilepsy after a traumatic brain injury, While undergoing the EEG, the patient had a cardiac arrest and died.

In the 30 seconds before and after blood flow to the brain stopped, the EEG showed an increase in gamma oscillations. These are brain waves known to be involved in high cognitive functions, including conscious perception and memory flashbacks.

Researchers also noted changes in alpha, theta, delta, and beta wave activity just before and just after cardiac arrest, and that changes in one type modulated changes in others. That suggests a coordinated rhythm, which further suggests the activity is more than just the firing of neurons as they die.

“When you observe this and you observe the rhythmic oscillation, you are inclined to think this may be a coordinated activity pattern of the brain rather than a mere discharge when the brain dies,” Dr. Zemmar said.

Although they’ve had the data since 2016, Dr. Zemmar and colleagues held off on publishing in the hopes of finding similar recordings in other individuals. That their 5-year search yielded no results illustrates just how difficult a study like this is to conduct, Dr. Zemmar noted. “We’re trying to figure out how to do this in a predictable way, but obtaining datasets like this is going to be challenging,” he said.

Although Dr. Zemmar was unable to find recordings of activity in the dying brains of other humans, he did find a similar study conducted with rats in 2013. In that research, investigators reported a surge of brain activity in rats just prior to and immediately after experimental cardiac arrest. Changes in high- and low-frequency brain waves mirrored those documented in the current case study.
 

Bringing a picture together

Commenting on the new study, George Mashour, MD, PhD, professor and chair of anesthesiology and professor of neurosurgery and pharmacology at the University of Michigan, Ann Arbor, said the results are eerily similar to a 2013 study that he coauthored.

Although the current research is just a single case study, Dr. Mashour said when taken with his team’s findings in rats and other work, the new findings are “starting to put a picture together of what might be going on in the dying brain.”

“They were able to record throughout the process of cardiac arrest and death and what they found was strikingly similar to what we found in our highly controlled animal study,” said Dr. Mashour, who is also the founding director of the Center for Consciousness Science at the University of Michigan.

“There was a surge of higher-frequency activity and there was coherence across different parts of the brain,” he added. “That suggests that what we found in the rigorous controlled setting of a laboratory actually translates to humans who are undergoing the clinical process of dying.”

What remains unclear is whether this brain activity explains the near-death experiences described in the literature, which include “life recall” of memories, Dr. Mashour said. “This higher-frequency surge that’s happening around the time of death, is that correlated with experiencing something like this near-death experience? Or is it just a neural feature that can just as easily happen in an unconscious brain?”

The study was funded by the Heidi Demetriades Foundation, the ETH Zürich Foundation, and the Henan Provincial People’s Hospital Outstanding Talents Founding Grant Project. Dr. Zemmar and Dr. Mashour disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

The predilection for brain metastases in human epidermal growth factor receptor 2 (HER2)-positive breast cancer has historically presented a therapeutic challenge, and agents with enhanced central nervous system (CNS) penetrance are certainly desired. Pyrotinib is a small molecule irreversible tyrosine kinase inhibitor against epidermal growth factor receptor (EGFR), HER2, and HER4. Yan et al investigated the activity and safety of pyrotinib + capecitabine in the single-arm, two-cohort, phase 2 PERMEATE study among 78 patients with HER2-positive metastatic breast cancer (MBC) with brain metastases. The intracranial objective response rate was 74.6% in radiotherapy-naive patients and 42.1% in those progressing after prior radiotherapy. The combination showed good tolerability with the most common grade 3 treatment-related adverse events of diarrhea and neutropenia. Additional studies have shown impressive CNS activity with other HER2-targeted therapies including tucatinib + capecitabine + trastuzumab combination, as well as trastuzumab deruxtecan (HER2CLIMB and DESTINY-Breast03 trials, respectively). The evolution of these agents in both the metastatic and early settings will continue to transform the treatment algorithm for HER2-positive breast cancer. A particularly interesting concept is whether earlier use of drugs with better CNS efficacy can reduce risk or prevent development of brain metastases.

Endocrine therapy in early-stage hormone receptor-positive (HR+) breast cancer leads to significant reductions in recurrence and breast cancer mortality. A meta-analysis was performed by Early Breast Cancer Trialists' Collaborative Group including four trials (ABCSG XII, SOFT, TEXT and HOBOE), 7030 premenopausal patients with early-stage ER+ breast cancer, who received an aromatase inhibitor or tamoxifen for 3-5 years with ovarian suppression. Rates of breast cancer recurrence were lower with an aromatase inhibitor vs tamoxifen, with the main benefit seen during years 0-4 (relative risk [RR] 0.68, P < .0001) and an absolute reduction in 5-year recurrence risk of 3.2% (6.9% vs 10.1%). Aromatase inhibitor use was associated with decreased distant recurrence risk (RR 0.83), but there was no significant difference for breast cancer or all-cause mortality. The favored endocrine therapy approach for an individual patient is often complex and based on overall risk, comorbidities and toxicity concerns, as well as patient preference. Longer follow-up of trials with endocrine therapy and ovarian suppression will provide further insight on mortality impact.

Aromatase inhibitor (AI)-associated musculoskeletal symptoms are not infrequent and can contribute to treatment discontinuation. Current management practices include use of non-steroidal anti-inflammatory drugs (NSAID), weight loss and exercise, trial of alternative AI or tamoxifen, use of serotonin and norepinephrine reuptake inhibitors (SNRI) (duloxetine) and acupuncture. Martinez et al reported on outcomes of the non-selective NSAID, sulindac (150mg twice daily for 12 months), in a phase 2 study among postmenopausal women with early HR+ breast cancer who were stable on AI therapy for at least 3 months. At 12 months, patients receiving sulindac (n = 43) reported improvements (decreases) in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index (-5.85, P = .003), pain (-5.40, P = .043), stiffness (-9.53, P < .001) and physical function (-5.61, P = .006); those in the observation group (n = 40) did not experience improvements in these variables. The most significant improvement with sulindac was seen in those with a higher degree of baseline symptoms and in overweight/obese patients. These findings support further investigation into abbreviated NSAID use and strategies focused on exercise and healthy body weight maintenance for breast cancer patients.

