Women's Health

Most women with breast cancer undergo primary surgery within 8 weeks of diagnosis and any later may be associated with worse overall survival, according to findings from a case series.

With no national quality metrics delineating optimal breast cancer surgery timing, the researchers recommend surgery before 8 weeks from breast cancer diagnosis.

“This time interval does not appear to have a detrimental association with cancer outcomes and allows for multidisciplinary care,” the researchers, led by Alyssa A. Wiener, MD, from University of Wisconsin–Madison, said.

But, in an accompanying editorial, two surgical oncologists questioned whether faster surgery is always better.

“Efficiency might associate with quality, but doesn’t always ensure it,” Rita Mukhtar, MD, and Laura Esserman, MD, with the division of surgical oncology, University of California, San Francisco, said.

The study and editorial were published online in JAMA Surgery.


 

Optimal timing for surgery?

Some studies have found worse survival outcomes for women who experience delays between breast cancer diagnosis and surgical treatment, but the optimal window for surgery and the point at which surgery becomes less advantageous remain unknown.

Using the National Cancer Database, Dr. Wiener and colleagues identified 373,334 women (median age, 61) who were diagnosed with stage I to stage III ductal or lobular breast cancer from 2010 to 2014 and followed up through 2019.

All women underwent surgery as their first course of treatment. Patients with prior breast cancer, those who had neoadjuvant or experimental therapy or missing receptor information, and those who were diagnosed with breast cancer on the date of their primary surgery were excluded.

Most patients had timely surgery. The median time to surgery was 30 days, and 88% of patients underwent surgery before the 57-day time point.

Only 12% of patients had surgery more than 8 weeks after their diagnosis. Factors associated with longer times to surgery included age younger than 45, having Medicaid or no insurance, and lower household income.

The overall 5-year survival for the cohort was high at 90%. On multivariable analysis, the researchers found no statistically significant association between time to surgery and overall survival when surgery was performed between 0 and 8 weeks.

However, women who had surgery 9 or more weeks after diagnosis had a significantly higher rate of death within 5 years, compared with those who had surgery performed between 0 and 4 weeks (hazard ratio, 1.15; P < .001). Performing surgery up to 9 weeks (57-63 days) post diagnosis also did not appear to be negatively associated with survival.

This study “highlights that time to treatment of breast cancer is important,” said Sarah P. Cate, MD, director, Breast Surgery Quality Program, Mount Sinai Health System, New York, who wasn’t involved in the study. “Surgery is only one-third of the treatment of breast cancer, so these patients who had longer delays to the OR may have also not started their postsurgery treatments in time.”

In addition, the study found that socioeconomic status – Medicaid or uninsured status and lower household incomes – was associated with longer times to surgery.

“Socioeconomic factors like these may be independently associated with worse outcomes and may contribute to some of the disparities in cancer outcomes observed for resource-limited patients due to delayed care,” the authors said.

Identifying 8 weeks as a goal for time to surgery can help uncover delays associated with socioeconomic factors and provide adequate time for decision-making, the researchers noted.
 

Is faster always better?

Dr. Wiener and colleagues cautioned, however, that their findings should be considered “hypothesis generating,” given that decision-making surrounding breast cancer surgery is complex.

Importantly, the authors noted, tumor characteristics, such as tumor size, nodal status, and receptor subtype, appeared to have a pronounced impact on overall survival, compared with timing of surgery. For instance, compared with a tumor size of 2 cm or fewer, larger tumors – those > 2 cm to ≤ 5 cm and > 5 cm – were associated with worse survival (HR, 1.80 and 2.62, respectively).

“This highlights that tumor biology is the primary driver of patients’ breast cancer outcomes,” the authors noted.

In an accompanying editorial, two surgical oncologists highlighted that faster may not always be better.

For instance, Dr. Mukhtar and Dr. Esserman explained, if a patient with a large node-positive, triple-negative breast cancer receives surgery within a week of diagnosis, “one must question whether this timely care represents quality care, as the opportunity to understand tumor response and affect breast cancer survival has been lost.”

The editorialists noted that time to surgery might also matter very little for indolent, screen-detected cancers, and time to treatment start might matter a lot for fast-growing, interval cancers.

In addition, they questioned whether including the socioeconomic factors highlighted in the overall model would “mitigate the association between time to surgery and survival seen in this study.”

Overall, “operating too soon could indicate lack of quality, while operating too late perhaps reflects lack of access to care,” the editorialists said.

This study was supported by grants from the National Cancer Institute and the National Institutes of Health. Dr. Wiener and Dr. Cate report no relevant financial relationships. Dr. Esserman is a member of the Blue Cross Medical advisory panel, is a board member of the Quantum Leap Healthcare Collaborative, and leads an investigator-initiated vaccine trial for high-risk ductal carcinoma in situ, which is funded by Merck.

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

Most women with breast cancer undergo primary surgery within 8 weeks of diagnosis and any later may be associated with worse overall survival, according to findings from a case series.

With no national quality metrics delineating optimal breast cancer surgery timing, the researchers recommend surgery before 8 weeks from breast cancer diagnosis.

“This time interval does not appear to have a detrimental association with cancer outcomes and allows for multidisciplinary care,” the researchers, led by Alyssa A. Wiener, MD, from University of Wisconsin–Madison, said.

But, in an accompanying editorial, two surgical oncologists questioned whether faster surgery is always better.

“Efficiency might associate with quality, but doesn’t always ensure it,” Rita Mukhtar, MD, and Laura Esserman, MD, with the division of surgical oncology, University of California, San Francisco, said.

The study and editorial were published online in JAMA Surgery.


 

Optimal timing for surgery?

Some studies have found worse survival outcomes for women who experience delays between breast cancer diagnosis and surgical treatment, but the optimal window for surgery and the point at which surgery becomes less advantageous remain unknown.

Using the National Cancer Database, Dr. Wiener and colleagues identified 373,334 women (median age, 61) who were diagnosed with stage I to stage III ductal or lobular breast cancer from 2010 to 2014 and followed up through 2019.

All women underwent surgery as their first course of treatment. Patients with prior breast cancer, those who had neoadjuvant or experimental therapy or missing receptor information, and those who were diagnosed with breast cancer on the date of their primary surgery were excluded.

Most patients had timely surgery. The median time to surgery was 30 days, and 88% of patients underwent surgery before the 57-day time point.

Only 12% of patients had surgery more than 8 weeks after their diagnosis. Factors associated with longer times to surgery included age younger than 45, having Medicaid or no insurance, and lower household income.

The overall 5-year survival for the cohort was high at 90%. On multivariable analysis, the researchers found no statistically significant association between time to surgery and overall survival when surgery was performed between 0 and 8 weeks.

However, women who had surgery 9 or more weeks after diagnosis had a significantly higher rate of death within 5 years, compared with those who had surgery performed between 0 and 4 weeks (hazard ratio, 1.15; P < .001). Performing surgery up to 9 weeks (57-63 days) post diagnosis also did not appear to be negatively associated with survival.

This study “highlights that time to treatment of breast cancer is important,” said Sarah P. Cate, MD, director, Breast Surgery Quality Program, Mount Sinai Health System, New York, who wasn’t involved in the study. “Surgery is only one-third of the treatment of breast cancer, so these patients who had longer delays to the OR may have also not started their postsurgery treatments in time.”

In addition, the study found that socioeconomic status – Medicaid or uninsured status and lower household incomes – was associated with longer times to surgery.

“Socioeconomic factors like these may be independently associated with worse outcomes and may contribute to some of the disparities in cancer outcomes observed for resource-limited patients due to delayed care,” the authors said.

Identifying 8 weeks as a goal for time to surgery can help uncover delays associated with socioeconomic factors and provide adequate time for decision-making, the researchers noted.
 

Is faster always better?

Dr. Wiener and colleagues cautioned, however, that their findings should be considered “hypothesis generating,” given that decision-making surrounding breast cancer surgery is complex.

Importantly, the authors noted, tumor characteristics, such as tumor size, nodal status, and receptor subtype, appeared to have a pronounced impact on overall survival, compared with timing of surgery. For instance, compared with a tumor size of 2 cm or fewer, larger tumors – those > 2 cm to ≤ 5 cm and > 5 cm – were associated with worse survival (HR, 1.80 and 2.62, respectively).

“This highlights that tumor biology is the primary driver of patients’ breast cancer outcomes,” the authors noted.

In an accompanying editorial, two surgical oncologists highlighted that faster may not always be better.

For instance, Dr. Mukhtar and Dr. Esserman explained, if a patient with a large node-positive, triple-negative breast cancer receives surgery within a week of diagnosis, “one must question whether this timely care represents quality care, as the opportunity to understand tumor response and affect breast cancer survival has been lost.”

The editorialists noted that time to surgery might also matter very little for indolent, screen-detected cancers, and time to treatment start might matter a lot for fast-growing, interval cancers.

In addition, they questioned whether including the socioeconomic factors highlighted in the overall model would “mitigate the association between time to surgery and survival seen in this study.”

Overall, “operating too soon could indicate lack of quality, while operating too late perhaps reflects lack of access to care,” the editorialists said.

This study was supported by grants from the National Cancer Institute and the National Institutes of Health. Dr. Wiener and Dr. Cate report no relevant financial relationships. Dr. Esserman is a member of the Blue Cross Medical advisory panel, is a board member of the Quantum Leap Healthcare Collaborative, and leads an investigator-initiated vaccine trial for high-risk ductal carcinoma in situ, which is funded by Merck.

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

Most women with breast cancer undergo primary surgery within 8 weeks of diagnosis and any later may be associated with worse overall survival, according to findings from a case series.

With no national quality metrics delineating optimal breast cancer surgery timing, the researchers recommend surgery before 8 weeks from breast cancer diagnosis.

“This time interval does not appear to have a detrimental association with cancer outcomes and allows for multidisciplinary care,” the researchers, led by Alyssa A. Wiener, MD, from University of Wisconsin–Madison, said.

But, in an accompanying editorial, two surgical oncologists questioned whether faster surgery is always better.

“Efficiency might associate with quality, but doesn’t always ensure it,” Rita Mukhtar, MD, and Laura Esserman, MD, with the division of surgical oncology, University of California, San Francisco, said.

The study and editorial were published online in JAMA Surgery.


 

Optimal timing for surgery?

Some studies have found worse survival outcomes for women who experience delays between breast cancer diagnosis and surgical treatment, but the optimal window for surgery and the point at which surgery becomes less advantageous remain unknown.

Using the National Cancer Database, Dr. Wiener and colleagues identified 373,334 women (median age, 61) who were diagnosed with stage I to stage III ductal or lobular breast cancer from 2010 to 2014 and followed up through 2019.

All women underwent surgery as their first course of treatment. Patients with prior breast cancer, those who had neoadjuvant or experimental therapy or missing receptor information, and those who were diagnosed with breast cancer on the date of their primary surgery were excluded.

Most patients had timely surgery. The median time to surgery was 30 days, and 88% of patients underwent surgery before the 57-day time point.

Only 12% of patients had surgery more than 8 weeks after their diagnosis. Factors associated with longer times to surgery included age younger than 45, having Medicaid or no insurance, and lower household income.

The overall 5-year survival for the cohort was high at 90%. On multivariable analysis, the researchers found no statistically significant association between time to surgery and overall survival when surgery was performed between 0 and 8 weeks.

However, women who had surgery 9 or more weeks after diagnosis had a significantly higher rate of death within 5 years, compared with those who had surgery performed between 0 and 4 weeks (hazard ratio, 1.15; P < .001). Performing surgery up to 9 weeks (57-63 days) post diagnosis also did not appear to be negatively associated with survival.

This study “highlights that time to treatment of breast cancer is important,” said Sarah P. Cate, MD, director, Breast Surgery Quality Program, Mount Sinai Health System, New York, who wasn’t involved in the study. “Surgery is only one-third of the treatment of breast cancer, so these patients who had longer delays to the OR may have also not started their postsurgery treatments in time.”

In addition, the study found that socioeconomic status – Medicaid or uninsured status and lower household incomes – was associated with longer times to surgery.

“Socioeconomic factors like these may be independently associated with worse outcomes and may contribute to some of the disparities in cancer outcomes observed for resource-limited patients due to delayed care,” the authors said.

Identifying 8 weeks as a goal for time to surgery can help uncover delays associated with socioeconomic factors and provide adequate time for decision-making, the researchers noted.
 

Is faster always better?

Dr. Wiener and colleagues cautioned, however, that their findings should be considered “hypothesis generating,” given that decision-making surrounding breast cancer surgery is complex.

Importantly, the authors noted, tumor characteristics, such as tumor size, nodal status, and receptor subtype, appeared to have a pronounced impact on overall survival, compared with timing of surgery. For instance, compared with a tumor size of 2 cm or fewer, larger tumors – those > 2 cm to ≤ 5 cm and > 5 cm – were associated with worse survival (HR, 1.80 and 2.62, respectively).

“This highlights that tumor biology is the primary driver of patients’ breast cancer outcomes,” the authors noted.

In an accompanying editorial, two surgical oncologists highlighted that faster may not always be better.

For instance, Dr. Mukhtar and Dr. Esserman explained, if a patient with a large node-positive, triple-negative breast cancer receives surgery within a week of diagnosis, “one must question whether this timely care represents quality care, as the opportunity to understand tumor response and affect breast cancer survival has been lost.”

The editorialists noted that time to surgery might also matter very little for indolent, screen-detected cancers, and time to treatment start might matter a lot for fast-growing, interval cancers.

In addition, they questioned whether including the socioeconomic factors highlighted in the overall model would “mitigate the association between time to surgery and survival seen in this study.”

Overall, “operating too soon could indicate lack of quality, while operating too late perhaps reflects lack of access to care,” the editorialists said.

This study was supported by grants from the National Cancer Institute and the National Institutes of Health. Dr. Wiener and Dr. Cate report no relevant financial relationships. Dr. Esserman is a member of the Blue Cross Medical advisory panel, is a board member of the Quantum Leap Healthcare Collaborative, and leads an investigator-initiated vaccine trial for high-risk ductal carcinoma in situ, which is funded by Merck.

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

Much attention has been focused recently on the idea that breast cancer with a low expression of HER2 can be treated with HER2-targeted agents. Not surprisingly, manufacturers of these drugs have pounced on this idea, as it opens up a whole new patient population: previously these drugs were only for tumors with a high HER2 expression.

There is a large potential market at stake: HER2-low (also referred to as ERBB2-low), as defined by a score of 0 to 3+ on immunohistochemistry (IHC), is seen in approximately 50%-60% of all breast cancers

However, there is still much debate over whether low-HER2 breast cancer is, in fact, a separate clinical entity.

A new large-scale analysis concludes that it is not. The authors argued that it actually it represents a series of biological differences from HER2-negative disease that do not have a strong bearing on outcomes.

The analysis was published online in JAMA Oncology.

For the study, researchers from the University of Chicago examined data on more than 1.1 million breast cancer patients recorded as HER2-negative in the U.S. National Cancer Database, and re-classified almost two thirds as HER2-low on further analysis.

They found that HER2-low status was associated with higher estrogen receptor (ER) expression, as well as a lower rate of pathologic complete response, compared with HER2-negative disease. It was also linked to an improvement in overall survival on multivariate analysis of up to 9% in advance stage triple negative tumors.

“However, the clinical significance of these differences is questionable,” the researchers commented.

HER2-low status alone “should not influence neoadjuvant treatment decisions with currently approved regimens,” they added.

These results “do not support classification of HER2-low breast cancer as a distinct clinical subtype,” the team concluded.

Not necessarily, according to Giuseppe Curigliano, MD, PhD, director of the new drugs and early drug development for innovative therapies division at the European Institute of Oncology, Milan. He argued the opposite case, that HER2-low is a separate clinical entity, in a recent debate on the topic held at the 2022 San Antonio Breast Cancer Symposium.

In a comment, Dr. Curigliano said that a “major strength” of the current study is its large patient cohort, which reflects the majority of cancer diagnoses in the United States, but that it nevertheless has “important limitations that should be considered when interpreting the results.”

The inclusion of only overall survival in the dataset limits the ability to make associations between HER2-low status and cancer-specific prognosis, as “survival may lag years behind recurrence.”

The lack of centralized assessment of IHC results is also an issue, as “some of the results may be associated with regional variation in practice of classifying cases as HER2 0 versus HER2 1+.”

“In my opinion, this is a great limitation,” he said, in being able to conclude that there is “no prognostic difference between ERBB2-low and -negative patients.”

He also noted that, from a molecular point of view, “the key determinant of the gene expression profile is the expression of hormone receptors, [and] if we perform a correction for hormone receptor expression, only marginal differences in gene expression are found” between HER2-low and HER2-negative tumors.

“Similarly, large genomic studies have identified no specific and consistent difference in genomic profiles,” Dr. Curigliano said, and so, HER2-low disease, “as currently defined, should not be considered a distinct molecular entity, but rather a heterogeneous group of tumors, with biology primarily driven by hormone receptor expression.”
 

Analysis quoted by both sides

Senior author of the new analysis, Frederick M. Howard, MD, from the section of hematology-oncology in the department of medicine at the University of Chicago, said that his team’s work was quoted by both sides of the debate at SABCS 2022.

This reflects the fact that, while differences between ERBB2-low and -negative are present, it is “questionable how clinically significant those differences are,” he said in an interview. It’s a matter of “the eye of the beholder.”

Dr. Howard does not think that clinicians are going to modify standard treatment regimens based solely on HER2-low status, and that low expression of the protein “is probably just a reflection of some underlying biologic processes.”

Dr. Howard agreed with Dr. Curigliano that a “caveat” of their study is that the IHC analyses were performed locally, especially as it has shown that there can be discordance between pathologists in around 40% of cases, and that the associations they found might therefore be “strengthened” by more precise quantification of HER2 expression.

