Breast Cancer ICYMI

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Acute migraine headache attacks

A recent review in the Journal of Neuro-Ophthalmology by Konstantinos Spingos and colleagues (including me as the senior author) details typical and new treatments for migraine. We all know about the longstanding options, including the 7 triptans and ergots, as well as over-the-counter analgesics, which can be combined with caffeine, nonsteroidal anti-inflammatory drugs; and many use the 2 categories of medication that I no longer use for migraine, butalbital-containing medications, and opioids.

Now 2 gepants are available—small molecule calcitonin gene-related peptide (CGRP) receptor antagonists. These medications are thought to be a useful alternative for those in whom triptans do not work or are relatively contraindicated due to coronary and cerebrovascular problems and other cardiac risk factors like obesity, smoking, lack of exercise, high cholesterol, and diabetes. Ubrogepant was approved by the FDA in 2019, and rimegepant soon followed in 2020.

• Ubrogepant: In the ACHIEVE trials, approximately 1 in 5 participants who received the 50 mg dose were pain-free at 2 hours. Moreover, nearly 40% of individuals who received it said their worst migraine symptom was resolved at 2 hours. Pain relief at 2 hours was 59%
• Rimegepant: Like ubrogepant, about 20% of trial participants who received the 75 mg melt tablet dose of rimegepant were pain-free at 2 hours. Thirty-seven percent reported that their worst migraine symptom was gone at 2 hours. Patients began to return to normal functioning in 15 minutes.

In addition to gepants, there is 1 ditan approved, which stimulates 5-HT_1F receptors. Lasmiditan is the first medication in this class to be FDA-approved. It, too, is considered an alternative in patients in whom triptans are ineffective or when patients should not take a vasoconstrictor. In the most recent phase 3 study, the percentage of individuals who received lasmiditan and were pain-free at 2 hours were 28% (50 mg), 31% (100 mg) and 39% (200 mg). Relief from the migraine sufferers’ most bothersome symptom at 2 hours occurred in 41%, 44%, and 49% of patients, respectively. Lasmiditan is a Class V controlled substance. It has 18% dizziness in clinical trials. After administration, patients should not drive for 8 hours, and it should only be used once in a 24-hour period.

Non-pharmaceutical treatment options for acute migraine include nerve stimulation using electrical and magnetic stimulation devices, and behavioral approaches such as biofeedback training and mindfulness.  The Nerivio device for the upper arm is controlled by a smart phone app and seems to work as well as a triptan in some patients with almost no adverse events. Just approved in February is the Relivion device which is worn like a tiara on the head and stimulates the frontal branches of the trigeminal nerve as well as the 2 occipital nerves in the back of the head.

Acute care of cluster headache attacks

In 2011, Ashkenazi and Schwedt published a comprehensive table in Headache outlining the treatment options for acute cluster headache. More recently, a review in CNS Drugs by Brandt and colleagues presented the choices with level 1 evidence for efficacy. They include:

• Sumatriptan, 6 mg subcutaneous injection, or 20 mg nasal spray
• Zolmitriptan, 5 or 10 mg nasal spray
• Oxygen, 100%, 7 to 12 liters per minute via a mask over the nose and mouth

The authors recommend subcutaneous sumatriptan 6 mg and/or high-flow oxygen at 9- to 12- liters per minute for 15 minutes. Subcutaneous sumatriptan, they note, has been shown to achieve pain relief within 15 minutes in 75% of patients who receive it. Moreover, one-third report pain freedom. Oxygen’s efficacy has long been established, and relief comes with no adverse events. As for mask type, though no significant differences have been observed in studies, patients appear to express a preference for the demand valve oxygen type, which allows a high flow rate and is dependent on the user’s breathing rate.

Lidocaine intranasally has been found to be effective when triptans or oxygen do not work, according to a review in The Lancet Neurology by Hoffman and May. The medication is dripped or sprayed into the ipsilateral nostril at a concentration of between 4% and 10%. Pain relief is typically achieved within 10 minutes. This review also reports efficacy with percutaneous vagus nerve stimulation with the gammaCore device and neurostimulation of the sphenopalatine ganglion, though the mechanisms of these approaches are poorly understood. 

Evolving therapies for acute cluster headache include the aforementioned CGRP receptor-antagonists. Additionally, intranasal ketamine hydrochloride is under investigation in an open-label, proof-of-concept study; and a zolmitriptan patch is being evaluated in a double-blind, placebo-controlled trial.

Attacks of migraine occur in 12% of the adult population, 3 times more in women than men and are painful and debilitating. Cluster attacks are even more painful and occur in about 0.1% of the population, somewhat more in men. Both types of headache have a variety of effective treatment as detailed above.