The treatment landscape for early-stage triple-negative breast cancer (TNBC) continues to evolve with integration of new drugs into our armamentarium, and use of pathologic complete response (pCR) as a surrogate for outcome and for tailoring adjuvant therapy. Geyer et al reported on event-free survival outcomes with a 4.5 year follow-up of the phase 3 BrighTNess trial, which included 634 patients with stage II-III TNBC. Significant improvement in event-free survival (EFS) was seen in the carboplatin + veliparib + paclitaxel arm vs. paclitaxel alone (HR 0.63, P = .02), but no difference in EFS in carboplatin + veliparib + paclitaxel vs. carboplatin + paclitaxel (HR 1.12, P = .62). The EFS rates at 4 years were 78% (carboplatin + veliparib + paclitaxel), 79% (carboplatin + paclitaxel) and 69% (paclitaxel alone). The phase 3 KEYNOTE-522 trial demonstrated improvement in EFS with the addition of neoadjuvant pembrolizumab to chemotherapy (carboplatin/paclitaxel followed by AC) followed by adjuvant pembrolizumab compared to chemotherapy alone in patients with stage II-III TNBC. The emergence of new therapies for early TNBC, including immunotherapy and  poly (ADP-ribose) polymerase (PARP) inhibitors (the latter for patients with germline BRCA mutations), has created more treatment options for patients along with questions regarding combinations and sequencing.  

Recommended Additional Reading:

Lin N et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;Spotlight Poster Session, PD4-04 Abstract 858. https://www.abstractsonline.com/pp8/#!/10462/presentation/482

Hurvitz S et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. https://www.abstractsonline.com/pp8/#!/10462/presentation/649

Rosati MS, Di Seri M, Baciarello G, et al. Etoricoxib and anastrozole in adjuvant early breast cancer: ETAN trial (phase III). J Clin Oncol. 2011;29:suppl.533. https://ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.533

Schmid P et al for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. https://www.nejm.org/doi/full/10.1056/NEJMoa2112651

The predilection for brain metastases in human epidermal growth factor receptor 2 (HER2)-positive breast cancer has historically presented a therapeutic challenge, and agents with enhanced central nervous system (CNS) penetrance are certainly desired. Pyrotinib is a small molecule irreversible tyrosine kinase inhibitor against epidermal growth factor receptor (EGFR), HER2, and HER4. Yan et al investigated the activity and safety of pyrotinib + capecitabine in the single-arm, two-cohort, phase 2 PERMEATE study among 78 patients with HER2-positive metastatic breast cancer (MBC) with brain metastases. The intracranial objective response rate was 74.6% in radiotherapy-naive patients and 42.1% in those progressing after prior radiotherapy. The combination showed good tolerability with the most common grade 3 treatment-related adverse events of diarrhea and neutropenia. Additional studies have shown impressive CNS activity with other HER2-targeted therapies including tucatinib + capecitabine + trastuzumab combination, as well as trastuzumab deruxtecan (HER2CLIMB and DESTINY-Breast03 trials, respectively). The evolution of these agents in both the metastatic and early settings will continue to transform the treatment algorithm for HER2-positive breast cancer. A particularly interesting concept is whether earlier use of drugs with better CNS efficacy can reduce risk or prevent development of brain metastases.

Endocrine therapy in early-stage hormone receptor-positive (HR+) breast cancer leads to significant reductions in recurrence and breast cancer mortality. A meta-analysis was performed by Early Breast Cancer Trialists' Collaborative Group including four trials (ABCSG XII, SOFT, TEXT and HOBOE), 7030 premenopausal patients with early-stage ER+ breast cancer, who received an aromatase inhibitor or tamoxifen for 3-5 years with ovarian suppression. Rates of breast cancer recurrence were lower with an aromatase inhibitor vs tamoxifen, with the main benefit seen during years 0-4 (relative risk [RR] 0.68, P < .0001) and an absolute reduction in 5-year recurrence risk of 3.2% (6.9% vs 10.1%). Aromatase inhibitor use was associated with decreased distant recurrence risk (RR 0.83), but there was no significant difference for breast cancer or all-cause mortality. The favored endocrine therapy approach for an individual patient is often complex and based on overall risk, comorbidities and toxicity concerns, as well as patient preference. Longer follow-up of trials with endocrine therapy and ovarian suppression will provide further insight on mortality impact.

Aromatase inhibitor (AI)-associated musculoskeletal symptoms are not infrequent and can contribute to treatment discontinuation. Current management practices include use of non-steroidal anti-inflammatory drugs (NSAID), weight loss and exercise, trial of alternative AI or tamoxifen, use of serotonin and norepinephrine reuptake inhibitors (SNRI) (duloxetine) and acupuncture. Martinez et al reported on outcomes of the non-selective NSAID, sulindac (150mg twice daily for 12 months), in a phase 2 study among postmenopausal women with early HR+ breast cancer who were stable on AI therapy for at least 3 months. At 12 months, patients receiving sulindac (n = 43) reported improvements (decreases) in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index (-5.85, P = .003), pain (-5.40, P = .043), stiffness (-9.53, P < .001) and physical function (-5.61, P = .006); those in the observation group (n = 40) did not experience improvements in these variables. The most significant improvement with sulindac was seen in those with a higher degree of baseline symptoms and in overweight/obese patients. These findings support further investigation into abbreviated NSAID use and strategies focused on exercise and healthy body weight maintenance for breast cancer patients.