“But, even then,” Dr. Howard continued, “I doubt that [ERBB2-low status] is going to be that strong a prognostic factor.”

He believes that advances in analytic techniques will, in the future, allow tumors to be characterized more precisely, and it may be that HER2-low tumors end up being called something else in 5 years.
 

Renewed interest in this subgroup

In their paper, Dr. Howard and colleagues pointed out that, as a group, HER2-low tumors are heterogeneous, with HER2-low found in both hormone receptor–positive and triple-negative breast cancers. Also, various studies have come to different conclusions about what HER2 low means prognostically, with conclusions ranging from negative to neutral and to positive prognoses.

However, new research has shown that patients with HER2-low tumors can benefit from HER2-targeted drugs. In particular, the recent report that the antibody-drug conjugate trastuzumab deruxtecan doubled progression-free survival versus chemotherapy in ERBB2-low tumors led to “renewed interest in the subgroup,” the researchers noted.

To examine this subgroup further, they embarked on their analysis. Examining the National Cancer Database, they gathered information on more than 1.1 million U.S. patients diagnosed with HER2-negative invasive breast cancer in the 10-year period 2010-2019, and for whom IHC results were available.

The patients were reclassified as having HER2-low disease if they had an IHC score of 1+, or 2+ with a negative in situ hybridization test, while those with an IHC score of 0 were deemed to be HER2-negative. They were followed up until Nov. 30, 2022.

These patients had a mean age of 62.4 years, and 99.1% were female. The majority (78.6%) were non-Hispanic white. HER2-low was identified in 65.5% of the cohort, while 34.5% were HER2-negative.

The proportion of HER2-low disease was lower in non-Hispanic black (62.8%) and Hispanic (61%) patients than in non-Hispanic White patients, at 66.1%.

HER2-low disease was also more common in hormone receptor–positive than triple-negative tumors, at just 51.5%, rising to 58.6% for progesterone receptor–positive, ER-negative, and 69.1% for PR-positive, ER-positive tumors.

Multivariate logistic regression analysis taking into account age, sex, race and ethnicity, comorbidity score, and treatment facility type, among other factors, revealed that the likelihood of HER2-low disease was significantly with increased ER expression, at an adjusted odds ratio of 1.15 for each 10% increase (P < .001).

Non-Hispanic Black, Asian, and Pacific Islander patients had similar rates of HER2-low disease as non-Hispanic White patients after adjustment, whereas Native American patients had an increased rate, at an aOR of 1.22 (P < .001), and Hispanic patients had a lower rate, at an aOR of 0.85 (P < .001).

HER2-low status was associated with a slightly reduced likelihood of having a pathologic complete response (aOR, 0.89; P < .001), with similar results when restricting the analysis to patients with triple negative or hormone receptor-positive tumors.

After a median follow-up of 54 months, HER2-low disease was associated with a minor improvement in survival on multivariate analysis, at an adjusted hazard ratio for death of 0.98 (P < .001).

The greatest improvement in survival was seen in patients with stage III and IV triple-negative breast cancer, at HRs of 0.92 and 0.91, respectively, although the researchers noted that this represented only a 2% and 0.4% improvement in 5-year overall survival, respectively.

The study was supported by the Breast Cancer Research Foundation, the American Society of Clinical Oncology/Conquer Cancer Foundation, the Department of Defense, the National Institutes of Health/National Cancer Institute, Susan G. Komen, the Breast Cancer Research Foundation, and the University of Chicago Elwood V. Jensen Scholars Program. Dr. Howard reported no relevant financial relationships. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, Veracyte, Daiichi Sankyo, AstraZeneca, Merck, Seagen, Exact Sciences, Gilead, Bristol-Myers Squibb, Scientific Affairs Group, and Ellipsis.

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

Much attention has been focused recently on the idea that breast cancer with a low expression of HER2 can be treated with HER2-targeted agents. Not surprisingly, manufacturers of these drugs have pounced on this idea, as it opens up a whole new patient population: previously these drugs were only for tumors with a high HER2 expression.

There is a large potential market at stake: HER2-low (also referred to as ERBB2-low), as defined by a score of 0 to 3+ on immunohistochemistry (IHC), is seen in approximately 50%-60% of all breast cancers

However, there is still much debate over whether low-HER2 breast cancer is, in fact, a separate clinical entity.

A new large-scale analysis concludes that it is not. The authors argued that it actually it represents a series of biological differences from HER2-negative disease that do not have a strong bearing on outcomes.

The analysis was published online in JAMA Oncology.

For the study, researchers from the University of Chicago examined data on more than 1.1 million breast cancer patients recorded as HER2-negative in the U.S. National Cancer Database, and re-classified almost two thirds as HER2-low on further analysis.

They found that HER2-low status was associated with higher estrogen receptor (ER) expression, as well as a lower rate of pathologic complete response, compared with HER2-negative disease. It was also linked to an improvement in overall survival on multivariate analysis of up to 9% in advance stage triple negative tumors.

“However, the clinical significance of these differences is questionable,” the researchers commented.

HER2-low status alone “should not influence neoadjuvant treatment decisions with currently approved regimens,” they added.

These results “do not support classification of HER2-low breast cancer as a distinct clinical subtype,” the team concluded.

Not necessarily, according to Giuseppe Curigliano, MD, PhD, director of the new drugs and early drug development for innovative therapies division at the European Institute of Oncology, Milan. He argued the opposite case, that HER2-low is a separate clinical entity, in a recent debate on the topic held at the 2022 San Antonio Breast Cancer Symposium.

In a comment, Dr. Curigliano said that a “major strength” of the current study is its large patient cohort, which reflects the majority of cancer diagnoses in the United States, but that it nevertheless has “important limitations that should be considered when interpreting the results.”

The inclusion of only overall survival in the dataset limits the ability to make associations between HER2-low status and cancer-specific prognosis, as “survival may lag years behind recurrence.”

The lack of centralized assessment of IHC results is also an issue, as “some of the results may be associated with regional variation in practice of classifying cases as HER2 0 versus HER2 1+.”

“In my opinion, this is a great limitation,” he said, in being able to conclude that there is “no prognostic difference between ERBB2-low and -negative patients.”

He also noted that, from a molecular point of view, “the key determinant of the gene expression profile is the expression of hormone receptors, [and] if we perform a correction for hormone receptor expression, only marginal differences in gene expression are found” between HER2-low and HER2-negative tumors.

“Similarly, large genomic studies have identified no specific and consistent difference in genomic profiles,” Dr. Curigliano said, and so, HER2-low disease, “as currently defined, should not be considered a distinct molecular entity, but rather a heterogeneous group of tumors, with biology primarily driven by hormone receptor expression.”
 

Analysis quoted by both sides

Senior author of the new analysis, Frederick M. Howard, MD, from the section of hematology-oncology in the department of medicine at the University of Chicago, said that his team’s work was quoted by both sides of the debate at SABCS 2022.

This reflects the fact that, while differences between ERBB2-low and -negative are present, it is “questionable how clinically significant those differences are,” he said in an interview. It’s a matter of “the eye of the beholder.”

Dr. Howard does not think that clinicians are going to modify standard treatment regimens based solely on HER2-low status, and that low expression of the protein “is probably just a reflection of some underlying biologic processes.”

Dr. Howard agreed with Dr. Curigliano that a “caveat” of their study is that the IHC analyses were performed locally, especially as it has shown that there can be discordance between pathologists in around 40% of cases, and that the associations they found might therefore be “strengthened” by more precise quantification of HER2 expression.

“But, even then,” Dr. Howard continued, “I doubt that [ERBB2-low status] is going to be that strong a prognostic factor.”

He believes that advances in analytic techniques will, in the future, allow tumors to be characterized more precisely, and it may be that HER2-low tumors end up being called something else in 5 years.
 

Renewed interest in this subgroup

In their paper, Dr. Howard and colleagues pointed out that, as a group, HER2-low tumors are heterogeneous, with HER2-low found in both hormone receptor–positive and triple-negative breast cancers. Also, various studies have come to different conclusions about what HER2 low means prognostically, with conclusions ranging from negative to neutral and to positive prognoses.

However, new research has shown that patients with HER2-low tumors can benefit from HER2-targeted drugs. In particular, the recent report that the antibody-drug conjugate trastuzumab deruxtecan doubled progression-free survival versus chemotherapy in ERBB2-low tumors led to “renewed interest in the subgroup,” the researchers noted.

To examine this subgroup further, they embarked on their analysis. Examining the National Cancer Database, they gathered information on more than 1.1 million U.S. patients diagnosed with HER2-negative invasive breast cancer in the 10-year period 2010-2019, and for whom IHC results were available.

The patients were reclassified as having HER2-low disease if they had an IHC score of 1+, or 2+ with a negative in situ hybridization test, while those with an IHC score of 0 were deemed to be HER2-negative. They were followed up until Nov. 30, 2022.

These patients had a mean age of 62.4 years, and 99.1% were female. The majority (78.6%) were non-Hispanic white. HER2-low was identified in 65.5% of the cohort, while 34.5% were HER2-negative.

The proportion of HER2-low disease was lower in non-Hispanic black (62.8%) and Hispanic (61%) patients than in non-Hispanic White patients, at 66.1%.

HER2-low disease was also more common in hormone receptor–positive than triple-negative tumors, at just 51.5%, rising to 58.6% for progesterone receptor–positive, ER-negative, and 69.1% for PR-positive, ER-positive tumors.

Multivariate logistic regression analysis taking into account age, sex, race and ethnicity, comorbidity score, and treatment facility type, among other factors, revealed that the likelihood of HER2-low disease was significantly with increased ER expression, at an adjusted odds ratio of 1.15 for each 10% increase (P < .001).

Non-Hispanic Black, Asian, and Pacific Islander patients had similar rates of HER2-low disease as non-Hispanic White patients after adjustment, whereas Native American patients had an increased rate, at an aOR of 1.22 (P < .001), and Hispanic patients had a lower rate, at an aOR of 0.85 (P < .001).

HER2-low status was associated with a slightly reduced likelihood of having a pathologic complete response (aOR, 0.89; P < .001), with similar results when restricting the analysis to patients with triple negative or hormone receptor-positive tumors.

After a median follow-up of 54 months, HER2-low disease was associated with a minor improvement in survival on multivariate analysis, at an adjusted hazard ratio for death of 0.98 (P < .001).

The greatest improvement in survival was seen in patients with stage III and IV triple-negative breast cancer, at HRs of 0.92 and 0.91, respectively, although the researchers noted that this represented only a 2% and 0.4% improvement in 5-year overall survival, respectively.

The study was supported by the Breast Cancer Research Foundation, the American Society of Clinical Oncology/Conquer Cancer Foundation, the Department of Defense, the National Institutes of Health/National Cancer Institute, Susan G. Komen, the Breast Cancer Research Foundation, and the University of Chicago Elwood V. Jensen Scholars Program. Dr. Howard reported no relevant financial relationships. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, Veracyte, Daiichi Sankyo, AstraZeneca, Merck, Seagen, Exact Sciences, Gilead, Bristol-Myers Squibb, Scientific Affairs Group, and Ellipsis.

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

Much attention has been focused recently on the idea that breast cancer with a low expression of HER2 can be treated with HER2-targeted agents. Not surprisingly, manufacturers of these drugs have pounced on this idea, as it opens up a whole new patient population: previously these drugs were only for tumors with a high HER2 expression.

There is a large potential market at stake: HER2-low (also referred to as ERBB2-low), as defined by a score of 0 to 3+ on immunohistochemistry (IHC), is seen in approximately 50%-60% of all breast cancers

However, there is still much debate over whether low-HER2 breast cancer is, in fact, a separate clinical entity.

A new large-scale analysis concludes that it is not. The authors argued that it actually it represents a series of biological differences from HER2-negative disease that do not have a strong bearing on outcomes.

The analysis was published online in JAMA Oncology.

For the study, researchers from the University of Chicago examined data on more than 1.1 million breast cancer patients recorded as HER2-negative in the U.S. National Cancer Database, and re-classified almost two thirds as HER2-low on further analysis.

They found that HER2-low status was associated with higher estrogen receptor (ER) expression, as well as a lower rate of pathologic complete response, compared with HER2-negative disease. It was also linked to an improvement in overall survival on multivariate analysis of up to 9% in advance stage triple negative tumors.

“However, the clinical significance of these differences is questionable,” the researchers commented.

HER2-low status alone “should not influence neoadjuvant treatment decisions with currently approved regimens,” they added.

These results “do not support classification of HER2-low breast cancer as a distinct clinical subtype,” the team concluded.

Not necessarily, according to Giuseppe Curigliano, MD, PhD, director of the new drugs and early drug development for innovative therapies division at the European Institute of Oncology, Milan. He argued the opposite case, that HER2-low is a separate clinical entity, in a recent debate on the topic held at the 2022 San Antonio Breast Cancer Symposium.

In a comment, Dr. Curigliano said that a “major strength” of the current study is its large patient cohort, which reflects the majority of cancer diagnoses in the United States, but that it nevertheless has “important limitations that should be considered when interpreting the results.”

The inclusion of only overall survival in the dataset limits the ability to make associations between HER2-low status and cancer-specific prognosis, as “survival may lag years behind recurrence.”

The lack of centralized assessment of IHC results is also an issue, as “some of the results may be associated with regional variation in practice of classifying cases as HER2 0 versus HER2 1+.”

“In my opinion, this is a great limitation,” he said, in being able to conclude that there is “no prognostic difference between ERBB2-low and -negative patients.”

He also noted that, from a molecular point of view, “the key determinant of the gene expression profile is the expression of hormone receptors, [and] if we perform a correction for hormone receptor expression, only marginal differences in gene expression are found” between HER2-low and HER2-negative tumors.

“Similarly, large genomic studies have identified no specific and consistent difference in genomic profiles,” Dr. Curigliano said, and so, HER2-low disease, “as currently defined, should not be considered a distinct molecular entity, but rather a heterogeneous group of tumors, with biology primarily driven by hormone receptor expression.”
 

Analysis quoted by both sides

Senior author of the new analysis, Frederick M. Howard, MD, from the section of hematology-oncology in the department of medicine at the University of Chicago, said that his team’s work was quoted by both sides of the debate at SABCS 2022.

This reflects the fact that, while differences between ERBB2-low and -negative are present, it is “questionable how clinically significant those differences are,” he said in an interview. It’s a matter of “the eye of the beholder.”

Dr. Howard does not think that clinicians are going to modify standard treatment regimens based solely on HER2-low status, and that low expression of the protein “is probably just a reflection of some underlying biologic processes.”

Dr. Howard agreed with Dr. Curigliano that a “caveat” of their study is that the IHC analyses were performed locally, especially as it has shown that there can be discordance between pathologists in around 40% of cases, and that the associations they found might therefore be “strengthened” by more precise quantification of HER2 expression.

“But, even then,” Dr. Howard continued, “I doubt that [ERBB2-low status] is going to be that strong a prognostic factor.”

He believes that advances in analytic techniques will, in the future, allow tumors to be characterized more precisely, and it may be that HER2-low tumors end up being called something else in 5 years.
 

Renewed interest in this subgroup

In their paper, Dr. Howard and colleagues pointed out that, as a group, HER2-low tumors are heterogeneous, with HER2-low found in both hormone receptor–positive and triple-negative breast cancers. Also, various studies have come to different conclusions about what HER2 low means prognostically, with conclusions ranging from negative to neutral and to positive prognoses.

However, new research has shown that patients with HER2-low tumors can benefit from HER2-targeted drugs. In particular, the recent report that the antibody-drug conjugate trastuzumab deruxtecan doubled progression-free survival versus chemotherapy in ERBB2-low tumors led to “renewed interest in the subgroup,” the researchers noted.

To examine this subgroup further, they embarked on their analysis. Examining the National Cancer Database, they gathered information on more than 1.1 million U.S. patients diagnosed with HER2-negative invasive breast cancer in the 10-year period 2010-2019, and for whom IHC results were available.

The patients were reclassified as having HER2-low disease if they had an IHC score of 1+, or 2+ with a negative in situ hybridization test, while those with an IHC score of 0 were deemed to be HER2-negative. They were followed up until Nov. 30, 2022.

These patients had a mean age of 62.4 years, and 99.1% were female. The majority (78.6%) were non-Hispanic white. HER2-low was identified in 65.5% of the cohort, while 34.5% were HER2-negative.

The proportion of HER2-low disease was lower in non-Hispanic black (62.8%) and Hispanic (61%) patients than in non-Hispanic White patients, at 66.1%.

HER2-low disease was also more common in hormone receptor–positive than triple-negative tumors, at just 51.5%, rising to 58.6% for progesterone receptor–positive, ER-negative, and 69.1% for PR-positive, ER-positive tumors.

Multivariate logistic regression analysis taking into account age, sex, race and ethnicity, comorbidity score, and treatment facility type, among other factors, revealed that the likelihood of HER2-low disease was significantly with increased ER expression, at an adjusted odds ratio of 1.15 for each 10% increase (P < .001).

Non-Hispanic Black, Asian, and Pacific Islander patients had similar rates of HER2-low disease as non-Hispanic White patients after adjustment, whereas Native American patients had an increased rate, at an aOR of 1.22 (P < .001), and Hispanic patients had a lower rate, at an aOR of 0.85 (P < .001).

HER2-low status was associated with a slightly reduced likelihood of having a pathologic complete response (aOR, 0.89; P < .001), with similar results when restricting the analysis to patients with triple negative or hormone receptor-positive tumors.

After a median follow-up of 54 months, HER2-low disease was associated with a minor improvement in survival on multivariate analysis, at an adjusted hazard ratio for death of 0.98 (P < .001).