The treatment landscape for early-stage triple-negative breast cancer (TNBC) continues to evolve with integration of new drugs into our armamentarium, and use of pathologic complete response (pCR) as a surrogate for outcome and for tailoring adjuvant therapy. Geyer et al reported on event-free survival outcomes with a 4.5 year follow-up of the phase 3 BrighTNess trial, which included 634 patients with stage II-III TNBC. Significant improvement in event-free survival (EFS) was seen in the carboplatin + veliparib + paclitaxel arm vs. paclitaxel alone (HR 0.63, P = .02), but no difference in EFS in carboplatin + veliparib + paclitaxel vs. carboplatin + paclitaxel (HR 1.12, P = .62). The EFS rates at 4 years were 78% (carboplatin + veliparib + paclitaxel), 79% (carboplatin + paclitaxel) and 69% (paclitaxel alone). The phase 3 KEYNOTE-522 trial demonstrated improvement in EFS with the addition of neoadjuvant pembrolizumab to chemotherapy (carboplatin/paclitaxel followed by AC) followed by adjuvant pembrolizumab compared to chemotherapy alone in patients with stage II-III TNBC. The emergence of new therapies for early TNBC, including immunotherapy and  poly (ADP-ribose) polymerase (PARP) inhibitors (the latter for patients with germline BRCA mutations), has created more treatment options for patients along with questions regarding combinations and sequencing.  

Recommended Additional Reading:

Lin N et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;Spotlight Poster Session, PD4-04 Abstract 858. https://www.abstractsonline.com/pp8/#!/10462/presentation/482

Hurvitz S et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. https://www.abstractsonline.com/pp8/#!/10462/presentation/649

Rosati MS, Di Seri M, Baciarello G, et al. Etoricoxib and anastrozole in adjuvant early breast cancer: ETAN trial (phase III). J Clin Oncol. 2011;29:suppl.533. https://ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.533

Schmid P et al for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. https://www.nejm.org/doi/full/10.1056/NEJMoa2112651

The predilection for brain metastases in human epidermal growth factor receptor 2 (HER2)-positive breast cancer has historically presented a therapeutic challenge, and agents with enhanced central nervous system (CNS) penetrance are certainly desired. Pyrotinib is a small molecule irreversible tyrosine kinase inhibitor against epidermal growth factor receptor (EGFR), HER2, and HER4. Yan et al investigated the activity and safety of pyrotinib + capecitabine in the single-arm, two-cohort, phase 2 PERMEATE study among 78 patients with HER2-positive metastatic breast cancer (MBC) with brain metastases. The intracranial objective response rate was 74.6% in radiotherapy-naive patients and 42.1% in those progressing after prior radiotherapy. The combination showed good tolerability with the most common grade 3 treatment-related adverse events of diarrhea and neutropenia. Additional studies have shown impressive CNS activity with other HER2-targeted therapies including tucatinib + capecitabine + trastuzumab combination, as well as trastuzumab deruxtecan (HER2CLIMB and DESTINY-Breast03 trials, respectively). The evolution of these agents in both the metastatic and early settings will continue to transform the treatment algorithm for HER2-positive breast cancer. A particularly interesting concept is whether earlier use of drugs with better CNS efficacy can reduce risk or prevent development of brain metastases.

Endocrine therapy in early-stage hormone receptor-positive (HR+) breast cancer leads to significant reductions in recurrence and breast cancer mortality. A meta-analysis was performed by Early Breast Cancer Trialists' Collaborative Group including four trials (ABCSG XII, SOFT, TEXT and HOBOE), 7030 premenopausal patients with early-stage ER+ breast cancer, who received an aromatase inhibitor or tamoxifen for 3-5 years with ovarian suppression. Rates of breast cancer recurrence were lower with an aromatase inhibitor vs tamoxifen, with the main benefit seen during years 0-4 (relative risk [RR] 0.68, P < .0001) and an absolute reduction in 5-year recurrence risk of 3.2% (6.9% vs 10.1%). Aromatase inhibitor use was associated with decreased distant recurrence risk (RR 0.83), but there was no significant difference for breast cancer or all-cause mortality. The favored endocrine therapy approach for an individual patient is often complex and based on overall risk, comorbidities and toxicity concerns, as well as patient preference. Longer follow-up of trials with endocrine therapy and ovarian suppression will provide further insight on mortality impact.

Aromatase inhibitor (AI)-associated musculoskeletal symptoms are not infrequent and can contribute to treatment discontinuation. Current management practices include use of non-steroidal anti-inflammatory drugs (NSAID), weight loss and exercise, trial of alternative AI or tamoxifen, use of serotonin and norepinephrine reuptake inhibitors (SNRI) (duloxetine) and acupuncture. Martinez et al reported on outcomes of the non-selective NSAID, sulindac (150mg twice daily for 12 months), in a phase 2 study among postmenopausal women with early HR+ breast cancer who were stable on AI therapy for at least 3 months. At 12 months, patients receiving sulindac (n = 43) reported improvements (decreases) in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index (-5.85, P = .003), pain (-5.40, P = .043), stiffness (-9.53, P < .001) and physical function (-5.61, P = .006); those in the observation group (n = 40) did not experience improvements in these variables. The most significant improvement with sulindac was seen in those with a higher degree of baseline symptoms and in overweight/obese patients. These findings support further investigation into abbreviated NSAID use and strategies focused on exercise and healthy body weight maintenance for breast cancer patients.

The treatment landscape for early-stage triple-negative breast cancer (TNBC) continues to evolve with integration of new drugs into our armamentarium, and use of pathologic complete response (pCR) as a surrogate for outcome and for tailoring adjuvant therapy. Geyer et al reported on event-free survival outcomes with a 4.5 year follow-up of the phase 3 BrighTNess trial, which included 634 patients with stage II-III TNBC. Significant improvement in event-free survival (EFS) was seen in the carboplatin + veliparib + paclitaxel arm vs. paclitaxel alone (HR 0.63, P = .02), but no difference in EFS in carboplatin + veliparib + paclitaxel vs. carboplatin + paclitaxel (HR 1.12, P = .62). The EFS rates at 4 years were 78% (carboplatin + veliparib + paclitaxel), 79% (carboplatin + paclitaxel) and 69% (paclitaxel alone). The phase 3 KEYNOTE-522 trial demonstrated improvement in EFS with the addition of neoadjuvant pembrolizumab to chemotherapy (carboplatin/paclitaxel followed by AC) followed by adjuvant pembrolizumab compared to chemotherapy alone in patients with stage II-III TNBC. The emergence of new therapies for early TNBC, including immunotherapy and  poly (ADP-ribose) polymerase (PARP) inhibitors (the latter for patients with germline BRCA mutations), has created more treatment options for patients along with questions regarding combinations and sequencing.  

Recommended Additional Reading:

Lin N et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;Spotlight Poster Session, PD4-04 Abstract 858. https://www.abstractsonline.com/pp8/#!/10462/presentation/482

Hurvitz S et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. https://www.abstractsonline.com/pp8/#!/10462/presentation/649

Rosati MS, Di Seri M, Baciarello G, et al. Etoricoxib and anastrozole in adjuvant early breast cancer: ETAN trial (phase III). J Clin Oncol. 2011;29:suppl.533. https://ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.533

Schmid P et al for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. https://www.nejm.org/doi/full/10.1056/NEJMoa2112651

Breast cancer risk genes are generally associated with triple-negative and high-grade disease, but differ substantially in their associated pathology, a large case-control analysis shows.

The findings have potential implications for genetic testing, risk prediction, variant classification, and screening, the authors noted.

To assess links between pathogenic germline variants in nine major breast cancer (BC) susceptibility genes and pathological features of nonmetastasized breast tumors, investigators from the Breast Cancer Association Consortium compared 42,680 women with breast cancer and 42,387 population-matched controls from the BRIDGES large-scale sequencing study.

They looked specifically at features relevant to prognosis and distinct therapeutic options, including tumor subtype, morphology, size, stage, and lymph node involvement, and found substantial differences in tumor subtype distribution by gene.

“Pathogenic [protein-truncating variants and pathogenic missense variants] in these ... susceptibility genes were disproportionately associated with more aggressive breast caner, particularly among younger women,” they wrote, noting that carriers of rare genetic variants in the nine genes comprised more than 27% of women diagnosed at age 40 or younger with triple-negative disease (driven mainly by BRCA1) and about 16% of those diagnosed with hormone receptor (HR)–positive, HER2-negative high-grade disease.

All together, the nine genes were associated with 14.4% of tumors in women aged 40 years and younger, but less than 4% in women over age 60 years, and among younger women, the prevalence of variants combined was higher in those with triple-negative and HR-positive, HER2-negative disease versus other subtypes, they said.

The findings were published online on Jan. 27, 2022, in JAMA Oncology.

Study subjects were women aged 18-79 years who were sampled, independently of family history, from 38 international population- or hospital-based studies conducted between 1991 and 2016.

The genes assessed included ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

Substantial heterogeneity was observed in the distribution of intrinsic subtypes by gene. For example, RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (odds ratios, 6.19, 6.19, and 10.05 respectively), and CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease, the authors found.

“For ATM variants, the association was strongest for [HR-positive, HER2-negative]high-grade subtype (OR, 4.99). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32),” they wrote.

BRCA2 and PALB2 variants were also associated with triple-negative disease, TP53 variants were most strongly associated with HR-positive, HER2-negative and HR-negative, HER2-positive subtypes, and tumors occurring in pathogenic variant carriers were of higher grade, they added, noting that for most genes and subtypes, a decline in ORs was observed with increasing age.

All genes except CHEK2 were more strongly associated with high-grade disease.

These and other findings from the study can “inform guidelines for eligibility for gene panel sequencing and breast cancer surveillance in the general population,” the authors explained, adding that tumor characteristics can also be used to determine whether variants of uncertain significance are likely to be pathogenic.

The data should therefore “improve the precision of variant classification algorithms and extend them to a larger set of genes,” they noted.

“This case-control study suggests that rare variants in BC susceptibility genes display marked heterogeneity with respect to tumor phenotype, but also similarities between genes that are consistent with known biological functions. This present study provides detailed quantification of subtype-specific breast cancer risks; these can potentially improve risk prediction models and breast cancer prevention strategies,” they concluded.

More specifically, women found to be carrying variants in these genes may be offered enhanced screening, including by MRI, risk-reducing surgery, chemoprevention, and genetic counseling, corresponding author Nasim Mavaddat, MBBS, PhD, explained in an interview.

“Understanding tumor pathology associated with the genes can inform breast cancer risk prediction models, and management and treatment of women harboring pathogenic variants,” she noted.

The findings “enhance our understanding of breast cancer biology and aid efforts to classify whether genetic variants of uncertain significance are also likely to be pathogenic,” added Dr. Mavaddat, a senior research associate at the University of Cambridge (England).

She also said the investigators are taking steps to include the results in “CanRisk,” a cancer risk prediction model used by genetic counselors and other clinicians, and are “exploring whether variants in these genes are associated with contralateral breast cancer risk and survival after a breast cancer.”

As most participants were European, analyses should be extended to women of other racial and ethnic groups, she added.

The BRIDGES panel sequencing was supported by the European Union Horizon 2020 research and innovation program BRIDGES and the Wellcome Trust. The Breast Cancer Association Consortium is also funded by the European Union Horizon 2020 research and innovation program, the PERSPECTIVE I&I project, which is funded by the Government of Canada, and the Confluence project, which is funded with intramural funds from the National Cancer Institute. Dr. Mavaddat reported grants from the University of Cambridge, European Union Horizon 2020, Wellcome Trust, Genome Canada, Canadian Institutes of Health Research, and National Cancer Institute during the conduct of the study.

Breast cancer risk genes are generally associated with triple-negative and high-grade disease, but differ substantially in their associated pathology, a large case-control analysis shows.

The findings have potential implications for genetic testing, risk prediction, variant classification, and screening, the authors noted.

To assess links between pathogenic germline variants in nine major breast cancer (BC) susceptibility genes and pathological features of nonmetastasized breast tumors, investigators from the Breast Cancer Association Consortium compared 42,680 women with breast cancer and 42,387 population-matched controls from the BRIDGES large-scale sequencing study.

They looked specifically at features relevant to prognosis and distinct therapeutic options, including tumor subtype, morphology, size, stage, and lymph node involvement, and found substantial differences in tumor subtype distribution by gene.