The greatest improvement in survival was seen in patients with stage III and IV triple-negative breast cancer, at HRs of 0.92 and 0.91, respectively, although the researchers noted that this represented only a 2% and 0.4% improvement in 5-year overall survival, respectively.

The study was supported by the Breast Cancer Research Foundation, the American Society of Clinical Oncology/Conquer Cancer Foundation, the Department of Defense, the National Institutes of Health/National Cancer Institute, Susan G. Komen, the Breast Cancer Research Foundation, and the University of Chicago Elwood V. Jensen Scholars Program. Dr. Howard reported no relevant financial relationships. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, Veracyte, Daiichi Sankyo, AstraZeneca, Merck, Seagen, Exact Sciences, Gilead, Bristol-Myers Squibb, Scientific Affairs Group, and Ellipsis.

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

The Food and Drug Administration has expanded the indication for adjuvant abemaciclib (Verzenio) in combination with endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer who are at high risk for recurrence.

Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.

The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.

At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.

“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.

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

The Food and Drug Administration has expanded the indication for adjuvant abemaciclib (Verzenio) in combination with endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer who are at high risk for recurrence.

Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.

The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.

At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.

“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.

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

The Food and Drug Administration has expanded the indication for adjuvant abemaciclib (Verzenio) in combination with endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer who are at high risk for recurrence.

Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.

The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.

At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.

“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.

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

I am often asked about the impact of dietary nutrients on bone health, particularly as many patients with low bone density, many with a history of multiple fractures, are referred to me. Many factors affect bone density, an important predictor of fracture risk, including genetics, body weight and muscle mass, bone loading exercise, menstrual status, other hormonal factors, nutritional status, optimal absorption of dietary nutrients, and medication use.

Dietary nutrients include macronutrients (carbohydrates, proteins, fat, and fiber) and micronutrients (such as dietary minerals and vitamins). The importance of micronutrients such as calcium, phosphorus, magnesium, and vitamins C, D, and K in optimizing bone mineralization and bone formation has been well documented.

The impact of protein intake on bone health is slightly more controversial, with some studies suggesting that increased protein intake may be deleterious to bone by increasing acid load, which in turn, increases calcium loss in urine. Overall data analysis from multiple studies support the finding that a higher protein intake is modestly beneficial for bone at certain sites, such as the spine.

Though data regarding the impact of dietary carbohydrates on bone are not as robust, it’s important to understand these effects given the increasing knowledge of the deleterious impact of processed carbohydrates on weight and cardiometabolic outcomes. This leads to the growing recommendations to limit carbohydrates in diet.
 

Quality and quantity of carbs affect bone health

Available studies suggest that both the quality and quantity of carbohydrates that are in a diet as well as the glycemic index of food may affect bone outcomes. Glycemic index refers to the extent of blood glucose elevation that occurs after the intake of any specific food. Foods with a higher glycemic index cause a rapid increase in blood glucose, whereas those with a low glycemic index result in a slower and more gradual increase. Examples of high–glycemic index food include processed and baked foods (such as breakfast cereals [unless whole grain], pretzels, cookies, doughnuts, pastries, cake, white bread, bagels, croissants, and corn chips), sugar-sweetened beverages, white rice, fast food (such as pizza and burgers), and potatoes. Examples of low glycemic index foods include vegetables, fruits, legumes, dairy and dairy products (without added sugar), whole-grain foods (such as oat porridge), and nuts.

A high–glycemic index diet has been associated with a greater risk for obesity and cardiovascular disease, and with lower bone density, an increased risk for fracture. This has been attributed to acute increases in glucose and insulin levels after consumption of high–glycemic index food, which causes increased oxidative stress and secretion of inflammatory cytokines, such as interleukin 6 and tumor necrosis factor alpha, that activate cells in bone that increase bone loss.

Higher blood glucose concentrations induced by a higher dietary glycemic index can have deleterious effects on osteoblasts, the cells important for bone formation, and increase bone loss through production of advanced glycation end products that affect the cross linking of collagen in bone (important for bone strength), as well as calcium loss in urine. This was recently reported in a study by Garcia-Gavilan and others, in which the authors showed that high dietary glycemic index and dietary glucose load are associated with a higher risk for osteoporosis-related fractures in an older Mediterranean population who are at high risk for cardiovascular events. Similar data were reported by Nouri and coauthors in a study from Iran.

The quantity and quality of dietary carbohydrates may also have an impact on bone. The quality of carbohydrates has been assessed using the carbohydrate quality index (CQI) and the low carbohydrate diet score (LCDS). The CQI takes into account dietary fiber intake, glycemic index, intake of processed vs. whole grain, and solid vs. total carbohydrates in diet. A higher CQI diet is associated with reduced cardiovascular risk. Higher LCDS reflects lower carbohydrate and higher fat and protein intake.

Diets that are rich in refined or processed carbohydrates with added sugar are proinflammatory and increase oxidative stress, which may lead to increased bone loss, low bone density, and increased fracture risk. These foods also have a high glycemic index.

In contrast, diets that are rich in whole grains, legumes, fruits, vegetables, nuts, and olive oil have a lower glycemic index and are beneficial to bone. These diets have a higher CQI and LCDS (as reported by Nouri and coauthors) and provide a rich source of antioxidants, vitamins, minerals, and other nutrients (such as calcium, magnesium, and vitamins B, C, and K), which are all beneficial to bone. Gao and others have reported that implementing a low glycemic index pulse-based diet (lentils, peas, beans) is superior to a regular hospital diet in preventing the increase in bone loss that typically occurs during hospitalization with enforced bed rest.

Most reports of the impact of carbohydrates on bone health are from observational studies. In an interventional study, Dalskov and coauthors randomly assigned children aged 5-18 years who had parents with overweight to one of five diets (high protein/low glycemic index, high protein/high glycemic index, low protein/low glycemic index, low protein/high glycemic index, or regular) for 6 months.

Contrasting with our understanding that protein intake is overall good for bone, this study found that among patients receiving a high–glycemic index diet, those who were on a high-protein diet had greater reductions in a bone formation marker than did those on a low-protein diet, with no major changes observed with the other diets. This suggests the influence of associated dietary nutrients on bone outcomes and that protein intake may modify the effects of dietary carbohydrates on bone formation. Similarly, the fat content of food can alter the glycemic index and thus may modify the impact of dietary carbohydrates on bone.

In summary, available data suggest that the quantity and quality of carbohydrates, including the glycemic index of food, may affect bone health and that it is important to exercise moderation in the consumption of such foods. However, there are only a few studies that have examined these associations, and more studies are necessary to further clarify the impact of dietary carbohydrates on bone as well as any modifications of these effects by other associated food groups. These studies will allow us to refine our recommendations to our patients as we advance our understanding of the impact of the combined effects of various dietary nutrients on bone.

Madhusmita Misra, MD, MPH, is chief of the division of pediatric endocrinology, Mass General for Children, Boston, and serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for AbbVie, Sanofi, and Ipsen.

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

I am often asked about the impact of dietary nutrients on bone health, particularly as many patients with low bone density, many with a history of multiple fractures, are referred to me. Many factors affect bone density, an important predictor of fracture risk, including genetics, body weight and muscle mass, bone loading exercise, menstrual status, other hormonal factors, nutritional status, optimal absorption of dietary nutrients, and medication use.

Dietary nutrients include macronutrients (carbohydrates, proteins, fat, and fiber) and micronutrients (such as dietary minerals and vitamins). The importance of micronutrients such as calcium, phosphorus, magnesium, and vitamins C, D, and K in optimizing bone mineralization and bone formation has been well documented.

The impact of protein intake on bone health is slightly more controversial, with some studies suggesting that increased protein intake may be deleterious to bone by increasing acid load, which in turn, increases calcium loss in urine. Overall data analysis from multiple studies support the finding that a higher protein intake is modestly beneficial for bone at certain sites, such as the spine.

Though data regarding the impact of dietary carbohydrates on bone are not as robust, it’s important to understand these effects given the increasing knowledge of the deleterious impact of processed carbohydrates on weight and cardiometabolic outcomes. This leads to the growing recommendations to limit carbohydrates in diet.
 

Quality and quantity of carbs affect bone health

Available studies suggest that both the quality and quantity of carbohydrates that are in a diet as well as the glycemic index of food may affect bone outcomes. Glycemic index refers to the extent of blood glucose elevation that occurs after the intake of any specific food. Foods with a higher glycemic index cause a rapid increase in blood glucose, whereas those with a low glycemic index result in a slower and more gradual increase. Examples of high–glycemic index food include processed and baked foods (such as breakfast cereals [unless whole grain], pretzels, cookies, doughnuts, pastries, cake, white bread, bagels, croissants, and corn chips), sugar-sweetened beverages, white rice, fast food (such as pizza and burgers), and potatoes. Examples of low glycemic index foods include vegetables, fruits, legumes, dairy and dairy products (without added sugar), whole-grain foods (such as oat porridge), and nuts.

A high–glycemic index diet has been associated with a greater risk for obesity and cardiovascular disease, and with lower bone density, an increased risk for fracture. This has been attributed to acute increases in glucose and insulin levels after consumption of high–glycemic index food, which causes increased oxidative stress and secretion of inflammatory cytokines, such as interleukin 6 and tumor necrosis factor alpha, that activate cells in bone that increase bone loss.

Higher blood glucose concentrations induced by a higher dietary glycemic index can have deleterious effects on osteoblasts, the cells important for bone formation, and increase bone loss through production of advanced glycation end products that affect the cross linking of collagen in bone (important for bone strength), as well as calcium loss in urine. This was recently reported in a study by Garcia-Gavilan and others, in which the authors showed that high dietary glycemic index and dietary glucose load are associated with a higher risk for osteoporosis-related fractures in an older Mediterranean population who are at high risk for cardiovascular events. Similar data were reported by Nouri and coauthors in a study from Iran.

The quantity and quality of dietary carbohydrates may also have an impact on bone. The quality of carbohydrates has been assessed using the carbohydrate quality index (CQI) and the low carbohydrate diet score (LCDS). The CQI takes into account dietary fiber intake, glycemic index, intake of processed vs. whole grain, and solid vs. total carbohydrates in diet. A higher CQI diet is associated with reduced cardiovascular risk. Higher LCDS reflects lower carbohydrate and higher fat and protein intake.

Diets that are rich in refined or processed carbohydrates with added sugar are proinflammatory and increase oxidative stress, which may lead to increased bone loss, low bone density, and increased fracture risk. These foods also have a high glycemic index.

In contrast, diets that are rich in whole grains, legumes, fruits, vegetables, nuts, and olive oil have a lower glycemic index and are beneficial to bone. These diets have a higher CQI and LCDS (as reported by Nouri and coauthors) and provide a rich source of antioxidants, vitamins, minerals, and other nutrients (such as calcium, magnesium, and vitamins B, C, and K), which are all beneficial to bone. Gao and others have reported that implementing a low glycemic index pulse-based diet (lentils, peas, beans) is superior to a regular hospital diet in preventing the increase in bone loss that typically occurs during hospitalization with enforced bed rest.

Most reports of the impact of carbohydrates on bone health are from observational studies. In an interventional study, Dalskov and coauthors randomly assigned children aged 5-18 years who had parents with overweight to one of five diets (high protein/low glycemic index, high protein/high glycemic index, low protein/low glycemic index, low protein/high glycemic index, or regular) for 6 months.

Contrasting with our understanding that protein intake is overall good for bone, this study found that among patients receiving a high–glycemic index diet, those who were on a high-protein diet had greater reductions in a bone formation marker than did those on a low-protein diet, with no major changes observed with the other diets. This suggests the influence of associated dietary nutrients on bone outcomes and that protein intake may modify the effects of dietary carbohydrates on bone formation. Similarly, the fat content of food can alter the glycemic index and thus may modify the impact of dietary carbohydrates on bone.

In summary, available data suggest that the quantity and quality of carbohydrates, including the glycemic index of food, may affect bone health and that it is important to exercise moderation in the consumption of such foods. However, there are only a few studies that have examined these associations, and more studies are necessary to further clarify the impact of dietary carbohydrates on bone as well as any modifications of these effects by other associated food groups. These studies will allow us to refine our recommendations to our patients as we advance our understanding of the impact of the combined effects of various dietary nutrients on bone.

Madhusmita Misra, MD, MPH, is chief of the division of pediatric endocrinology, Mass General for Children, Boston, and serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for AbbVie, Sanofi, and Ipsen.

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

I am often asked about the impact of dietary nutrients on bone health, particularly as many patients with low bone density, many with a history of multiple fractures, are referred to me. Many factors affect bone density, an important predictor of fracture risk, including genetics, body weight and muscle mass, bone loading exercise, menstrual status, other hormonal factors, nutritional status, optimal absorption of dietary nutrients, and medication use.

Dietary nutrients include macronutrients (carbohydrates, proteins, fat, and fiber) and micronutrients (such as dietary minerals and vitamins). The importance of micronutrients such as calcium, phosphorus, magnesium, and vitamins C, D, and K in optimizing bone mineralization and bone formation has been well documented.

The impact of protein intake on bone health is slightly more controversial, with some studies suggesting that increased protein intake may be deleterious to bone by increasing acid load, which in turn, increases calcium loss in urine. Overall data analysis from multiple studies support the finding that a higher protein intake is modestly beneficial for bone at certain sites, such as the spine.

Though data regarding the impact of dietary carbohydrates on bone are not as robust, it’s important to understand these effects given the increasing knowledge of the deleterious impact of processed carbohydrates on weight and cardiometabolic outcomes. This leads to the growing recommendations to limit carbohydrates in diet.
 

Quality and quantity of carbs affect bone health

Available studies suggest that both the quality and quantity of carbohydrates that are in a diet as well as the glycemic index of food may affect bone outcomes. Glycemic index refers to the extent of blood glucose elevation that occurs after the intake of any specific food. Foods with a higher glycemic index cause a rapid increase in blood glucose, whereas those with a low glycemic index result in a slower and more gradual increase. Examples of high–glycemic index food include processed and baked foods (such as breakfast cereals [unless whole grain], pretzels, cookies, doughnuts, pastries, cake, white bread, bagels, croissants, and corn chips), sugar-sweetened beverages, white rice, fast food (such as pizza and burgers), and potatoes. Examples of low glycemic index foods include vegetables, fruits, legumes, dairy and dairy products (without added sugar), whole-grain foods (such as oat porridge), and nuts.

A high–glycemic index diet has been associated with a greater risk for obesity and cardiovascular disease, and with lower bone density, an increased risk for fracture. This has been attributed to acute increases in glucose and insulin levels after consumption of high–glycemic index food, which causes increased oxidative stress and secretion of inflammatory cytokines, such as interleukin 6 and tumor necrosis factor alpha, that activate cells in bone that increase bone loss.

Higher blood glucose concentrations induced by a higher dietary glycemic index can have deleterious effects on osteoblasts, the cells important for bone formation, and increase bone loss through production of advanced glycation end products that affect the cross linking of collagen in bone (important for bone strength), as well as calcium loss in urine. This was recently reported in a study by Garcia-Gavilan and others, in which the authors showed that high dietary glycemic index and dietary glucose load are associated with a higher risk for osteoporosis-related fractures in an older Mediterranean population who are at high risk for cardiovascular events. Similar data were reported by Nouri and coauthors in a study from Iran.

The quantity and quality of dietary carbohydrates may also have an impact on bone. The quality of carbohydrates has been assessed using the carbohydrate quality index (CQI) and the low carbohydrate diet score (LCDS). The CQI takes into account dietary fiber intake, glycemic index, intake of processed vs. whole grain, and solid vs. total carbohydrates in diet. A higher CQI diet is associated with reduced cardiovascular risk. Higher LCDS reflects lower carbohydrate and higher fat and protein intake.

Diets that are rich in refined or processed carbohydrates with added sugar are proinflammatory and increase oxidative stress, which may lead to increased bone loss, low bone density, and increased fracture risk. These foods also have a high glycemic index.

In contrast, diets that are rich in whole grains, legumes, fruits, vegetables, nuts, and olive oil have a lower glycemic index and are beneficial to bone. These diets have a higher CQI and LCDS (as reported by Nouri and coauthors) and provide a rich source of antioxidants, vitamins, minerals, and other nutrients (such as calcium, magnesium, and vitamins B, C, and K), which are all beneficial to bone. Gao and others have reported that implementing a low glycemic index pulse-based diet (lentils, peas, beans) is superior to a regular hospital diet in preventing the increase in bone loss that typically occurs during hospitalization with enforced bed rest.

Most reports of the impact of carbohydrates on bone health are from observational studies. In an interventional study, Dalskov and coauthors randomly assigned children aged 5-18 years who had parents with overweight to one of five diets (high protein/low glycemic index, high protein/high glycemic index, low protein/low glycemic index, low protein/high glycemic index, or regular) for 6 months.

Contrasting with our understanding that protein intake is overall good for bone, this study found that among patients receiving a high–glycemic index diet, those who were on a high-protein diet had greater reductions in a bone formation marker than did those on a low-protein diet, with no major changes observed with the other diets. This suggests the influence of associated dietary nutrients on bone outcomes and that protein intake may modify the effects of dietary carbohydrates on bone formation. Similarly, the fat content of food can alter the glycemic index and thus may modify the impact of dietary carbohydrates on bone.

In summary, available data suggest that the quantity and quality of carbohydrates, including the glycemic index of food, may affect bone health and that it is important to exercise moderation in the consumption of such foods. However, there are only a few studies that have examined these associations, and more studies are necessary to further clarify the impact of dietary carbohydrates on bone as well as any modifications of these effects by other associated food groups. These studies will allow us to refine our recommendations to our patients as we advance our understanding of the impact of the combined effects of various dietary nutrients on bone.