“Pathogenic [protein-truncating variants and pathogenic missense variants] in these ... susceptibility genes were disproportionately associated with more aggressive breast caner, particularly among younger women,” they wrote, noting that carriers of rare genetic variants in the nine genes comprised more than 27% of women diagnosed at age 40 or younger with triple-negative disease (driven mainly by BRCA1) and about 16% of those diagnosed with hormone receptor (HR)–positive, HER2-negative high-grade disease.

All together, the nine genes were associated with 14.4% of tumors in women aged 40 years and younger, but less than 4% in women over age 60 years, and among younger women, the prevalence of variants combined was higher in those with triple-negative and HR-positive, HER2-negative disease versus other subtypes, they said.

The findings were published online on Jan. 27, 2022, in JAMA Oncology.

Study subjects were women aged 18-79 years who were sampled, independently of family history, from 38 international population- or hospital-based studies conducted between 1991 and 2016.

The genes assessed included ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

Substantial heterogeneity was observed in the distribution of intrinsic subtypes by gene. For example, RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (odds ratios, 6.19, 6.19, and 10.05 respectively), and CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease, the authors found.

“For ATM variants, the association was strongest for [HR-positive, HER2-negative]high-grade subtype (OR, 4.99). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32),” they wrote.

BRCA2 and PALB2 variants were also associated with triple-negative disease, TP53 variants were most strongly associated with HR-positive, HER2-negative and HR-negative, HER2-positive subtypes, and tumors occurring in pathogenic variant carriers were of higher grade, they added, noting that for most genes and subtypes, a decline in ORs was observed with increasing age.

All genes except CHEK2 were more strongly associated with high-grade disease.

These and other findings from the study can “inform guidelines for eligibility for gene panel sequencing and breast cancer surveillance in the general population,” the authors explained, adding that tumor characteristics can also be used to determine whether variants of uncertain significance are likely to be pathogenic.

The data should therefore “improve the precision of variant classification algorithms and extend them to a larger set of genes,” they noted.

“This case-control study suggests that rare variants in BC susceptibility genes display marked heterogeneity with respect to tumor phenotype, but also similarities between genes that are consistent with known biological functions. This present study provides detailed quantification of subtype-specific breast cancer risks; these can potentially improve risk prediction models and breast cancer prevention strategies,” they concluded.

More specifically, women found to be carrying variants in these genes may be offered enhanced screening, including by MRI, risk-reducing surgery, chemoprevention, and genetic counseling, corresponding author Nasim Mavaddat, MBBS, PhD, explained in an interview.

“Understanding tumor pathology associated with the genes can inform breast cancer risk prediction models, and management and treatment of women harboring pathogenic variants,” she noted.

The findings “enhance our understanding of breast cancer biology and aid efforts to classify whether genetic variants of uncertain significance are also likely to be pathogenic,” added Dr. Mavaddat, a senior research associate at the University of Cambridge (England).

She also said the investigators are taking steps to include the results in “CanRisk,” a cancer risk prediction model used by genetic counselors and other clinicians, and are “exploring whether variants in these genes are associated with contralateral breast cancer risk and survival after a breast cancer.”

As most participants were European, analyses should be extended to women of other racial and ethnic groups, she added.

The BRIDGES panel sequencing was supported by the European Union Horizon 2020 research and innovation program BRIDGES and the Wellcome Trust. The Breast Cancer Association Consortium is also funded by the European Union Horizon 2020 research and innovation program, the PERSPECTIVE I&I project, which is funded by the Government of Canada, and the Confluence project, which is funded with intramural funds from the National Cancer Institute. Dr. Mavaddat reported grants from the University of Cambridge, European Union Horizon 2020, Wellcome Trust, Genome Canada, Canadian Institutes of Health Research, and National Cancer Institute during the conduct of the study.

Breast cancer risk genes are generally associated with triple-negative and high-grade disease, but differ substantially in their associated pathology, a large case-control analysis shows.

The findings have potential implications for genetic testing, risk prediction, variant classification, and screening, the authors noted.

To assess links between pathogenic germline variants in nine major breast cancer (BC) susceptibility genes and pathological features of nonmetastasized breast tumors, investigators from the Breast Cancer Association Consortium compared 42,680 women with breast cancer and 42,387 population-matched controls from the BRIDGES large-scale sequencing study.

They looked specifically at features relevant to prognosis and distinct therapeutic options, including tumor subtype, morphology, size, stage, and lymph node involvement, and found substantial differences in tumor subtype distribution by gene.

“Pathogenic [protein-truncating variants and pathogenic missense variants] in these ... susceptibility genes were disproportionately associated with more aggressive breast caner, particularly among younger women,” they wrote, noting that carriers of rare genetic variants in the nine genes comprised more than 27% of women diagnosed at age 40 or younger with triple-negative disease (driven mainly by BRCA1) and about 16% of those diagnosed with hormone receptor (HR)–positive, HER2-negative high-grade disease.

All together, the nine genes were associated with 14.4% of tumors in women aged 40 years and younger, but less than 4% in women over age 60 years, and among younger women, the prevalence of variants combined was higher in those with triple-negative and HR-positive, HER2-negative disease versus other subtypes, they said.

The findings were published online on Jan. 27, 2022, in JAMA Oncology.

Study subjects were women aged 18-79 years who were sampled, independently of family history, from 38 international population- or hospital-based studies conducted between 1991 and 2016.

The genes assessed included ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

Substantial heterogeneity was observed in the distribution of intrinsic subtypes by gene. For example, RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (odds ratios, 6.19, 6.19, and 10.05 respectively), and CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease, the authors found.

“For ATM variants, the association was strongest for [HR-positive, HER2-negative]high-grade subtype (OR, 4.99). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32),” they wrote.

BRCA2 and PALB2 variants were also associated with triple-negative disease, TP53 variants were most strongly associated with HR-positive, HER2-negative and HR-negative, HER2-positive subtypes, and tumors occurring in pathogenic variant carriers were of higher grade, they added, noting that for most genes and subtypes, a decline in ORs was observed with increasing age.

All genes except CHEK2 were more strongly associated with high-grade disease.