Madhusmita Misra, MD, MPH, is chief of the division of pediatric endocrinology, Mass General for Children, Boston, and serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for AbbVie, Sanofi, and Ipsen.

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

Frequent aspirin intake may reduce a woman’s risk of getting ovarian cancer, regardless of genetic susceptibility, new research suggests.

The study found that daily or almost daily aspirin use was associated with a 13% reduction in ovarian cancer risk, which was not modified by an individual’s polygenic score (PGS).

“Our findings suggest that frequent use of aspirin is associated with reduced ovarian cancer risk, regardless of whether a woman has lower or higher genetic susceptibility to ovarian cancer, as predicted by a set of known, common risk variants,” said lead author Lauren M. Hurwitz, PhD, MHS, division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

The study was published online in JAMA Network Open.

Patients diagnosed with ovarian cancer face difficult survival odds, which make preventive strategies especially important. Evidence suggests that frequent aspirin use can reduce the risk for ovarian cancer by about 13%, but it’s unclear whether genetic factors change those odds.

Although promising for chemoprevention, aspirin use can also come with downsides, including gastric ulcer and hemorrhagic stroke, which is why identifying and targeting individuals at higher risk for ovarian cancer who may benefit from frequent aspirin use is important.

In the current analysis, Dr. Hurwitz and colleagues used a PGS to determine whether the protective effects of daily or near-daily aspirin use for 6 months or more could be modified by genetics.

The study was a pooled analysis of eight case-controlled studies from the Ovarian Cancer Association Consortium conducted in the United Kingdom, the United States, and Australia over a 14-year period. The researchers looked at genetic data and data on frequent aspirin use among 4,476 case patients with nonmucinous ovarian cancer (average age, 57) and 6,659 control participants (average age, 58). Overall, 575 patients (13%) and 1,030 controls (15%) reported frequent aspirin use.

The authors used a PGS previously developed using 22 single-nucleotide variants. Because this PGS was developed for nonmucinous epithelial ovarian cancer, only these patients were included in the analysis.

Consistent with previous evidence, the authors found that frequent aspirin use was associated with a 13% lower risk for nonmucinous ovarian cancer (odds ratio, 0.87). And, notably, this association did not differ by PGS. Risk reductions were greatest for high-grade serous (OR, 0.83) and endometrioid tumors (OR, 0.73), with no evidence that PGS modified this association.

Overall, “we observed consistent protective associations between frequent aspirin use and nonmucinous ovarian cancer across strata of genetic susceptibility to ovarian cancer,” the authors conclude. “This work expands on the evidence base to suggest that chemoprevention programs could target individuals at higher risk of ovarian cancer.”

However, the authors noted that they were unable to test for effect modifications by specific pathogenic variants, such as BRCA1 or BRCA2.  

“Our study did not address whether aspirin use is associated with reduced ovarian cancer risk among BRCA or other pathogenic variant carriers, and so our findings should not be used to inform discussions around aspirin use for these specific high-risk groups,” Dr. Hurwitz said. “Women with higher genetic susceptibility to ovarian cancer based on these common risk variants should discuss with their doctor the benefits and harms of taking aspirin for disease prevention.”

This study was supported by a grant from the DoD Ovarian Cancer Research Program. Dr. Hurwitz reports no relevant financial relationships, but several coauthors did report funding and support.
 

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

Frequent aspirin intake may reduce a woman’s risk of getting ovarian cancer, regardless of genetic susceptibility, new research suggests.

The study found that daily or almost daily aspirin use was associated with a 13% reduction in ovarian cancer risk, which was not modified by an individual’s polygenic score (PGS).

“Our findings suggest that frequent use of aspirin is associated with reduced ovarian cancer risk, regardless of whether a woman has lower or higher genetic susceptibility to ovarian cancer, as predicted by a set of known, common risk variants,” said lead author Lauren M. Hurwitz, PhD, MHS, division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

The study was published online in JAMA Network Open.

Patients diagnosed with ovarian cancer face difficult survival odds, which make preventive strategies especially important. Evidence suggests that frequent aspirin use can reduce the risk for ovarian cancer by about 13%, but it’s unclear whether genetic factors change those odds.

Although promising for chemoprevention, aspirin use can also come with downsides, including gastric ulcer and hemorrhagic stroke, which is why identifying and targeting individuals at higher risk for ovarian cancer who may benefit from frequent aspirin use is important.

In the current analysis, Dr. Hurwitz and colleagues used a PGS to determine whether the protective effects of daily or near-daily aspirin use for 6 months or more could be modified by genetics.

The study was a pooled analysis of eight case-controlled studies from the Ovarian Cancer Association Consortium conducted in the United Kingdom, the United States, and Australia over a 14-year period. The researchers looked at genetic data and data on frequent aspirin use among 4,476 case patients with nonmucinous ovarian cancer (average age, 57) and 6,659 control participants (average age, 58). Overall, 575 patients (13%) and 1,030 controls (15%) reported frequent aspirin use.

The authors used a PGS previously developed using 22 single-nucleotide variants. Because this PGS was developed for nonmucinous epithelial ovarian cancer, only these patients were included in the analysis.

Consistent with previous evidence, the authors found that frequent aspirin use was associated with a 13% lower risk for nonmucinous ovarian cancer (odds ratio, 0.87). And, notably, this association did not differ by PGS. Risk reductions were greatest for high-grade serous (OR, 0.83) and endometrioid tumors (OR, 0.73), with no evidence that PGS modified this association.

Overall, “we observed consistent protective associations between frequent aspirin use and nonmucinous ovarian cancer across strata of genetic susceptibility to ovarian cancer,” the authors conclude. “This work expands on the evidence base to suggest that chemoprevention programs could target individuals at higher risk of ovarian cancer.”

However, the authors noted that they were unable to test for effect modifications by specific pathogenic variants, such as BRCA1 or BRCA2.  

“Our study did not address whether aspirin use is associated with reduced ovarian cancer risk among BRCA or other pathogenic variant carriers, and so our findings should not be used to inform discussions around aspirin use for these specific high-risk groups,” Dr. Hurwitz said. “Women with higher genetic susceptibility to ovarian cancer based on these common risk variants should discuss with their doctor the benefits and harms of taking aspirin for disease prevention.”

This study was supported by a grant from the DoD Ovarian Cancer Research Program. Dr. Hurwitz reports no relevant financial relationships, but several coauthors did report funding and support.
 

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

Frequent aspirin intake may reduce a woman’s risk of getting ovarian cancer, regardless of genetic susceptibility, new research suggests.

The study found that daily or almost daily aspirin use was associated with a 13% reduction in ovarian cancer risk, which was not modified by an individual’s polygenic score (PGS).

“Our findings suggest that frequent use of aspirin is associated with reduced ovarian cancer risk, regardless of whether a woman has lower or higher genetic susceptibility to ovarian cancer, as predicted by a set of known, common risk variants,” said lead author Lauren M. Hurwitz, PhD, MHS, division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

The study was published online in JAMA Network Open.

Patients diagnosed with ovarian cancer face difficult survival odds, which make preventive strategies especially important. Evidence suggests that frequent aspirin use can reduce the risk for ovarian cancer by about 13%, but it’s unclear whether genetic factors change those odds.

Although promising for chemoprevention, aspirin use can also come with downsides, including gastric ulcer and hemorrhagic stroke, which is why identifying and targeting individuals at higher risk for ovarian cancer who may benefit from frequent aspirin use is important.

In the current analysis, Dr. Hurwitz and colleagues used a PGS to determine whether the protective effects of daily or near-daily aspirin use for 6 months or more could be modified by genetics.

The study was a pooled analysis of eight case-controlled studies from the Ovarian Cancer Association Consortium conducted in the United Kingdom, the United States, and Australia over a 14-year period. The researchers looked at genetic data and data on frequent aspirin use among 4,476 case patients with nonmucinous ovarian cancer (average age, 57) and 6,659 control participants (average age, 58). Overall, 575 patients (13%) and 1,030 controls (15%) reported frequent aspirin use.

The authors used a PGS previously developed using 22 single-nucleotide variants. Because this PGS was developed for nonmucinous epithelial ovarian cancer, only these patients were included in the analysis.

Consistent with previous evidence, the authors found that frequent aspirin use was associated with a 13% lower risk for nonmucinous ovarian cancer (odds ratio, 0.87). And, notably, this association did not differ by PGS. Risk reductions were greatest for high-grade serous (OR, 0.83) and endometrioid tumors (OR, 0.73), with no evidence that PGS modified this association.

Overall, “we observed consistent protective associations between frequent aspirin use and nonmucinous ovarian cancer across strata of genetic susceptibility to ovarian cancer,” the authors conclude. “This work expands on the evidence base to suggest that chemoprevention programs could target individuals at higher risk of ovarian cancer.”

However, the authors noted that they were unable to test for effect modifications by specific pathogenic variants, such as BRCA1 or BRCA2.  

“Our study did not address whether aspirin use is associated with reduced ovarian cancer risk among BRCA or other pathogenic variant carriers, and so our findings should not be used to inform discussions around aspirin use for these specific high-risk groups,” Dr. Hurwitz said. “Women with higher genetic susceptibility to ovarian cancer based on these common risk variants should discuss with their doctor the benefits and harms of taking aspirin for disease prevention.”

This study was supported by a grant from the DoD Ovarian Cancer Research Program. Dr. Hurwitz reports no relevant financial relationships, but several coauthors did report funding and support.
 

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

Lille, France – The American College of Physicians has just updated its guidelines for osteoporosis treatment. Bernard Cortet, MD, PhD, chairperson of the Osteoporosis Research and Information Group and head of the rheumatology department at Lille (France) University Hospital, has agreed to compare the new U.S. guidelines to the 2018 French recommendations written under the aegis of the French Society for Rheumatology and GRIO. Dr. Cortet participated in drafting the French recommendations.

Question: The ACP “strongly” recommends initial pharmacologic treatment with bisphosphonate antiresorptive drugs (alendronate, ibandronate, risedronate, zoledronate) in postmenopausal females diagnosed with primary osteoporosis. Isn’t this what the SFR–GRIO have been recommending for many years?

Answer: The ACP reinforces its stance by arguing that in postmenopausal females with primary osteoporosis, bisphosphonates have the most favorable balance between benefits, harms, patient values and preferences, and cost among the drug classes that were evaluated. In addition to net clinical benefits, bisphosphonates are much cheaper than other pharmacologic treatments and are available in generic oral and injectable formulations.

Our French recommendations specify the choice of drug based on the type of fracture in women and on their bone mineral density (BMD). However, bisphosphonates are definitely given pride of place. When treatment for osteoporosis needs to be started, most of the time, a bisphosphonate is the treatment of choice.

Nevertheless, as also highlighted by the ACP, a more “aggressive” approach must be considered for more severe cases.

In the case of a severe fracture, the French recommendations indicate that all treatments can be prescribed. However, zoledronic acid should be favored as first-line treatment for a hip fracture. In other cases – with or without a nonsevere fracture – the therapeutic indication depends on the BMD values, and in difficult cases, on tools such as FRAX [the Fracture Risk Assessment Tool].

Our guidance strongly recommends opting for an injection in other contexts, such as significant decrease in bone density, presence of comorbidities, poor treatment compliance, brain function disorders, and polymedication.

Q. But it’s not really as simple as prescribing a bisphosphonate, is it?

A. You’re right, many people find the idea of taking bisphosphonates worrying because of associated jaw problems – osteonecrosis of the jaw – or atypical femoral fractures, based on what they’ve read on the Internet, where these serious adverse events are on display front and center with no mention of how often they actually happen and, often, failing to mention how effective bisphosphonates truly are.

These complications are real, but fortunately rare, especially during the first 5 years of treatment. To put this into context, for bisphosphonates, there’s one case of osteonecrosis of the jaw for every 10,000. And for denosumab, there are five cases for every 10,000. For atypical fractures, there’s one case for every 30,000 to 50,000.

Q. The U.S. guidelines also recommend that clinicians use a RANK ligand inhibitor – denosumab, also an antiresorptive drug – as second-line medical treatment. This is to reduce the risk of fractures in postmenopausal women diagnosed with primary osteoporosis and presenting with contraindications or side effects of bisphosphonates. Do you support the use of denosumab as second-line treatment?

A. French legislation classifies it as a second-line treatment, after bisphosphonates. However, there are arguments in favor of prescribing it as first-line treatment in some contexts. If denosumab is to be prescribed – via a twice-yearly subcutaneous injection – full compliance must be observed. If a patient is to stop taking denosumab, an opinion from a medical professional is required before treatment can be discontinued, and then treatment with bisphosphonates must be prescribed.

Q. The ACP recommends that clinicians use either a sclerostin inhibitor – romosozumab – or recombinant human parathyroid hormone – teriparatide – two anabolic agents, followed by a bisphosphonate, with the aim of reducing the risk of fractures. This is only used in women with primary osteoporosis who are at a very high risk of fracture. As romosozumab is not available in France, it’s not really worth discussing its use. Does this strategy seem advisable to you, though?

A. The main issue is what is understood by “women at a very high risk of fracture.” There’s no consensus on the definition of what constitutes a woman at a very high risk of fracture, but we can assume that it involves the combination of low BMD and at least one severe fracture.

The role of anabolic bone treatment, as [the ACP] has defined it, seems logical to me, because in cases of severe osteoporosis with fracture, the risk of recurrence is very high in the next 2-3 years. In a study comparing risedronate and teriparatide in cases of severe osteoporosis, teriparatide was more effective in reducing the recurrence of vertebral fractures.

The favorable opinion of the French National Authority for Health in relation to medical coverage for romosozumab in the treatment of severe postmenopausal osteoporosis in women under the age of 75 years with a history of severe fractures, a T-score less than –2.5, and no previous history of coronary artery disease dates to 2021. This is because medical coverage for this specific group was not listed in the marketing authorization (MA) description for this drug.

But the review by the Economic Committee for Health Products failed to reach a consensus regarding the price. Today, in theory, romosozumab can be dispensed in France by hospital pharmacies, because it is approved for use in public hospitals. Romosozumab is a very interesting drug for relatively young women, especially those with multiple vertebral fractures. This injectable treatment is more effective than teriparatide in increasing BMD values and more effective than alendronate in preventing the recurrence of fractures.

Regarding medical coverage, as it stands, in cases where patients have a T-score less than or equal to –3, the 2018 SFR–GRIO recommends starting treatment even if the patient has no fractures. In cases with severe fractures combined with very low BMD (T-score ≤ –3), injectable treatments may be used to reach a bone density target (T-score > –2.5 to –2 for the hip) at the end of the treatment plan. [These treatments include] zoledronic acid, denosumab (in case of bisphosphonate failure or intolerance), or a treatment plan with teriparatide (covered by medical insurance if the patient has at least two vertebral fractures) followed by an antiresorptive drug (bisphosphonate or denosumab).

Romosozumab is a humanized monoclonal antibody (IgG2) that binds to sclerostin and acts as an inhibitor. This increases bone formation because of the activation of [bone lining cells], the production of bone matrix by osteoblasts, and the recruitment of osteochondroprogenitor cells. Moreover, romosozumab causes changes in the expression of osteoclast mediators, which decreases bone resorption. Together, these two effects that increase bone formation and decrease bone resorption lead to the rapid increase of trabecular and cortical bone mass, as well as improvements in bone structure and strength.

Women treated with a bone anabolic agent must take an antiresorptive agent at the end of their treatment so that the benefits from the treatment remain in the long term. The French and U.S. guidelines line up on this point.

In patients with two prevalent vertebral fractures, the U.S. guidelines state that teriparatide can be prescribed as first-line treatment at diagnosis in the absence of any contraindications. We agree on this point as well.

Moreover, in women under the age of 70 years with osteoporosis requiring treatment, French experts recommend prescribing raloxifene, a selective estrogen-receptor modulator. This is if the risk of nonvertebral fracture is low, as defined by the absence of the following criteria: low hip T-score, risk of falling, and history of nonvertebral fracture. Opportunities for its use are limited, and it doesn’t even figure among the U.S. recommendations.

Q. The ACP recommends that clinicians adopt an individualized approach regarding whether to start medical treatment with a bisphosphonate in women over age 65 years with low bone mass (osteopenia) to reduce the risk of fractures. If treatment is started, they›re of the opinion that a bisphosphonate must be used. What are the recommendations in France?

A. It should be noted that this recommendation by the ACP is conditional because of the low-certainty evidence.

Here’s a brief reminder of important things to note: a T-score between –2.5 and –1 indicates osteopenia; a T-score less than or equal to –2.5 indicates osteoporosis; a T-score less than or equal to –2.5 with one or several fractures indicates severe osteoporosis. The French recommendations state that treatment is not justified if a patient’s T-score is higher than –2 and there’s no presence of fractures, even with risk factors (and/or multiple falls). For T-scores less than or equal to –2 and higher than –3, the decision to prescribe depends on the specialist.

Q. The ACP recommends that clinicians use bisphosphonates for the initial medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis.

A. The ACP recommends that clinicians use a RANK ligand inhibitor – denosumab – as second-line medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis who present with contraindications or who are experiencing side effects of bisphosphonates. This treatment is not covered by health insurance for men in France.

Between 20% and 25% of clinical osteoporotic fractures occur in men. After age 50 years, men are roughly 20% more likely to experience an osteoporotic fracture in their lifetime. The French recommendations regarding the management and treatment of osteoporosis in men were published in 2021.

In the case of severe fractures (vertebrae, pelvis, upper end of the femur, distal femur, proximal humerus) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –1.

In the case of nonsevere fractures (particularly wrist and ankle) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –2. If there are no fractures, osteoporosis treatment is recommended in men at risk of bone fragility or of falling and if one of the T-scores is less than or equal to –3. In patients who had a fracture of the upper end of the femur attributable to bone fragility, zoledronic acid is recommended as first-line treatment.