These and other findings from the study can “inform guidelines for eligibility for gene panel sequencing and breast cancer surveillance in the general population,” the authors explained, adding that tumor characteristics can also be used to determine whether variants of uncertain significance are likely to be pathogenic.

The data should therefore “improve the precision of variant classification algorithms and extend them to a larger set of genes,” they noted.

“This case-control study suggests that rare variants in BC susceptibility genes display marked heterogeneity with respect to tumor phenotype, but also similarities between genes that are consistent with known biological functions. This present study provides detailed quantification of subtype-specific breast cancer risks; these can potentially improve risk prediction models and breast cancer prevention strategies,” they concluded.

More specifically, women found to be carrying variants in these genes may be offered enhanced screening, including by MRI, risk-reducing surgery, chemoprevention, and genetic counseling, corresponding author Nasim Mavaddat, MBBS, PhD, explained in an interview.

“Understanding tumor pathology associated with the genes can inform breast cancer risk prediction models, and management and treatment of women harboring pathogenic variants,” she noted.

The findings “enhance our understanding of breast cancer biology and aid efforts to classify whether genetic variants of uncertain significance are also likely to be pathogenic,” added Dr. Mavaddat, a senior research associate at the University of Cambridge (England).

She also said the investigators are taking steps to include the results in “CanRisk,” a cancer risk prediction model used by genetic counselors and other clinicians, and are “exploring whether variants in these genes are associated with contralateral breast cancer risk and survival after a breast cancer.”

As most participants were European, analyses should be extended to women of other racial and ethnic groups, she added.

The BRIDGES panel sequencing was supported by the European Union Horizon 2020 research and innovation program BRIDGES and the Wellcome Trust. The Breast Cancer Association Consortium is also funded by the European Union Horizon 2020 research and innovation program, the PERSPECTIVE I&I project, which is funded by the Government of Canada, and the Confluence project, which is funded with intramural funds from the National Cancer Institute. Dr. Mavaddat reported grants from the University of Cambridge, European Union Horizon 2020, Wellcome Trust, Genome Canada, Canadian Institutes of Health Research, and National Cancer Institute during the conduct of the study.

Women with early-stage breast cancer who are poorly represented in clinical trials have worse survival than their well-represented peers, according to a real-world analysis.

The study shows that more than half of women with early breast cancer are not well represented in clinical trials because of age, comorbidities, or race, yet they receive therapies based on the results of these trials.

“The most interesting finding is that patients with comorbidities resulting in lab abnormalities that would typically exclude them from receiving medication on a trial are still frequently receiving these medications and have an almost threefold higher mortality,” Gabrielle Rocque, MD, with the division of hematology and oncology, University of Alabama at Birmingham, told this news organization.

“We need to do a deeper dive to better understand what is driving this mortality difference and test specific medications in patients with these conditions to understand the optimal treatment for this population,” Dr. Rocque added.

The study was published Feb. 1 in JCO Oncology Practice.

Many patient groups are not well represented in clinical trials, including patients of color, older patients, and those with comorbidities, and it remains unclear how treatment outcomes may differ among these patients, compared with those who are well represented in trials.

To investigate, Dr. Rocque and colleagues looked at 11,770 women diagnosed with stage I-III breast cancer between 2005 and 2015 in the American Society of Clinical Oncology CancerLinQ database.

White women between 45 and 69 years of age with no comorbid conditions were considered well represented and made up 48% of the cohort.

Non-White women and/or those younger than 45 years or older than 70 were considered under represented and made up 45% of the cohort. The unrepresented group (7%) included women with comorbidities – such as liver disease, renal insufficiency, thrombocytopenia, anemia, or uncontrolled diabetes – or concurrent cancer.

The majority of the women received a high-intensity chemotherapy regimen, including 58% of unrepresented, 66% of underrepresented, and 63% of well-represented patients.

Compared with well-represented women, unrepresented women had a higher risk of death at 5 years (adjusted hazard ratio, 2.71; 95% confidence interval, 2.08-3.52).

Overall, the team found no significant increase in the risk of death at 5 years in underrepresented vs. well-represented women (aHR, 1.19; 95% CI, 0.98-1.45). However, that risk varied with age. Among underrepresented women, those aged 70 and older had more than a twofold higher risk of 5-year mortality (aHR, 2.21), while those younger than 45 had a lower risk of 5-year mortality (aHR, 0.63), compared with those aged 45-69 years.

For three cancer subtypes, unrepresented patients had a greater than twofold higher risk of 5-year mortality, compared with well-represented patients (aHR, 2.50 for HER2-positive disease; aHR, 2.54 for HR-positive/HER2-negative disease; and aHR, 2.75 for triple-negative disease).

Underrepresented patients with HR-positive/HER2-negative disease had a 38% increased risk of 5-year mortality, compared with their well-represented peers (aHR, 1.38). However, there were no significant differences in 5-year mortality for underrepresented vs. well-represented patients with HER2-positive or triple-negative subtypes.
 

Risky business?

This analysis shows that unrepresented populations receive common treatment regimens at a similar rate as well-represented patients, the researchers note.

“By excluding patients with differing clinical conditions from trials but including them in the population to which drugs can be disseminated, one runs the risk of inadvertently causing injury,” the authors caution.

“To inform the practice of evidence-based medicine in an equitable manner, our findings support a need to both expand clinical trial inclusion criteria and report on clinical trial outcomes by clinical and demographic characteristics,” Dr. Rocque and colleagues conclude.

Charles Shapiro, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, New York, is not surprised by the findings of this study.

“We know that clinical trials are too restrictive and include only a selected population largely without comorbidities, but in the real world, people have comorbidities,” Dr. Shapiro, who was not involved in the research, told this news organization.

The study “starkly illustrates” the poorer survival of populations not represented in clinical trials.

“It could be that we need to change clinical trials, maybe ask fewer questions or maybe ask more important questions and loosen the eligibility up, because in the real world, there are people with comorbidities and people who are over 70,” Dr. Shapiro stated.

Are strides being made to change that? “Not really,” Dr. Shapiro said in an interview.