For men with a severe nonvertebral fracture, single vertebral fracture, or nonsevere fracture, two treatments are indicated and covered by health insurance in France: zoledronic acid and risedronate. In men with at least two vertebral fractures, the following treatments are indicated and covered by health insurance in France: teriparatide and risedronate. In this case, teriparatide is prescribed for a period of 18 months. It must be followed by a prescription of oral or intravenous bisphosphonates.

Q. What is your take on the HAS update to the proper use of osteoporosis medication that’s just been published?

A. Like in the 2018 SFR–GRIO guidelines, no update has been made to the section on postmenopausal osteoporosis, except for the HAS introduction to the proper use of romosozumab, even though it’s not covered by health insurance in France.

In accordance with the MA, it doesn’t make sense to include this drug on the list of treatment options available for women with and without fractures, as it’s not included in the HAS-selected list of drugs covered by health insurance in France.

But I’m glad that the HAS has adopted the GRIO and SFR recommendations regarding corticosteroid-induced osteoporosis. Preventive treatment for corticosteroid-induced osteoporosis must be considered as soon as the daily dose of corticosteroids reaches or exceeds the equivalent of 7.5 mg of prednisone and when the estimated duration of corticosteroid therapy exceeds 3 months.

In summary, in women and men over the age of 50 years, the intake of the equivalent of 7.5 mg/day or more of prednisone or a history of a low-trauma fracture or being age 70 years or older, even with a T-score less than or equal to –2.5 for one of the two sites, indicates prescribing a bisphosphonate. Teriparatide is indicated if the patient has two vertebral fractures.

This article was translated from Medscape’s French edition.

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

Lille, France – The American College of Physicians has just updated its guidelines for osteoporosis treatment. Bernard Cortet, MD, PhD, chairperson of the Osteoporosis Research and Information Group and head of the rheumatology department at Lille (France) University Hospital, has agreed to compare the new U.S. guidelines to the 2018 French recommendations written under the aegis of the French Society for Rheumatology and GRIO. Dr. Cortet participated in drafting the French recommendations.

Question: The ACP “strongly” recommends initial pharmacologic treatment with bisphosphonate antiresorptive drugs (alendronate, ibandronate, risedronate, zoledronate) in postmenopausal females diagnosed with primary osteoporosis. Isn’t this what the SFR–GRIO have been recommending for many years?

Answer: The ACP reinforces its stance by arguing that in postmenopausal females with primary osteoporosis, bisphosphonates have the most favorable balance between benefits, harms, patient values and preferences, and cost among the drug classes that were evaluated. In addition to net clinical benefits, bisphosphonates are much cheaper than other pharmacologic treatments and are available in generic oral and injectable formulations.

Our French recommendations specify the choice of drug based on the type of fracture in women and on their bone mineral density (BMD). However, bisphosphonates are definitely given pride of place. When treatment for osteoporosis needs to be started, most of the time, a bisphosphonate is the treatment of choice.

Nevertheless, as also highlighted by the ACP, a more “aggressive” approach must be considered for more severe cases.

In the case of a severe fracture, the French recommendations indicate that all treatments can be prescribed. However, zoledronic acid should be favored as first-line treatment for a hip fracture. In other cases – with or without a nonsevere fracture – the therapeutic indication depends on the BMD values, and in difficult cases, on tools such as FRAX [the Fracture Risk Assessment Tool].

Our guidance strongly recommends opting for an injection in other contexts, such as significant decrease in bone density, presence of comorbidities, poor treatment compliance, brain function disorders, and polymedication.

Q. But it’s not really as simple as prescribing a bisphosphonate, is it?

A. You’re right, many people find the idea of taking bisphosphonates worrying because of associated jaw problems – osteonecrosis of the jaw – or atypical femoral fractures, based on what they’ve read on the Internet, where these serious adverse events are on display front and center with no mention of how often they actually happen and, often, failing to mention how effective bisphosphonates truly are.

These complications are real, but fortunately rare, especially during the first 5 years of treatment. To put this into context, for bisphosphonates, there’s one case of osteonecrosis of the jaw for every 10,000. And for denosumab, there are five cases for every 10,000. For atypical fractures, there’s one case for every 30,000 to 50,000.

Q. The U.S. guidelines also recommend that clinicians use a RANK ligand inhibitor – denosumab, also an antiresorptive drug – as second-line medical treatment. This is to reduce the risk of fractures in postmenopausal women diagnosed with primary osteoporosis and presenting with contraindications or side effects of bisphosphonates. Do you support the use of denosumab as second-line treatment?

A. French legislation classifies it as a second-line treatment, after bisphosphonates. However, there are arguments in favor of prescribing it as first-line treatment in some contexts. If denosumab is to be prescribed – via a twice-yearly subcutaneous injection – full compliance must be observed. If a patient is to stop taking denosumab, an opinion from a medical professional is required before treatment can be discontinued, and then treatment with bisphosphonates must be prescribed.

Q. The ACP recommends that clinicians use either a sclerostin inhibitor – romosozumab – or recombinant human parathyroid hormone – teriparatide – two anabolic agents, followed by a bisphosphonate, with the aim of reducing the risk of fractures. This is only used in women with primary osteoporosis who are at a very high risk of fracture. As romosozumab is not available in France, it’s not really worth discussing its use. Does this strategy seem advisable to you, though?

A. The main issue is what is understood by “women at a very high risk of fracture.” There’s no consensus on the definition of what constitutes a woman at a very high risk of fracture, but we can assume that it involves the combination of low BMD and at least one severe fracture.

The role of anabolic bone treatment, as [the ACP] has defined it, seems logical to me, because in cases of severe osteoporosis with fracture, the risk of recurrence is very high in the next 2-3 years. In a study comparing risedronate and teriparatide in cases of severe osteoporosis, teriparatide was more effective in reducing the recurrence of vertebral fractures.

The favorable opinion of the French National Authority for Health in relation to medical coverage for romosozumab in the treatment of severe postmenopausal osteoporosis in women under the age of 75 years with a history of severe fractures, a T-score less than –2.5, and no previous history of coronary artery disease dates to 2021. This is because medical coverage for this specific group was not listed in the marketing authorization (MA) description for this drug.

But the review by the Economic Committee for Health Products failed to reach a consensus regarding the price. Today, in theory, romosozumab can be dispensed in France by hospital pharmacies, because it is approved for use in public hospitals. Romosozumab is a very interesting drug for relatively young women, especially those with multiple vertebral fractures. This injectable treatment is more effective than teriparatide in increasing BMD values and more effective than alendronate in preventing the recurrence of fractures.

Regarding medical coverage, as it stands, in cases where patients have a T-score less than or equal to –3, the 2018 SFR–GRIO recommends starting treatment even if the patient has no fractures. In cases with severe fractures combined with very low BMD (T-score ≤ –3), injectable treatments may be used to reach a bone density target (T-score > –2.5 to –2 for the hip) at the end of the treatment plan. [These treatments include] zoledronic acid, denosumab (in case of bisphosphonate failure or intolerance), or a treatment plan with teriparatide (covered by medical insurance if the patient has at least two vertebral fractures) followed by an antiresorptive drug (bisphosphonate or denosumab).

Romosozumab is a humanized monoclonal antibody (IgG2) that binds to sclerostin and acts as an inhibitor. This increases bone formation because of the activation of [bone lining cells], the production of bone matrix by osteoblasts, and the recruitment of osteochondroprogenitor cells. Moreover, romosozumab causes changes in the expression of osteoclast mediators, which decreases bone resorption. Together, these two effects that increase bone formation and decrease bone resorption lead to the rapid increase of trabecular and cortical bone mass, as well as improvements in bone structure and strength.

Women treated with a bone anabolic agent must take an antiresorptive agent at the end of their treatment so that the benefits from the treatment remain in the long term. The French and U.S. guidelines line up on this point.

In patients with two prevalent vertebral fractures, the U.S. guidelines state that teriparatide can be prescribed as first-line treatment at diagnosis in the absence of any contraindications. We agree on this point as well.

Moreover, in women under the age of 70 years with osteoporosis requiring treatment, French experts recommend prescribing raloxifene, a selective estrogen-receptor modulator. This is if the risk of nonvertebral fracture is low, as defined by the absence of the following criteria: low hip T-score, risk of falling, and history of nonvertebral fracture. Opportunities for its use are limited, and it doesn’t even figure among the U.S. recommendations.

Q. The ACP recommends that clinicians adopt an individualized approach regarding whether to start medical treatment with a bisphosphonate in women over age 65 years with low bone mass (osteopenia) to reduce the risk of fractures. If treatment is started, they›re of the opinion that a bisphosphonate must be used. What are the recommendations in France?

A. It should be noted that this recommendation by the ACP is conditional because of the low-certainty evidence.

Here’s a brief reminder of important things to note: a T-score between –2.5 and –1 indicates osteopenia; a T-score less than or equal to –2.5 indicates osteoporosis; a T-score less than or equal to –2.5 with one or several fractures indicates severe osteoporosis. The French recommendations state that treatment is not justified if a patient’s T-score is higher than –2 and there’s no presence of fractures, even with risk factors (and/or multiple falls). For T-scores less than or equal to –2 and higher than –3, the decision to prescribe depends on the specialist.

Q. The ACP recommends that clinicians use bisphosphonates for the initial medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis.

A. The ACP recommends that clinicians use a RANK ligand inhibitor – denosumab – as second-line medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis who present with contraindications or who are experiencing side effects of bisphosphonates. This treatment is not covered by health insurance for men in France.

Between 20% and 25% of clinical osteoporotic fractures occur in men. After age 50 years, men are roughly 20% more likely to experience an osteoporotic fracture in their lifetime. The French recommendations regarding the management and treatment of osteoporosis in men were published in 2021.

In the case of severe fractures (vertebrae, pelvis, upper end of the femur, distal femur, proximal humerus) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –1.

In the case of nonsevere fractures (particularly wrist and ankle) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –2. If there are no fractures, osteoporosis treatment is recommended in men at risk of bone fragility or of falling and if one of the T-scores is less than or equal to –3. In patients who had a fracture of the upper end of the femur attributable to bone fragility, zoledronic acid is recommended as first-line treatment.

For men with a severe nonvertebral fracture, single vertebral fracture, or nonsevere fracture, two treatments are indicated and covered by health insurance in France: zoledronic acid and risedronate. In men with at least two vertebral fractures, the following treatments are indicated and covered by health insurance in France: teriparatide and risedronate. In this case, teriparatide is prescribed for a period of 18 months. It must be followed by a prescription of oral or intravenous bisphosphonates.

Q. What is your take on the HAS update to the proper use of osteoporosis medication that’s just been published?

A. Like in the 2018 SFR–GRIO guidelines, no update has been made to the section on postmenopausal osteoporosis, except for the HAS introduction to the proper use of romosozumab, even though it’s not covered by health insurance in France.

In accordance with the MA, it doesn’t make sense to include this drug on the list of treatment options available for women with and without fractures, as it’s not included in the HAS-selected list of drugs covered by health insurance in France.

But I’m glad that the HAS has adopted the GRIO and SFR recommendations regarding corticosteroid-induced osteoporosis. Preventive treatment for corticosteroid-induced osteoporosis must be considered as soon as the daily dose of corticosteroids reaches or exceeds the equivalent of 7.5 mg of prednisone and when the estimated duration of corticosteroid therapy exceeds 3 months.

In summary, in women and men over the age of 50 years, the intake of the equivalent of 7.5 mg/day or more of prednisone or a history of a low-trauma fracture or being age 70 years or older, even with a T-score less than or equal to –2.5 for one of the two sites, indicates prescribing a bisphosphonate. Teriparatide is indicated if the patient has two vertebral fractures.

This article was translated from Medscape’s French edition.

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

Lille, France – The American College of Physicians has just updated its guidelines for osteoporosis treatment. Bernard Cortet, MD, PhD, chairperson of the Osteoporosis Research and Information Group and head of the rheumatology department at Lille (France) University Hospital, has agreed to compare the new U.S. guidelines to the 2018 French recommendations written under the aegis of the French Society for Rheumatology and GRIO. Dr. Cortet participated in drafting the French recommendations.

Question: The ACP “strongly” recommends initial pharmacologic treatment with bisphosphonate antiresorptive drugs (alendronate, ibandronate, risedronate, zoledronate) in postmenopausal females diagnosed with primary osteoporosis. Isn’t this what the SFR–GRIO have been recommending for many years?

Answer: The ACP reinforces its stance by arguing that in postmenopausal females with primary osteoporosis, bisphosphonates have the most favorable balance between benefits, harms, patient values and preferences, and cost among the drug classes that were evaluated. In addition to net clinical benefits, bisphosphonates are much cheaper than other pharmacologic treatments and are available in generic oral and injectable formulations.

Our French recommendations specify the choice of drug based on the type of fracture in women and on their bone mineral density (BMD). However, bisphosphonates are definitely given pride of place. When treatment for osteoporosis needs to be started, most of the time, a bisphosphonate is the treatment of choice.

Nevertheless, as also highlighted by the ACP, a more “aggressive” approach must be considered for more severe cases.

In the case of a severe fracture, the French recommendations indicate that all treatments can be prescribed. However, zoledronic acid should be favored as first-line treatment for a hip fracture. In other cases – with or without a nonsevere fracture – the therapeutic indication depends on the BMD values, and in difficult cases, on tools such as FRAX [the Fracture Risk Assessment Tool].

Our guidance strongly recommends opting for an injection in other contexts, such as significant decrease in bone density, presence of comorbidities, poor treatment compliance, brain function disorders, and polymedication.

Q. But it’s not really as simple as prescribing a bisphosphonate, is it?

A. You’re right, many people find the idea of taking bisphosphonates worrying because of associated jaw problems – osteonecrosis of the jaw – or atypical femoral fractures, based on what they’ve read on the Internet, where these serious adverse events are on display front and center with no mention of how often they actually happen and, often, failing to mention how effective bisphosphonates truly are.

These complications are real, but fortunately rare, especially during the first 5 years of treatment. To put this into context, for bisphosphonates, there’s one case of osteonecrosis of the jaw for every 10,000. And for denosumab, there are five cases for every 10,000. For atypical fractures, there’s one case for every 30,000 to 50,000.

Q. The U.S. guidelines also recommend that clinicians use a RANK ligand inhibitor – denosumab, also an antiresorptive drug – as second-line medical treatment. This is to reduce the risk of fractures in postmenopausal women diagnosed with primary osteoporosis and presenting with contraindications or side effects of bisphosphonates. Do you support the use of denosumab as second-line treatment?

A. French legislation classifies it as a second-line treatment, after bisphosphonates. However, there are arguments in favor of prescribing it as first-line treatment in some contexts. If denosumab is to be prescribed – via a twice-yearly subcutaneous injection – full compliance must be observed. If a patient is to stop taking denosumab, an opinion from a medical professional is required before treatment can be discontinued, and then treatment with bisphosphonates must be prescribed.

Q. The ACP recommends that clinicians use either a sclerostin inhibitor – romosozumab – or recombinant human parathyroid hormone – teriparatide – two anabolic agents, followed by a bisphosphonate, with the aim of reducing the risk of fractures. This is only used in women with primary osteoporosis who are at a very high risk of fracture. As romosozumab is not available in France, it’s not really worth discussing its use. Does this strategy seem advisable to you, though?

A. The main issue is what is understood by “women at a very high risk of fracture.” There’s no consensus on the definition of what constitutes a woman at a very high risk of fracture, but we can assume that it involves the combination of low BMD and at least one severe fracture.

The role of anabolic bone treatment, as [the ACP] has defined it, seems logical to me, because in cases of severe osteoporosis with fracture, the risk of recurrence is very high in the next 2-3 years. In a study comparing risedronate and teriparatide in cases of severe osteoporosis, teriparatide was more effective in reducing the recurrence of vertebral fractures.

The favorable opinion of the French National Authority for Health in relation to medical coverage for romosozumab in the treatment of severe postmenopausal osteoporosis in women under the age of 75 years with a history of severe fractures, a T-score less than –2.5, and no previous history of coronary artery disease dates to 2021. This is because medical coverage for this specific group was not listed in the marketing authorization (MA) description for this drug.

But the review by the Economic Committee for Health Products failed to reach a consensus regarding the price. Today, in theory, romosozumab can be dispensed in France by hospital pharmacies, because it is approved for use in public hospitals. Romosozumab is a very interesting drug for relatively young women, especially those with multiple vertebral fractures. This injectable treatment is more effective than teriparatide in increasing BMD values and more effective than alendronate in preventing the recurrence of fractures.

Regarding medical coverage, as it stands, in cases where patients have a T-score less than or equal to –3, the 2018 SFR–GRIO recommends starting treatment even if the patient has no fractures. In cases with severe fractures combined with very low BMD (T-score ≤ –3), injectable treatments may be used to reach a bone density target (T-score > –2.5 to –2 for the hip) at the end of the treatment plan. [These treatments include] zoledronic acid, denosumab (in case of bisphosphonate failure or intolerance), or a treatment plan with teriparatide (covered by medical insurance if the patient has at least two vertebral fractures) followed by an antiresorptive drug (bisphosphonate or denosumab).

Romosozumab is a humanized monoclonal antibody (IgG2) that binds to sclerostin and acts as an inhibitor. This increases bone formation because of the activation of [bone lining cells], the production of bone matrix by osteoblasts, and the recruitment of osteochondroprogenitor cells. Moreover, romosozumab causes changes in the expression of osteoclast mediators, which decreases bone resorption. Together, these two effects that increase bone formation and decrease bone resorption lead to the rapid increase of trabecular and cortical bone mass, as well as improvements in bone structure and strength.