The study was supported by grants from the Robert Wood Johnson Foundation and the American Cancer Society. Dr. Rocque has served as a consultant or advisor for Pfizer; has received research funding from Carevive Systems, Genentech, and Pfizer; and has received travel, accommodations, and expenses from Carevive. Dr. Shapiro has financial relationships with UptoDate, 2nd MD, and Anthenum.

A version of this article first appeared on Medscape.com.

Women with early-stage breast cancer who are poorly represented in clinical trials have worse survival than their well-represented peers, according to a real-world analysis.

The study shows that more than half of women with early breast cancer are not well represented in clinical trials because of age, comorbidities, or race, yet they receive therapies based on the results of these trials.

“The most interesting finding is that patients with comorbidities resulting in lab abnormalities that would typically exclude them from receiving medication on a trial are still frequently receiving these medications and have an almost threefold higher mortality,” Gabrielle Rocque, MD, with the division of hematology and oncology, University of Alabama at Birmingham, told this news organization.

“We need to do a deeper dive to better understand what is driving this mortality difference and test specific medications in patients with these conditions to understand the optimal treatment for this population,” Dr. Rocque added.

The study was published Feb. 1 in JCO Oncology Practice.

Many patient groups are not well represented in clinical trials, including patients of color, older patients, and those with comorbidities, and it remains unclear how treatment outcomes may differ among these patients, compared with those who are well represented in trials.

To investigate, Dr. Rocque and colleagues looked at 11,770 women diagnosed with stage I-III breast cancer between 2005 and 2015 in the American Society of Clinical Oncology CancerLinQ database.

White women between 45 and 69 years of age with no comorbid conditions were considered well represented and made up 48% of the cohort.

Non-White women and/or those younger than 45 years or older than 70 were considered under represented and made up 45% of the cohort. The unrepresented group (7%) included women with comorbidities – such as liver disease, renal insufficiency, thrombocytopenia, anemia, or uncontrolled diabetes – or concurrent cancer.

The majority of the women received a high-intensity chemotherapy regimen, including 58% of unrepresented, 66% of underrepresented, and 63% of well-represented patients.

Compared with well-represented women, unrepresented women had a higher risk of death at 5 years (adjusted hazard ratio, 2.71; 95% confidence interval, 2.08-3.52).

Overall, the team found no significant increase in the risk of death at 5 years in underrepresented vs. well-represented women (aHR, 1.19; 95% CI, 0.98-1.45). However, that risk varied with age. Among underrepresented women, those aged 70 and older had more than a twofold higher risk of 5-year mortality (aHR, 2.21), while those younger than 45 had a lower risk of 5-year mortality (aHR, 0.63), compared with those aged 45-69 years.

For three cancer subtypes, unrepresented patients had a greater than twofold higher risk of 5-year mortality, compared with well-represented patients (aHR, 2.50 for HER2-positive disease; aHR, 2.54 for HR-positive/HER2-negative disease; and aHR, 2.75 for triple-negative disease).

Underrepresented patients with HR-positive/HER2-negative disease had a 38% increased risk of 5-year mortality, compared with their well-represented peers (aHR, 1.38). However, there were no significant differences in 5-year mortality for underrepresented vs. well-represented patients with HER2-positive or triple-negative subtypes.
 

Risky business?

This analysis shows that unrepresented populations receive common treatment regimens at a similar rate as well-represented patients, the researchers note.

“By excluding patients with differing clinical conditions from trials but including them in the population to which drugs can be disseminated, one runs the risk of inadvertently causing injury,” the authors caution.

“To inform the practice of evidence-based medicine in an equitable manner, our findings support a need to both expand clinical trial inclusion criteria and report on clinical trial outcomes by clinical and demographic characteristics,” Dr. Rocque and colleagues conclude.

Charles Shapiro, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, New York, is not surprised by the findings of this study.

“We know that clinical trials are too restrictive and include only a selected population largely without comorbidities, but in the real world, people have comorbidities,” Dr. Shapiro, who was not involved in the research, told this news organization.

The study “starkly illustrates” the poorer survival of populations not represented in clinical trials.

“It could be that we need to change clinical trials, maybe ask fewer questions or maybe ask more important questions and loosen the eligibility up, because in the real world, there are people with comorbidities and people who are over 70,” Dr. Shapiro stated.

Are strides being made to change that? “Not really,” Dr. Shapiro said in an interview.

The study was supported by grants from the Robert Wood Johnson Foundation and the American Cancer Society. Dr. Rocque has served as a consultant or advisor for Pfizer; has received research funding from Carevive Systems, Genentech, and Pfizer; and has received travel, accommodations, and expenses from Carevive. Dr. Shapiro has financial relationships with UptoDate, 2nd MD, and Anthenum.

A version of this article first appeared on Medscape.com.

Women with early-stage breast cancer who are poorly represented in clinical trials have worse survival than their well-represented peers, according to a real-world analysis.

The study shows that more than half of women with early breast cancer are not well represented in clinical trials because of age, comorbidities, or race, yet they receive therapies based on the results of these trials.

“The most interesting finding is that patients with comorbidities resulting in lab abnormalities that would typically exclude them from receiving medication on a trial are still frequently receiving these medications and have an almost threefold higher mortality,” Gabrielle Rocque, MD, with the division of hematology and oncology, University of Alabama at Birmingham, told this news organization.

“We need to do a deeper dive to better understand what is driving this mortality difference and test specific medications in patients with these conditions to understand the optimal treatment for this population,” Dr. Rocque added.

The study was published Feb. 1 in JCO Oncology Practice.

Many patient groups are not well represented in clinical trials, including patients of color, older patients, and those with comorbidities, and it remains unclear how treatment outcomes may differ among these patients, compared with those who are well represented in trials.

To investigate, Dr. Rocque and colleagues looked at 11,770 women diagnosed with stage I-III breast cancer between 2005 and 2015 in the American Society of Clinical Oncology CancerLinQ database.

White women between 45 and 69 years of age with no comorbid conditions were considered well represented and made up 48% of the cohort.