Women treated with a bone anabolic agent must take an antiresorptive agent at the end of their treatment so that the benefits from the treatment remain in the long term. The French and U.S. guidelines line up on this point.

In patients with two prevalent vertebral fractures, the U.S. guidelines state that teriparatide can be prescribed as first-line treatment at diagnosis in the absence of any contraindications. We agree on this point as well.

Moreover, in women under the age of 70 years with osteoporosis requiring treatment, French experts recommend prescribing raloxifene, a selective estrogen-receptor modulator. This is if the risk of nonvertebral fracture is low, as defined by the absence of the following criteria: low hip T-score, risk of falling, and history of nonvertebral fracture. Opportunities for its use are limited, and it doesn’t even figure among the U.S. recommendations.

Q. The ACP recommends that clinicians adopt an individualized approach regarding whether to start medical treatment with a bisphosphonate in women over age 65 years with low bone mass (osteopenia) to reduce the risk of fractures. If treatment is started, they›re of the opinion that a bisphosphonate must be used. What are the recommendations in France?

A. It should be noted that this recommendation by the ACP is conditional because of the low-certainty evidence.

Here’s a brief reminder of important things to note: a T-score between –2.5 and –1 indicates osteopenia; a T-score less than or equal to –2.5 indicates osteoporosis; a T-score less than or equal to –2.5 with one or several fractures indicates severe osteoporosis. The French recommendations state that treatment is not justified if a patient’s T-score is higher than –2 and there’s no presence of fractures, even with risk factors (and/or multiple falls). For T-scores less than or equal to –2 and higher than –3, the decision to prescribe depends on the specialist.

Q. The ACP recommends that clinicians use bisphosphonates for the initial medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis.

A. The ACP recommends that clinicians use a RANK ligand inhibitor – denosumab – as second-line medical treatment to reduce the risk of fractures in men diagnosed with primary osteoporosis who present with contraindications or who are experiencing side effects of bisphosphonates. This treatment is not covered by health insurance for men in France.

Between 20% and 25% of clinical osteoporotic fractures occur in men. After age 50 years, men are roughly 20% more likely to experience an osteoporotic fracture in their lifetime. The French recommendations regarding the management and treatment of osteoporosis in men were published in 2021.

In the case of severe fractures (vertebrae, pelvis, upper end of the femur, distal femur, proximal humerus) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –1.

In the case of nonsevere fractures (particularly wrist and ankle) attributable to bone fragility, osteoporosis treatment is recommended if one of the T-scores is less than or equal to –2. If there are no fractures, osteoporosis treatment is recommended in men at risk of bone fragility or of falling and if one of the T-scores is less than or equal to –3. In patients who had a fracture of the upper end of the femur attributable to bone fragility, zoledronic acid is recommended as first-line treatment.

For men with a severe nonvertebral fracture, single vertebral fracture, or nonsevere fracture, two treatments are indicated and covered by health insurance in France: zoledronic acid and risedronate. In men with at least two vertebral fractures, the following treatments are indicated and covered by health insurance in France: teriparatide and risedronate. In this case, teriparatide is prescribed for a period of 18 months. It must be followed by a prescription of oral or intravenous bisphosphonates.

Q. What is your take on the HAS update to the proper use of osteoporosis medication that’s just been published?

A. Like in the 2018 SFR–GRIO guidelines, no update has been made to the section on postmenopausal osteoporosis, except for the HAS introduction to the proper use of romosozumab, even though it’s not covered by health insurance in France.

In accordance with the MA, it doesn’t make sense to include this drug on the list of treatment options available for women with and without fractures, as it’s not included in the HAS-selected list of drugs covered by health insurance in France.

But I’m glad that the HAS has adopted the GRIO and SFR recommendations regarding corticosteroid-induced osteoporosis. Preventive treatment for corticosteroid-induced osteoporosis must be considered as soon as the daily dose of corticosteroids reaches or exceeds the equivalent of 7.5 mg of prednisone and when the estimated duration of corticosteroid therapy exceeds 3 months.

In summary, in women and men over the age of 50 years, the intake of the equivalent of 7.5 mg/day or more of prednisone or a history of a low-trauma fracture or being age 70 years or older, even with a T-score less than or equal to –2.5 for one of the two sites, indicates prescribing a bisphosphonate. Teriparatide is indicated if the patient has two vertebral fractures.

This article was translated from Medscape’s French edition.

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

When it comes to a woman’s risk for a breast cancer recurrence, hormone status appears to matter.

New research shows that patients with ER-negative disease have a higher risk of a second breast cancer within a 5-year window post diagnosis, compared with patients with ER-positive disease.

“Our findings suggest that primary breast cancer ER status could be used to identify women at highest risk of second breast cancer events during the early post-treatment period and should be a consideration for guidelines and decision-making regarding surveillance imaging regimens for breast cancer survivors,” the study authors, led by Kathryn P. Lowry, MD, of Fred Hutchinson Cancer Center in Seattle, concluded.

The study was published online in Cancer.

Breast cancer survivors are at risk for a second breast cancer, making ongoing surveillance essential. Surveillance could be informed by better understanding an individual’s recurrence risk, but whether differences exist for women with ER‐positive vs. ER‐negative cancers remains unclear.

Dr. Lowry and colleagues analyzed women diagnosed with stage I-III breast cancer between 2000 and 2017, drawing from six Breast Cancer Surveillance Consortium registries. The team collected information on patients’ ER status as well as second breast cancer events detectable by surveillance imaging. Second breast cancer rates were assessed 1-5 years and 6-10 years after diagnosis. The final study cohort included 23,139 women with ER-positive disease and 4,605 with ER-negative disease.

The researchers found that, at the 5-year mark, the cumulative breast cancer incidence was 7.1% for ER‐negative disease and 3.6% for ER‐positive disease. At the 10-year mark, the cumulative breast cancer incidence was still higher for women with ER-negative disease – 11.8% vs. 7.5% among those with ER-positive disease. 

Patients with ER-negative disease also had higher rates of second breast cancers within the first 5 years of follow-ups – 16.0 per 1,000 person‐years vs. 7.8 per 1,000 person‐years for those with ER‐positive breast cancer – though after 5 years, the rates by ER status were similar among the two groups (12.1 per 1,000 vs. 9.3 per 1,000 person‐years, respectively).

Overall, the findings indicate that the “ER status of the primary invasive cancer was an important prognostic factor for both the magnitude and the timing of second breast cancer events,” the authors concluded.

The team noted several limitations to their study, including that information on the presence of pathogenic variants, such as BRCA1 and BRCA2, were not available. Given that these variants tend to be more common among women with ER-negative breast cancers, this could represent a confounder.

Marisa C. Weiss, MD, chief medical officer and founder of Breastcancer.org, who was not involved in the research, highlighted two important details to keep in mind.

“We do know that triple negative breast cancers are associated with a higher risk of having an inherited genetic abnormality like BRCA1, which predicts a higher risk of second malignancies,” said Dr. Weiss, a breast oncologist at Lankenau Medical Center in Wynnewood, Pa. “Also, it should be noted that patients with HR-positive breast cancer have a higher incidence of local recurrence spread out over 10-plus years.”

What might these results mean for practice and following patients over the long term?

According to the researchers, “further study is needed to evaluate whether women with ER‐negative primary cancers may potentially benefit from more intensive surveillance in the early postdiagnosis period.”

Dr. Weiss noted as well that “each person’s situation is unique,” and it is “very important to develop a customized survivorship care plan with close surveillance,” which includes genetic testing.

Dr. Lowry reported grants from the American Cancer Society and personal fees from the Radiological Society of North America outside the submitted work. Several coauthors also reported disclosures. Dr. Weiss reported no relevant financial relationships.

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

When it comes to a woman’s risk for a breast cancer recurrence, hormone status appears to matter.

New research shows that patients with ER-negative disease have a higher risk of a second breast cancer within a 5-year window post diagnosis, compared with patients with ER-positive disease.

“Our findings suggest that primary breast cancer ER status could be used to identify women at highest risk of second breast cancer events during the early post-treatment period and should be a consideration for guidelines and decision-making regarding surveillance imaging regimens for breast cancer survivors,” the study authors, led by Kathryn P. Lowry, MD, of Fred Hutchinson Cancer Center in Seattle, concluded.

The study was published online in Cancer.

Breast cancer survivors are at risk for a second breast cancer, making ongoing surveillance essential. Surveillance could be informed by better understanding an individual’s recurrence risk, but whether differences exist for women with ER‐positive vs. ER‐negative cancers remains unclear.

Dr. Lowry and colleagues analyzed women diagnosed with stage I-III breast cancer between 2000 and 2017, drawing from six Breast Cancer Surveillance Consortium registries. The team collected information on patients’ ER status as well as second breast cancer events detectable by surveillance imaging. Second breast cancer rates were assessed 1-5 years and 6-10 years after diagnosis. The final study cohort included 23,139 women with ER-positive disease and 4,605 with ER-negative disease.

The researchers found that, at the 5-year mark, the cumulative breast cancer incidence was 7.1% for ER‐negative disease and 3.6% for ER‐positive disease. At the 10-year mark, the cumulative breast cancer incidence was still higher for women with ER-negative disease – 11.8% vs. 7.5% among those with ER-positive disease. 

Patients with ER-negative disease also had higher rates of second breast cancers within the first 5 years of follow-ups – 16.0 per 1,000 person‐years vs. 7.8 per 1,000 person‐years for those with ER‐positive breast cancer – though after 5 years, the rates by ER status were similar among the two groups (12.1 per 1,000 vs. 9.3 per 1,000 person‐years, respectively).

Overall, the findings indicate that the “ER status of the primary invasive cancer was an important prognostic factor for both the magnitude and the timing of second breast cancer events,” the authors concluded.

The team noted several limitations to their study, including that information on the presence of pathogenic variants, such as BRCA1 and BRCA2, were not available. Given that these variants tend to be more common among women with ER-negative breast cancers, this could represent a confounder.

Marisa C. Weiss, MD, chief medical officer and founder of Breastcancer.org, who was not involved in the research, highlighted two important details to keep in mind.

“We do know that triple negative breast cancers are associated with a higher risk of having an inherited genetic abnormality like BRCA1, which predicts a higher risk of second malignancies,” said Dr. Weiss, a breast oncologist at Lankenau Medical Center in Wynnewood, Pa. “Also, it should be noted that patients with HR-positive breast cancer have a higher incidence of local recurrence spread out over 10-plus years.”

What might these results mean for practice and following patients over the long term?

According to the researchers, “further study is needed to evaluate whether women with ER‐negative primary cancers may potentially benefit from more intensive surveillance in the early postdiagnosis period.”

Dr. Weiss noted as well that “each person’s situation is unique,” and it is “very important to develop a customized survivorship care plan with close surveillance,” which includes genetic testing.

Dr. Lowry reported grants from the American Cancer Society and personal fees from the Radiological Society of North America outside the submitted work. Several coauthors also reported disclosures. Dr. Weiss reported no relevant financial relationships.

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

When it comes to a woman’s risk for a breast cancer recurrence, hormone status appears to matter.

New research shows that patients with ER-negative disease have a higher risk of a second breast cancer within a 5-year window post diagnosis, compared with patients with ER-positive disease.

“Our findings suggest that primary breast cancer ER status could be used to identify women at highest risk of second breast cancer events during the early post-treatment period and should be a consideration for guidelines and decision-making regarding surveillance imaging regimens for breast cancer survivors,” the study authors, led by Kathryn P. Lowry, MD, of Fred Hutchinson Cancer Center in Seattle, concluded.

The study was published online in Cancer.

Breast cancer survivors are at risk for a second breast cancer, making ongoing surveillance essential. Surveillance could be informed by better understanding an individual’s recurrence risk, but whether differences exist for women with ER‐positive vs. ER‐negative cancers remains unclear.

Dr. Lowry and colleagues analyzed women diagnosed with stage I-III breast cancer between 2000 and 2017, drawing from six Breast Cancer Surveillance Consortium registries. The team collected information on patients’ ER status as well as second breast cancer events detectable by surveillance imaging. Second breast cancer rates were assessed 1-5 years and 6-10 years after diagnosis. The final study cohort included 23,139 women with ER-positive disease and 4,605 with ER-negative disease.

The researchers found that, at the 5-year mark, the cumulative breast cancer incidence was 7.1% for ER‐negative disease and 3.6% for ER‐positive disease. At the 10-year mark, the cumulative breast cancer incidence was still higher for women with ER-negative disease – 11.8% vs. 7.5% among those with ER-positive disease. 

Patients with ER-negative disease also had higher rates of second breast cancers within the first 5 years of follow-ups – 16.0 per 1,000 person‐years vs. 7.8 per 1,000 person‐years for those with ER‐positive breast cancer – though after 5 years, the rates by ER status were similar among the two groups (12.1 per 1,000 vs. 9.3 per 1,000 person‐years, respectively).

Overall, the findings indicate that the “ER status of the primary invasive cancer was an important prognostic factor for both the magnitude and the timing of second breast cancer events,” the authors concluded.

The team noted several limitations to their study, including that information on the presence of pathogenic variants, such as BRCA1 and BRCA2, were not available. Given that these variants tend to be more common among women with ER-negative breast cancers, this could represent a confounder.

Marisa C. Weiss, MD, chief medical officer and founder of Breastcancer.org, who was not involved in the research, highlighted two important details to keep in mind.

“We do know that triple negative breast cancers are associated with a higher risk of having an inherited genetic abnormality like BRCA1, which predicts a higher risk of second malignancies,” said Dr. Weiss, a breast oncologist at Lankenau Medical Center in Wynnewood, Pa. “Also, it should be noted that patients with HR-positive breast cancer have a higher incidence of local recurrence spread out over 10-plus years.”

What might these results mean for practice and following patients over the long term?

According to the researchers, “further study is needed to evaluate whether women with ER‐negative primary cancers may potentially benefit from more intensive surveillance in the early postdiagnosis period.”

Dr. Weiss noted as well that “each person’s situation is unique,” and it is “very important to develop a customized survivorship care plan with close surveillance,” which includes genetic testing.

Dr. Lowry reported grants from the American Cancer Society and personal fees from the Radiological Society of North America outside the submitted work. Several coauthors also reported disclosures. Dr. Weiss reported no relevant financial relationships.

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

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

Introduction: The preoperative evaluation for endometriosis – more than meets the eye

It is well known that it often takes 6-10 years for endometriosis to be diagnosed in patients who have the disease, depending on where the patient lives. I certainly am not surprised. During my residency at Parkland Memorial Hospital, if a patient had chronic pelvic pain and no fibroids, her diagnosis was usually pelvic inflammatory disease. Later, during my fellowship in reproductive endocrinology at the University of Pennsylvania, the diagnosis became endometriosis.

As I gained more interest and expertise in the treatment of endometriosis, I became aware of several articles concluding that if a woman sought treatment for chronic pelvic pain with an internist, the diagnosis would be irritable bowel syndrome (IBS); with a urologist, it would be interstitial cystitis; and with a gynecologist, endometriosis. Moreover, there is an increased propensity for IBS and IC in patients with endometriosis. There also is an increased risk of small intestine bacterial overgrowth (SIBO), as noted by our guest author for this latest installment of the Master Class in Gynecologic Surgery, Iris Orbuch, MD.

Like our guest author, I have also noted increased risk of pelvic floor myalgia. Dr. Orbuch clearly outlines why this occurs. In fact, we can now understand why many patients have multiple pelvic pain–inducing issues compounding their pain secondary to endometriosis and leading to remodeling of the central nervous system. Therefore, it certainly makes sense to follow Dr. Orbuch’s recommendation for a multidisciplinary pre- and postsurgical approach “to downregulate the pain generators.”

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in the treatment of patients diagnosed with endometriosis. Dr. Orbuch serves on the Board of Directors of the Foundation of the American Association of Gynecologic Laparoscopists and has served as the chair of the AAGL’s Special Interest Group on Endometriosis and Reproductive Surgery. She is the coauthor of the book “Beating Endo – How to Reclaim Your Life From Endometriosis” (New York: HarperCollins; 2019). The book is written for patients but addresses many issues discussed in this installment of the Master Class in Gynecologic Surgery.

Dr. Miller, MD, FACOG, is professor of obstetrics and gynecology, department of clinical sciences, Rosalind Franklin University of Medicine and Science, North Chicago. He has no conflicts of interest to report.

For optimal surgical outcomes, and to help our patients recover from years of this inflammatory, systemic disease, we must treat our patients holistically and work to downregulate their pain as much as possible before excision surgery. I work with patients a few months prior to surgery, often for 4-5 months, during which time they not only see me for informative follow-ups, but also pelvic floor physical therapists, gastroenterologists, mental health professionals, integrative nutritionists, and physiatrists or pain specialists, depending on their needs.¹

By identifying coexisting conditions in an initial consult and employing a presurgical multidisciplinary approach to downregulate the pain generators, my patients recover well from excision surgery, with greater and faster relief from pain, compared with those using standard approaches, and with little to no use of opioids.

At a minimum, given the unfortunate time constraints and productivity demands of working within health systems – and considering that surgeries are often scheduled a couple of months out – the surgeon could ensure that patients are engaged in at least 6-8 weeks of pelvic floor physical therapy before surgery to sufficiently lengthen the pelvic muscles and loosen surrounding fascia.

Short, tight pelvic floor muscles are almost universal in patients with delayed diagnosis of endometriosis and are significant generators of pain.
 

Appreciating sequelae of diagnostic delay

After my fellowship in advanced laparoscopic and pelvic surgery with Harry Reich, MD, and C. Y. Liu, MD, pioneers of endometriosis excision surgery, and as I did my residency in the early 2000s, I noticed puzzlement in the literature about why some patients still had lasting pain after thorough excision.

I didn’t doubt the efficacy of excision. It is the cornerstone of treatment, and at least one randomized double-blind trial² and a systematic review and meta-analysis³ have demonstrated its superior efficacy over ablation in symptom reduction. What I did doubt was any presumption that surgery alone was enough. I knew there was more to healing when a disease process wreaks havoc on the body for more than a decade and that there were other generators of pain in addition to the endometriosis implants themselves.

As I began to focus on endometriosis in my own surgical practice, I strove to detect and treat endometriosis in teens. But in those patients with longstanding disease, I recognized patterns and began to more fully appreciate the systemic sequelae of endometriosis.

To cope with dysmenorrhea, patients curl up and assume a fetal position, tensing the abdominal muscles, inner thigh muscles, and pelvic floor muscles. Over time, these muscles come to maintain a short, tight, and painful state. (Hence the need for physical therapy to undo this decade-long pattern.)

Endometriosis implants on or near the gastrointestinal tract tug on fascia and muscles and commonly cause constipation, leading women to further overwork the pelvic floor muscles. In the case of diarrhea-predominant dysfunction, our patients squeeze pelvic floor muscles to prevent leakage. And in the case of urinary urgency, they squeeze muscles to release urine that isn’t really there.

As the chronic inflammation of the disease grows, and as pain worsens, the patient is increasingly in sympathetic overdrive (also known as ”fight or flight”), as opposed to a parasympathetic state (also known as “rest and digest”). The bowel’s motility slows, allowing the bacteria of the small intestine to grow beyond what is normal, leading to SIBO, a condition increasingly recognized by gastroenterologists and others that can impede nutrient absorption and cause bloat and pain and exacerbate constipation and diarrhea.

Key to my conceptualization of pain was a review published in 2011 by Pam Stratton, MD, of the National Institutes of Health, and Karen J. Berkley, PhD, then of Florida State University, on chronic pain and endometriosis.⁴ They detailed how endometriotic lesions can develop their own nerve supply that interacts directly and in a two-way fashion with the CNS – and how the lesions can engage the nervous system in ways that create comorbid conditions and pain that becomes “independent of the disease itself.”

Sensitized peripheral nerve fibers innervating a deeply infiltrating lesion on the left uterosacral ligament, for instance, can sensitize neurons in the spinal sacral segment. Branches of these nerve fibers can extend to other segments of the spinal cord, and, once sensitized themselves, turn on neurons in these other segments. There is a resultant remodeling of the central nervous system, in essence, and what is called “remote central sensitization.” The CNS becomes independent from peripheral neural processes.

I now explain to both patients and physicians that those who have had endometriosis for years have had an enduring “hand on the stove,” with a persistent signal to the CNS. Tight muscles are a hand on the stove, painful bladder syndrome is another hand on the stove, and SIBO is yet another. So are anxiety and depression.

The CNS becomes so upregulated and overloaded that messages branch out through the spinal cord to other available pathways and to other organs, muscles, and nerves. The CNS also starts firing on its own – and once it becomes its own pain generator, taking one hand off the stove (for instance, excising implants) while leaving multiple other hands on the hot stove won’t remove all pain. We must downregulate the CNS more broadly.

As I began addressing pain generators and instigators of CNS sensitization – and waiting for excision surgery until the CNS had sufficiently cooled – I saw that my patients had a better chance of more significant and lasting pain relief.
 

Pearls for a multimodal approach

My initial physical exam includes an assessment of the pelvic floor for overly tight musculature. An abdominal exam will usually reveal whether there is asymmetry of the abdominal wall muscles, which typically informs me of the likelihood of tightness and pulling on either side of the pelvic anatomy. On the internal exam, then, the pelvic floor muscles can be palpated and assessed. These findings will guide my referrals and my discussions with patients about the value of pelvic floor physical therapy. The cervix should be in the midline of the vagina – equidistant from the left and right vaginal fornices. If the cervix is pulled away from this midline, and a palpation of a thickened uterosacral ligament reproduces pain, endometriosis is 90% likely.

Patients who report significant “burning” pain that’s suggestive of neuropathic pain should be referred to a physical medicine rehabilitation physician or a pain specialist who can help downregulate their CNS. And patients who have symptoms of depression, anxiety disorders (including obsessive-compulsive disorder), or posttraumatic stress disorder should be referred to pain therapists, psychologists, or other mental health professionals, preferably well before surgery. I will also often discuss mindfulness practices and give my patients “meditation challenges” to achieve during the presurgical phase.

Additional points of emphasis about a multidisciplinary, multimodal approach include:

Advanced pelvic floor therapy: Therapists with specialized training in pelvic health and manual therapy utilize a range of techniques and modalities to release tension in affected muscles, fascia, nerves, and bone, and in doing so, they help to downregulate the CNS. Myofascial release, myofascial trigger point release, neural mobilization, and visceral mobilization are among these techniques. In addition to using manual therapy, many of these therapists may also employ neuromuscular reeducation and other techniques that will be helpful for the longer term.

It is important to identify physical therapists who have training in this approach; women with endometriosis often have a history of treatment by physical therapists whose focus is on incontinence and muscle strengthening (that is, Kegel exercises), which is the opposite of what endometriosis patients need.

Treating SIBO: Symptoms commonly associated with SIBO often overlap with symptoms of irritable bowel syndrome (IBS) – namely constipation, diarrhea (or both), and bloating. Indeed, many patients with undiagnosed endometriosis have been diagnosed with IBS. I send every patient who has one of these symptoms for SIBO breath testing, which utilizes carbohydrate substrates (glucose or lactulose) and measures hydrogen and/or methane in the breath.

SIBO is typically treated with rifampin, which stays in the small bowel and will not negatively affect beneficial bacteria, with or without neomycin. Gastroenterologists with more integrative practices also consider the use of herbals in addition to – or instead of – antibiotics. It can sometimes take months or a couple of years to correct SIBO, depending on how long the patient has been affected, but with presurgical diagnosis and a start on treatment, we can remove or at least tone down another instigator of CNS sensitization.

I estimate that 80% of my patients have tested positive for SIBO. Notably, in a testament to the systemic nature of endometriosis, a study published in 2009 of 355 women undergoing operative laparoscopy for suspected endometriosis found that 90% had gastrointestinal symptoms, but only 7.6% of the vast majority whose endometriosis was confirmed were found to have endometrial implants on the bowel itself.⁵

Addressing bladder issues: I routinely administer the PUF (Pain, Urgency, Frequency) questionnaire as part of my intake package and follow it up with conversation. For just about every patient with painful bladder syndrome, pelvic floor physical therapy in combination with a low-acid, low-potassium diet will work effectively together to reduce symptoms and pain. The IC Network offers a helpful food list, and patients can be counseled to choose foods that are also anti-inflammatory. When referrals to a urologist for bladder instillations are possible, these can be helpful as well.

Our communication with patients

Our patients need to have their symptoms and pain validated and to understand why we’re recommending these measures before surgery. Some education is necessary. Few patients will go to an integrative nutritionist, for example, if we just write a referral without explaining how years of inflammation and disruption in the gut can affect the whole body – including mental health – and that it can be corrected over time.

Also necessary is an appreciation of the fact that patients with delayed diagnoses have lived with gastrointestinal and other symptoms and patterns for so long – and often have mothers whose endometriosis caused similar symptoms – that some of their own experiences can seem almost “normal.” A patient whose mother had bowel movements every 7 days may think that 4-5 day intervals are acceptable, for instance. This means we have to carefully consider how we ask our questions.

I always ask my patients as we’re going into surgery, what percentage better are you? I’ve long aimed for at least 30% improvement, but most of the time, with pelvic floor therapy and as many other pain-generator–focused measures as possible, we’re getting them 70% better.

Excision surgery will remove the inflammation that has helped fuel the SIBO and other coconditions. Then, everything done to prepare the body must continue for some time. Certain practices, such as eating an anti-inflammatory diet, should be lifelong.

One day, it is hoped, a pediatrician or other physician will suspect endometriosis early on. The patient will see the surgeon within several months of the onset of pain, and we won’t need to unravel layers of pain generation and CNS upregulation before operating. But until this happens and we shorten the diagnostic delay, we must consider the benefits of presurgical preparation.
 

References

1. Orbuch I, Stein A. Beating Endo: How to Reclaim Your Life From Endometriosis. (New York: HarperCollins, 2019).

2. Healey M et al. J Minim Invasive Gynecol. 2014;21(6):999-1004.

3. Pundir J et al. J Minim Invasive Gynecol. 2017;24(5):747-56.

4. Stratton P, Berkley KJ. Hum Repro Update. 2011;17(3):327-46.

5. Maroun P et al. Aust N Z J Obstet Gynaecol. 2009;49(4):411-4.

Dr. Orbuch is a minimally invasive gynecologic surgeon in Los Angeles who specializes in endometriosis. She has no conflicts of interest to report.

Increased public health and research efforts to optimize prepregnancy cardiovascular health are needed, particularly among those in under-represented racial and ethnic groups, according to a new scientific statement from the American Heart Association.

“We have released this statement at this time because there is a maternal health crisis in the U.S. with rising maternal morbidity and mortality rates, which are the highest among high-income countries,” chair of the scientific statement writing group, Sadiya S. Khan, MD, told this news organization.

Cardiovascular disease (CVD) is the leading cause of death during pregnancy and the postpartum period and represents 26.5% of pregnancy-related deaths, the statement reports.

“While there is a lot of emphasis in trying to reduce cardiovascular risk during the period of actual pregnancy, much of that risk has often already developed and the women have been living with it for some time, so interventions during pregnancy may be too late,” Dr. Khan, assistant professor of medicine and preventive medicine at Northwestern University, Chicago, said.

“We wanted to try and emphasize the importance of starting to reduce cardiovascular risk earlier before pregnancy. In terms of improving cardiovascular health, this should have benefits both for the mother and the child,” she added.

The statement, “Optimizing Prepregnancy Cardiovascular Health to Improve Outcomes in Pregnant and Postpartum Individuals and Offspring” was published online in a “Go Red For Women” spotlight issue of the AHA publication Circulation.

The statement notes that low levels of prepregnancy cardiovascular health are associated with several pregnancy complications, including hypertensive disorders of pregnancy, preterm birth, small-for-gestational-age birth, and gestational diabetes. Currently, nearly one in five births are complicated by such an adverse pregnancy outcome, and there is a strong association between these complications and risk for subsequent cardiovascular disease.
 

Prepregnancy window

Over the past decade, rates of adverse pregnancy outcomes have increased significantly in the United States, with a near doubling in rates of hypertensive disorders of pregnancy, and there are persistent disparities, with Black individuals significantly more likely to experience adverse pregnancy outcomes, the statement notes.

Emerging data suggest that these complications have, at least in part, prepregnancy origins. Thus, the prepregnancy period may be a critical window during which interventions have a great potential for benefit in both women and their offspring, it says.

The authors suggest a life-course approach to measure, modify, and monitor prepregnancy cardiovascular health, with all clinicians who interact with pregnancy-capable individuals emphasizing optimization of cardiovascular health beginning early in childhood.

“Leveraging these opportunities to target cardiovascular health has the potential to improve health across the life course and for subsequent generations,” they add.
 

Critical research gap

Despite the evidence linking an individual’s prepregnancy health to their offspring’s health, there are no large trials to test whether improving overall cardiovascular health before pregnancy will reduce pregnancy complications, pregnancy-related cardiovascular death, or cardiovascular risk for offspring. The statement authors suggest that such a trial should be considered.

“This would be a big undertaking, but it could be feasible and could be really impactful,” Dr. Khan said. “Of course it would be challenging to recruit women who are planning a pregnancy and to follow them to see if they do get pregnant and consider interventions and outcomes, but given the importance of the need, we think this is something that should be invested in.”

She pointed out that the main way to improve the cardiovascular health of this cohort would be through behavioral counseling on physical activity and diet. “We need to develop strategies tailored to this age group – young women and those who may already have young children – and often the last thing they are thinking about is themselves and their own health.”

She explained that while it is presumed that controlling cardiovascular risk factors will be beneficial, the bigger question is how that can be achieved. “Behavioral interventions are difficult to achieve and often have low adherence, so the focus of the trials should be on strategies on how to deliver behavioral counseling to achieve better cardiovascular health in this population.”

Dr. Khan stressed that any approaches to improving prepregnancy cardiovascular health must address the current racial disparities that are present. “We must make sure that our policies are successful not just in improving cardiovascular health but to ensure it is done equitably. We must find ways to ensure all individuals can access care.”

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

Increased public health and research efforts to optimize prepregnancy cardiovascular health are needed, particularly among those in under-represented racial and ethnic groups, according to a new scientific statement from the American Heart Association.

“We have released this statement at this time because there is a maternal health crisis in the U.S. with rising maternal morbidity and mortality rates, which are the highest among high-income countries,” chair of the scientific statement writing group, Sadiya S. Khan, MD, told this news organization.

Cardiovascular disease (CVD) is the leading cause of death during pregnancy and the postpartum period and represents 26.5% of pregnancy-related deaths, the statement reports.

“While there is a lot of emphasis in trying to reduce cardiovascular risk during the period of actual pregnancy, much of that risk has often already developed and the women have been living with it for some time, so interventions during pregnancy may be too late,” Dr. Khan, assistant professor of medicine and preventive medicine at Northwestern University, Chicago, said.

“We wanted to try and emphasize the importance of starting to reduce cardiovascular risk earlier before pregnancy. In terms of improving cardiovascular health, this should have benefits both for the mother and the child,” she added.

The statement, “Optimizing Prepregnancy Cardiovascular Health to Improve Outcomes in Pregnant and Postpartum Individuals and Offspring” was published online in a “Go Red For Women” spotlight issue of the AHA publication Circulation.

The statement notes that low levels of prepregnancy cardiovascular health are associated with several pregnancy complications, including hypertensive disorders of pregnancy, preterm birth, small-for-gestational-age birth, and gestational diabetes. Currently, nearly one in five births are complicated by such an adverse pregnancy outcome, and there is a strong association between these complications and risk for subsequent cardiovascular disease.
 

Prepregnancy window

Over the past decade, rates of adverse pregnancy outcomes have increased significantly in the United States, with a near doubling in rates of hypertensive disorders of pregnancy, and there are persistent disparities, with Black individuals significantly more likely to experience adverse pregnancy outcomes, the statement notes.

Emerging data suggest that these complications have, at least in part, prepregnancy origins. Thus, the prepregnancy period may be a critical window during which interventions have a great potential for benefit in both women and their offspring, it says.

The authors suggest a life-course approach to measure, modify, and monitor prepregnancy cardiovascular health, with all clinicians who interact with pregnancy-capable individuals emphasizing optimization of cardiovascular health beginning early in childhood.

“Leveraging these opportunities to target cardiovascular health has the potential to improve health across the life course and for subsequent generations,” they add.
 

Critical research gap

Despite the evidence linking an individual’s prepregnancy health to their offspring’s health, there are no large trials to test whether improving overall cardiovascular health before pregnancy will reduce pregnancy complications, pregnancy-related cardiovascular death, or cardiovascular risk for offspring. The statement authors suggest that such a trial should be considered.

“This would be a big undertaking, but it could be feasible and could be really impactful,” Dr. Khan said. “Of course it would be challenging to recruit women who are planning a pregnancy and to follow them to see if they do get pregnant and consider interventions and outcomes, but given the importance of the need, we think this is something that should be invested in.”

She pointed out that the main way to improve the cardiovascular health of this cohort would be through behavioral counseling on physical activity and diet. “We need to develop strategies tailored to this age group – young women and those who may already have young children – and often the last thing they are thinking about is themselves and their own health.”

She explained that while it is presumed that controlling cardiovascular risk factors will be beneficial, the bigger question is how that can be achieved. “Behavioral interventions are difficult to achieve and often have low adherence, so the focus of the trials should be on strategies on how to deliver behavioral counseling to achieve better cardiovascular health in this population.”

Dr. Khan stressed that any approaches to improving prepregnancy cardiovascular health must address the current racial disparities that are present. “We must make sure that our policies are successful not just in improving cardiovascular health but to ensure it is done equitably. We must find ways to ensure all individuals can access care.”

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

Increased public health and research efforts to optimize prepregnancy cardiovascular health are needed, particularly among those in under-represented racial and ethnic groups, according to a new scientific statement from the American Heart Association.

“We have released this statement at this time because there is a maternal health crisis in the U.S. with rising maternal morbidity and mortality rates, which are the highest among high-income countries,” chair of the scientific statement writing group, Sadiya S. Khan, MD, told this news organization.

Cardiovascular disease (CVD) is the leading cause of death during pregnancy and the postpartum period and represents 26.5% of pregnancy-related deaths, the statement reports.

“While there is a lot of emphasis in trying to reduce cardiovascular risk during the period of actual pregnancy, much of that risk has often already developed and the women have been living with it for some time, so interventions during pregnancy may be too late,” Dr. Khan, assistant professor of medicine and preventive medicine at Northwestern University, Chicago, said.

“We wanted to try and emphasize the importance of starting to reduce cardiovascular risk earlier before pregnancy. In terms of improving cardiovascular health, this should have benefits both for the mother and the child,” she added.

The statement, “Optimizing Prepregnancy Cardiovascular Health to Improve Outcomes in Pregnant and Postpartum Individuals and Offspring” was published online in a “Go Red For Women” spotlight issue of the AHA publication Circulation.

The statement notes that low levels of prepregnancy cardiovascular health are associated with several pregnancy complications, including hypertensive disorders of pregnancy, preterm birth, small-for-gestational-age birth, and gestational diabetes. Currently, nearly one in five births are complicated by such an adverse pregnancy outcome, and there is a strong association between these complications and risk for subsequent cardiovascular disease.
 