Non-White women and/or those younger than 45 years or older than 70 were considered under represented and made up 45% of the cohort. The unrepresented group (7%) included women with comorbidities – such as liver disease, renal insufficiency, thrombocytopenia, anemia, or uncontrolled diabetes – or concurrent cancer.

The majority of the women received a high-intensity chemotherapy regimen, including 58% of unrepresented, 66% of underrepresented, and 63% of well-represented patients.

Compared with well-represented women, unrepresented women had a higher risk of death at 5 years (adjusted hazard ratio, 2.71; 95% confidence interval, 2.08-3.52).

Overall, the team found no significant increase in the risk of death at 5 years in underrepresented vs. well-represented women (aHR, 1.19; 95% CI, 0.98-1.45). However, that risk varied with age. Among underrepresented women, those aged 70 and older had more than a twofold higher risk of 5-year mortality (aHR, 2.21), while those younger than 45 had a lower risk of 5-year mortality (aHR, 0.63), compared with those aged 45-69 years.

For three cancer subtypes, unrepresented patients had a greater than twofold higher risk of 5-year mortality, compared with well-represented patients (aHR, 2.50 for HER2-positive disease; aHR, 2.54 for HR-positive/HER2-negative disease; and aHR, 2.75 for triple-negative disease).

Underrepresented patients with HR-positive/HER2-negative disease had a 38% increased risk of 5-year mortality, compared with their well-represented peers (aHR, 1.38). However, there were no significant differences in 5-year mortality for underrepresented vs. well-represented patients with HER2-positive or triple-negative subtypes.
 

Risky business?

This analysis shows that unrepresented populations receive common treatment regimens at a similar rate as well-represented patients, the researchers note.

“By excluding patients with differing clinical conditions from trials but including them in the population to which drugs can be disseminated, one runs the risk of inadvertently causing injury,” the authors caution.

“To inform the practice of evidence-based medicine in an equitable manner, our findings support a need to both expand clinical trial inclusion criteria and report on clinical trial outcomes by clinical and demographic characteristics,” Dr. Rocque and colleagues conclude.

Charles Shapiro, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, New York, is not surprised by the findings of this study.

“We know that clinical trials are too restrictive and include only a selected population largely without comorbidities, but in the real world, people have comorbidities,” Dr. Shapiro, who was not involved in the research, told this news organization.

The study “starkly illustrates” the poorer survival of populations not represented in clinical trials.

“It could be that we need to change clinical trials, maybe ask fewer questions or maybe ask more important questions and loosen the eligibility up, because in the real world, there are people with comorbidities and people who are over 70,” Dr. Shapiro stated.

Are strides being made to change that? “Not really,” Dr. Shapiro said in an interview.

The study was supported by grants from the Robert Wood Johnson Foundation and the American Cancer Society. Dr. Rocque has served as a consultant or advisor for Pfizer; has received research funding from Carevive Systems, Genentech, and Pfizer; and has received travel, accommodations, and expenses from Carevive. Dr. Shapiro has financial relationships with UptoDate, 2nd MD, and Anthenum.

A version of this article first appeared on Medscape.com.

Key clinical point: Sulindac relieved musculoskeletal symptoms in patients with hormone receptor-positive (HR+) breast cancer (BC) who received aromatase inhibitor (AI) for ≥3 months.

Major finding: At 12 months, patients receiving sulindac reported a significant improvement in the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; − 5.85; P = .003), pain (−5.40; P = .043), stiffness (−9.53, P < .001), and physical function (− 5.61; P = .006) with 37% of patients with higher baseline symptoms reporting ≥50% improvement in total WOMAC along with an overall tolerable safety profile.

Study details: Findings are from a phase 2 study of postmenopausal women with HR+ BC stable on AI therapy for ≥3 months, of which 43 women received 150 mg sulindac twice daily for 12 months whereas 40 women formed the non-randomized control arm.

Disclosures: This study was supported by the US National Cancer Institute. The authors declared no conflicts of interest.

Source: Martinez JA et al. Breast Cancer Res Treat. 2022;192:113-122 (Jan 18). Doi: 10.1007/s10549-021-06485-0.

Key clinical point: Sulindac relieved musculoskeletal symptoms in patients with hormone receptor-positive (HR+) breast cancer (BC) who received aromatase inhibitor (AI) for ≥3 months.

Major finding: At 12 months, patients receiving sulindac reported a significant improvement in the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; − 5.85; P = .003), pain (−5.40; P = .043), stiffness (−9.53, P < .001), and physical function (− 5.61; P = .006) with 37% of patients with higher baseline symptoms reporting ≥50% improvement in total WOMAC along with an overall tolerable safety profile.

Study details: Findings are from a phase 2 study of postmenopausal women with HR+ BC stable on AI therapy for ≥3 months, of which 43 women received 150 mg sulindac twice daily for 12 months whereas 40 women formed the non-randomized control arm.

Disclosures: This study was supported by the US National Cancer Institute. The authors declared no conflicts of interest.

Source: Martinez JA et al. Breast Cancer Res Treat. 2022;192:113-122 (Jan 18). Doi: 10.1007/s10549-021-06485-0.

Key clinical point: Sulindac relieved musculoskeletal symptoms in patients with hormone receptor-positive (HR+) breast cancer (BC) who received aromatase inhibitor (AI) for ≥3 months.

Major finding: At 12 months, patients receiving sulindac reported a significant improvement in the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; − 5.85; P = .003), pain (−5.40; P = .043), stiffness (−9.53, P < .001), and physical function (− 5.61; P = .006) with 37% of patients with higher baseline symptoms reporting ≥50% improvement in total WOMAC along with an overall tolerable safety profile.

Study details: Findings are from a phase 2 study of postmenopausal women with HR+ BC stable on AI therapy for ≥3 months, of which 43 women received 150 mg sulindac twice daily for 12 months whereas 40 women formed the non-randomized control arm.

Disclosures: This study was supported by the US National Cancer Institute. The authors declared no conflicts of interest.

Source: Martinez JA et al. Breast Cancer Res Treat. 2022;192:113-122 (Jan 18). Doi: 10.1007/s10549-021-06485-0.