Prepregnancy window

Over the past decade, rates of adverse pregnancy outcomes have increased significantly in the United States, with a near doubling in rates of hypertensive disorders of pregnancy, and there are persistent disparities, with Black individuals significantly more likely to experience adverse pregnancy outcomes, the statement notes.

Emerging data suggest that these complications have, at least in part, prepregnancy origins. Thus, the prepregnancy period may be a critical window during which interventions have a great potential for benefit in both women and their offspring, it says.

The authors suggest a life-course approach to measure, modify, and monitor prepregnancy cardiovascular health, with all clinicians who interact with pregnancy-capable individuals emphasizing optimization of cardiovascular health beginning early in childhood.

“Leveraging these opportunities to target cardiovascular health has the potential to improve health across the life course and for subsequent generations,” they add.
 

Critical research gap

Despite the evidence linking an individual’s prepregnancy health to their offspring’s health, there are no large trials to test whether improving overall cardiovascular health before pregnancy will reduce pregnancy complications, pregnancy-related cardiovascular death, or cardiovascular risk for offspring. The statement authors suggest that such a trial should be considered.

“This would be a big undertaking, but it could be feasible and could be really impactful,” Dr. Khan said. “Of course it would be challenging to recruit women who are planning a pregnancy and to follow them to see if they do get pregnant and consider interventions and outcomes, but given the importance of the need, we think this is something that should be invested in.”

She pointed out that the main way to improve the cardiovascular health of this cohort would be through behavioral counseling on physical activity and diet. “We need to develop strategies tailored to this age group – young women and those who may already have young children – and often the last thing they are thinking about is themselves and their own health.”

She explained that while it is presumed that controlling cardiovascular risk factors will be beneficial, the bigger question is how that can be achieved. “Behavioral interventions are difficult to achieve and often have low adherence, so the focus of the trials should be on strategies on how to deliver behavioral counseling to achieve better cardiovascular health in this population.”

Dr. Khan stressed that any approaches to improving prepregnancy cardiovascular health must address the current racial disparities that are present. “We must make sure that our policies are successful not just in improving cardiovascular health but to ensure it is done equitably. We must find ways to ensure all individuals can access care.”

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

The age-adjusted incidence rate of pancreatic cancer is increasing in young women in the United States, and it doesn’t show signs of slowing down, according to a new study published in Gastroenterology.

Cedars-Sinai Medical Center

Between 2001 and 2018, there was a greater than 200% difference in the incidence trend between men and women for ages 15-34, wrote Yazan Abboud, MD, a postdoctoral research fellow in the pancreaticobiliary department of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai Medical Center, Los Angeles, and colleagues.

“The exact cause of the trend among younger women is unclear and may be driven by sex-based disproportional exposure or response to known or yet-to-be-explored risk factors,” they wrote. “Future efforts should aim to elucidate the causes of such a trend with the goal to formulate possible preventive measures.”

Although previous studies have found increasing pancreatic cancer incidence rates, especially in younger women, the data haven’t been externally validated outside of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) data, they wrote. In addition, there are limited data about the contributing factors, such as race, histopathological subtype, tumor location, and stage at diagnosis.

Using SEER-excluded data from the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR), Dr. Abboud and colleagues conducted a population-based time-trend analysis of pancreatic cancer incidence rates from 2001 to 2018 in younger adults under age 55, including the role of demographics and tumor characteristics. They analyzed age-adjusted incidence rates (aIR), mortality rates, annual percentage change (APC), and average annual percentage change (AAPC) for ages 55 and older and ages 55 and younger. In addition, the research team evaluated the impact of incidence trends on sex-specific mortality trends in younger adults using the CDC’s National Center of Health Statistics database.

Between 2001 and 2018, 748,132 patients were diagnosed with pancreatic cancer. After excluding SEER data, 454,611 patients met the inclusion criteria. About 48.9% were women.

The overall aIR of pancreatic cancer during that time was 12.18 per 100,000 people. Women had a significantly lower aIR, at 10.69 per 100,000, compared with men at 13.95 per 100,000.

In general, pancreatic cancer aIR significantly increased during that time (AAPC = 1.17%). Sex-specific trends increased among both women (AAPC = 1.27%) and men (AAPC = 1.14%), though they showed no significant difference and were parallel.

In ages 55 and older, 401,419 patients (49.7% women) were diagnosed with pancreatic cancer. The aIR significantly increased during the study period (AAPC = 1.11%), with sex-specific aIR increasing in both women (AAPC = 1.11%) and men (AAPC = 1.17%), without a significant difference.

However, a difference appeared in the 53,051 patients (42.9% women) who were ages 55 and younger. The aIR relatively increased (AAPC = 1.29%), with faster jumps in women (AAPC = 2.36%), compared with men (AAPC = .62%). There was an absolute significant difference of 1.74%.

The trends continued in breakdowns by age. For 50,599 patients (42.2% women) between ages 35 and 54, the aIR relatively increased (AAPC = 1.10%). Sex-specific aIR increased among women (AAPC = 2.09%) but remained stable among men (AAPC = 0.54%), with an absolute significant difference of 1.55%.

In the youngest cohort of 2,452 patients (57.3% women) between ages 15 and 34, aIR relatively increased (AAPC = 4.93). Sex-specific aIR also increased in both women (AAPC = 6.45%) and men (AAPC = 2.97%), with an absolute significant difference of 3.48%.

By race, although White women under age 55 experienced increasing aIR at a greater rate than men (AAPC difference = 1.59%), an even more dramatic increase was seen in Black women, as compared to counterpart men (AAPC difference = 2.23%). Sex-specific trends in people of other races were parallel.

Based on tumor characteristics in ages 55 and younger, the pancreatic ductal adenocarcinoma histopathological subtype had an AAPC difference of 0.89%, and a tumor location in the head-of-pancreas had an AAPC difference of 1.64%.

When evaluating tumors based on stage-at-diagnosis, the AAPC difference was nonsignificant in all subgroups. However, sex-specific trends differed in tumors diagnosed at localized stages, suggesting that aIR in women may be increasing at a greater rate than in men (AAPC difference = 1.64%).

Among 64,239 patients (39.3% women) who died from pancreatic cancer under age 55, the mortality rates were unchanged in women (AAPC = –0.09%) but declined in men (AAPC = –0.64%), with an absolute significant AAPC difference of 0.54%.

UCLA

“Pancreatic cancer has a very poor overall survival, accounting for 7% of cancer-related deaths. The incidence of cancers, in general, is expected to rise as life expectancy increases in the United States,” said Danny Issa, MD, a gastroenterologist at the University of California, Los Angeles, who wasn’t involved with this study.

“Recently, noncomparative studies showed a possible increase in the incidence of pancreatic cancer in younger White women and in older White men and women. These reports had limitations,” he said. “The findings of this study are monumental as they confirmed that age-adjusted incidence rates have been increasing at a higher rate in younger women compared to younger men.”

In addition, Dr. Issa said, the significant increases among Black women for adenocarcinoma and for cancers located in the head of the pancreas are notable and should be studied further.

“Over the past few decades, research studies have helped improve cancer treatment by uncovering risk factors and identifying the most affected (or protected) population,” he said. “Therefore, epidemiologic studies are crucial, especially for hard-to-treat cancers such as pancreatic cancer.”

The study was supported in part by a philanthropic grant from The Widjaja Family Fund for Pancreatic Cancer Research. The authors disclosed no conflicts of interest. Dr. Issa reported no relevant disclosures.

The age-adjusted incidence rate of pancreatic cancer is increasing in young women in the United States, and it doesn’t show signs of slowing down, according to a new study published in Gastroenterology.

Cedars-Sinai Medical Center

Between 2001 and 2018, there was a greater than 200% difference in the incidence trend between men and women for ages 15-34, wrote Yazan Abboud, MD, a postdoctoral research fellow in the pancreaticobiliary department of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai Medical Center, Los Angeles, and colleagues.

“The exact cause of the trend among younger women is unclear and may be driven by sex-based disproportional exposure or response to known or yet-to-be-explored risk factors,” they wrote. “Future efforts should aim to elucidate the causes of such a trend with the goal to formulate possible preventive measures.”

Although previous studies have found increasing pancreatic cancer incidence rates, especially in younger women, the data haven’t been externally validated outside of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) data, they wrote. In addition, there are limited data about the contributing factors, such as race, histopathological subtype, tumor location, and stage at diagnosis.

Using SEER-excluded data from the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR), Dr. Abboud and colleagues conducted a population-based time-trend analysis of pancreatic cancer incidence rates from 2001 to 2018 in younger adults under age 55, including the role of demographics and tumor characteristics. They analyzed age-adjusted incidence rates (aIR), mortality rates, annual percentage change (APC), and average annual percentage change (AAPC) for ages 55 and older and ages 55 and younger. In addition, the research team evaluated the impact of incidence trends on sex-specific mortality trends in younger adults using the CDC’s National Center of Health Statistics database.

Between 2001 and 2018, 748,132 patients were diagnosed with pancreatic cancer. After excluding SEER data, 454,611 patients met the inclusion criteria. About 48.9% were women.

The overall aIR of pancreatic cancer during that time was 12.18 per 100,000 people. Women had a significantly lower aIR, at 10.69 per 100,000, compared with men at 13.95 per 100,000.

In general, pancreatic cancer aIR significantly increased during that time (AAPC = 1.17%). Sex-specific trends increased among both women (AAPC = 1.27%) and men (AAPC = 1.14%), though they showed no significant difference and were parallel.

In ages 55 and older, 401,419 patients (49.7% women) were diagnosed with pancreatic cancer. The aIR significantly increased during the study period (AAPC = 1.11%), with sex-specific aIR increasing in both women (AAPC = 1.11%) and men (AAPC = 1.17%), without a significant difference.

However, a difference appeared in the 53,051 patients (42.9% women) who were ages 55 and younger. The aIR relatively increased (AAPC = 1.29%), with faster jumps in women (AAPC = 2.36%), compared with men (AAPC = .62%). There was an absolute significant difference of 1.74%.

The trends continued in breakdowns by age. For 50,599 patients (42.2% women) between ages 35 and 54, the aIR relatively increased (AAPC = 1.10%). Sex-specific aIR increased among women (AAPC = 2.09%) but remained stable among men (AAPC = 0.54%), with an absolute significant difference of 1.55%.

In the youngest cohort of 2,452 patients (57.3% women) between ages 15 and 34, aIR relatively increased (AAPC = 4.93). Sex-specific aIR also increased in both women (AAPC = 6.45%) and men (AAPC = 2.97%), with an absolute significant difference of 3.48%.

By race, although White women under age 55 experienced increasing aIR at a greater rate than men (AAPC difference = 1.59%), an even more dramatic increase was seen in Black women, as compared to counterpart men (AAPC difference = 2.23%). Sex-specific trends in people of other races were parallel.

Based on tumor characteristics in ages 55 and younger, the pancreatic ductal adenocarcinoma histopathological subtype had an AAPC difference of 0.89%, and a tumor location in the head-of-pancreas had an AAPC difference of 1.64%.

When evaluating tumors based on stage-at-diagnosis, the AAPC difference was nonsignificant in all subgroups. However, sex-specific trends differed in tumors diagnosed at localized stages, suggesting that aIR in women may be increasing at a greater rate than in men (AAPC difference = 1.64%).

Among 64,239 patients (39.3% women) who died from pancreatic cancer under age 55, the mortality rates were unchanged in women (AAPC = –0.09%) but declined in men (AAPC = –0.64%), with an absolute significant AAPC difference of 0.54%.

UCLA

“Pancreatic cancer has a very poor overall survival, accounting for 7% of cancer-related deaths. The incidence of cancers, in general, is expected to rise as life expectancy increases in the United States,” said Danny Issa, MD, a gastroenterologist at the University of California, Los Angeles, who wasn’t involved with this study.

“Recently, noncomparative studies showed a possible increase in the incidence of pancreatic cancer in younger White women and in older White men and women. These reports had limitations,” he said. “The findings of this study are monumental as they confirmed that age-adjusted incidence rates have been increasing at a higher rate in younger women compared to younger men.”

In addition, Dr. Issa said, the significant increases among Black women for adenocarcinoma and for cancers located in the head of the pancreas are notable and should be studied further.

“Over the past few decades, research studies have helped improve cancer treatment by uncovering risk factors and identifying the most affected (or protected) population,” he said. “Therefore, epidemiologic studies are crucial, especially for hard-to-treat cancers such as pancreatic cancer.”

The study was supported in part by a philanthropic grant from The Widjaja Family Fund for Pancreatic Cancer Research. The authors disclosed no conflicts of interest. Dr. Issa reported no relevant disclosures.

The age-adjusted incidence rate of pancreatic cancer is increasing in young women in the United States, and it doesn’t show signs of slowing down, according to a new study published in Gastroenterology.

Cedars-Sinai Medical Center

Between 2001 and 2018, there was a greater than 200% difference in the incidence trend between men and women for ages 15-34, wrote Yazan Abboud, MD, a postdoctoral research fellow in the pancreaticobiliary department of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai Medical Center, Los Angeles, and colleagues.

“The exact cause of the trend among younger women is unclear and may be driven by sex-based disproportional exposure or response to known or yet-to-be-explored risk factors,” they wrote. “Future efforts should aim to elucidate the causes of such a trend with the goal to formulate possible preventive measures.”

Although previous studies have found increasing pancreatic cancer incidence rates, especially in younger women, the data haven’t been externally validated outside of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) data, they wrote. In addition, there are limited data about the contributing factors, such as race, histopathological subtype, tumor location, and stage at diagnosis.

Using SEER-excluded data from the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR), Dr. Abboud and colleagues conducted a population-based time-trend analysis of pancreatic cancer incidence rates from 2001 to 2018 in younger adults under age 55, including the role of demographics and tumor characteristics. They analyzed age-adjusted incidence rates (aIR), mortality rates, annual percentage change (APC), and average annual percentage change (AAPC) for ages 55 and older and ages 55 and younger. In addition, the research team evaluated the impact of incidence trends on sex-specific mortality trends in younger adults using the CDC’s National Center of Health Statistics database.

Between 2001 and 2018, 748,132 patients were diagnosed with pancreatic cancer. After excluding SEER data, 454,611 patients met the inclusion criteria. About 48.9% were women.

The overall aIR of pancreatic cancer during that time was 12.18 per 100,000 people. Women had a significantly lower aIR, at 10.69 per 100,000, compared with men at 13.95 per 100,000.

In general, pancreatic cancer aIR significantly increased during that time (AAPC = 1.17%). Sex-specific trends increased among both women (AAPC = 1.27%) and men (AAPC = 1.14%), though they showed no significant difference and were parallel.

In ages 55 and older, 401,419 patients (49.7% women) were diagnosed with pancreatic cancer. The aIR significantly increased during the study period (AAPC = 1.11%), with sex-specific aIR increasing in both women (AAPC = 1.11%) and men (AAPC = 1.17%), without a significant difference.

However, a difference appeared in the 53,051 patients (42.9% women) who were ages 55 and younger. The aIR relatively increased (AAPC = 1.29%), with faster jumps in women (AAPC = 2.36%), compared with men (AAPC = .62%). There was an absolute significant difference of 1.74%.

The trends continued in breakdowns by age. For 50,599 patients (42.2% women) between ages 35 and 54, the aIR relatively increased (AAPC = 1.10%). Sex-specific aIR increased among women (AAPC = 2.09%) but remained stable among men (AAPC = 0.54%), with an absolute significant difference of 1.55%.

In the youngest cohort of 2,452 patients (57.3% women) between ages 15 and 34, aIR relatively increased (AAPC = 4.93). Sex-specific aIR also increased in both women (AAPC = 6.45%) and men (AAPC = 2.97%), with an absolute significant difference of 3.48%.

By race, although White women under age 55 experienced increasing aIR at a greater rate than men (AAPC difference = 1.59%), an even more dramatic increase was seen in Black women, as compared to counterpart men (AAPC difference = 2.23%). Sex-specific trends in people of other races were parallel.

Based on tumor characteristics in ages 55 and younger, the pancreatic ductal adenocarcinoma histopathological subtype had an AAPC difference of 0.89%, and a tumor location in the head-of-pancreas had an AAPC difference of 1.64%.

When evaluating tumors based on stage-at-diagnosis, the AAPC difference was nonsignificant in all subgroups. However, sex-specific trends differed in tumors diagnosed at localized stages, suggesting that aIR in women may be increasing at a greater rate than in men (AAPC difference = 1.64%).

Among 64,239 patients (39.3% women) who died from pancreatic cancer under age 55, the mortality rates were unchanged in women (AAPC = –0.09%) but declined in men (AAPC = –0.64%), with an absolute significant AAPC difference of 0.54%.

UCLA

“Pancreatic cancer has a very poor overall survival, accounting for 7% of cancer-related deaths. The incidence of cancers, in general, is expected to rise as life expectancy increases in the United States,” said Danny Issa, MD, a gastroenterologist at the University of California, Los Angeles, who wasn’t involved with this study.

“Recently, noncomparative studies showed a possible increase in the incidence of pancreatic cancer in younger White women and in older White men and women. These reports had limitations,” he said. “The findings of this study are monumental as they confirmed that age-adjusted incidence rates have been increasing at a higher rate in younger women compared to younger men.”

In addition, Dr. Issa said, the significant increases among Black women for adenocarcinoma and for cancers located in the head of the pancreas are notable and should be studied further.

“Over the past few decades, research studies have helped improve cancer treatment by uncovering risk factors and identifying the most affected (or protected) population,” he said. “Therefore, epidemiologic studies are crucial, especially for hard-to-treat cancers such as pancreatic cancer.”

The study was supported in part by a philanthropic grant from The Widjaja Family Fund for Pancreatic Cancer Research. The authors disclosed no conflicts of interest. Dr. Issa reported no relevant disclosures.