Acute migraine headache attacks

A recent review in the Journal of Neuro-Ophthalmology by Konstantinos Spingos and colleagues (including me as the senior author) details typical and new treatments for migraine. We all know about the longstanding options, including the 7 triptans and ergots, as well as over-the-counter analgesics, which can be combined with caffeine, nonsteroidal anti-inflammatory drugs; and many use the 2 categories of medication that I no longer use for migraine, butalbital-containing medications, and opioids.

Now 2 gepants are available—small molecule calcitonin gene-related peptide (CGRP) receptor antagonists. These medications are thought to be a useful alternative for those in whom triptans do not work or are relatively contraindicated due to coronary and cerebrovascular problems and other cardiac risk factors like obesity, smoking, lack of exercise, high cholesterol, and diabetes. Ubrogepant was approved by the FDA in 2019, and rimegepant soon followed in 2020.

• Ubrogepant: In the ACHIEVE trials, approximately 1 in 5 participants who received the 50 mg dose were pain-free at 2 hours. Moreover, nearly 40% of individuals who received it said their worst migraine symptom was resolved at 2 hours. Pain relief at 2 hours was 59%
• Rimegepant: Like ubrogepant, about 20% of trial participants who received the 75 mg melt tablet dose of rimegepant were pain-free at 2 hours. Thirty-seven percent reported that their worst migraine symptom was gone at 2 hours. Patients began to return to normal functioning in 15 minutes.

In addition to gepants, there is 1 ditan approved, which stimulates 5-HT_1F receptors. Lasmiditan is the first medication in this class to be FDA-approved. It, too, is considered an alternative in patients in whom triptans are ineffective or when patients should not take a vasoconstrictor. In the most recent phase 3 study, the percentage of individuals who received lasmiditan and were pain-free at 2 hours were 28% (50 mg), 31% (100 mg) and 39% (200 mg). Relief from the migraine sufferers’ most bothersome symptom at 2 hours occurred in 41%, 44%, and 49% of patients, respectively. Lasmiditan is a Class V controlled substance. It has 18% dizziness in clinical trials. After administration, patients should not drive for 8 hours, and it should only be used once in a 24-hour period.

Non-pharmaceutical treatment options for acute migraine include nerve stimulation using electrical and magnetic stimulation devices, and behavioral approaches such as biofeedback training and mindfulness.  The Nerivio device for the upper arm is controlled by a smart phone app and seems to work as well as a triptan in some patients with almost no adverse events. Just approved in February is the Relivion device which is worn like a tiara on the head and stimulates the frontal branches of the trigeminal nerve as well as the 2 occipital nerves in the back of the head.

Acute care of cluster headache attacks

In 2011, Ashkenazi and Schwedt published a comprehensive table in Headache outlining the treatment options for acute cluster headache. More recently, a review in CNS Drugs by Brandt and colleagues presented the choices with level 1 evidence for efficacy. They include:

• Sumatriptan, 6 mg subcutaneous injection, or 20 mg nasal spray
• Zolmitriptan, 5 or 10 mg nasal spray
• Oxygen, 100%, 7 to 12 liters per minute via a mask over the nose and mouth

The authors recommend subcutaneous sumatriptan 6 mg and/or high-flow oxygen at 9- to 12- liters per minute for 15 minutes. Subcutaneous sumatriptan, they note, has been shown to achieve pain relief within 15 minutes in 75% of patients who receive it. Moreover, one-third report pain freedom. Oxygen’s efficacy has long been established, and relief comes with no adverse events. As for mask type, though no significant differences have been observed in studies, patients appear to express a preference for the demand valve oxygen type, which allows a high flow rate and is dependent on the user’s breathing rate.

Lidocaine intranasally has been found to be effective when triptans or oxygen do not work, according to a review in The Lancet Neurology by Hoffman and May. The medication is dripped or sprayed into the ipsilateral nostril at a concentration of between 4% and 10%. Pain relief is typically achieved within 10 minutes. This review also reports efficacy with percutaneous vagus nerve stimulation with the gammaCore device and neurostimulation of the sphenopalatine ganglion, though the mechanisms of these approaches are poorly understood. 

Evolving therapies for acute cluster headache include the aforementioned CGRP receptor-antagonists. Additionally, intranasal ketamine hydrochloride is under investigation in an open-label, proof-of-concept study; and a zolmitriptan patch is being evaluated in a double-blind, placebo-controlled trial.

Attacks of migraine occur in 12% of the adult population, 3 times more in women than men and are painful and debilitating. Cluster attacks are even more painful and occur in about 0.1% of the population, somewhat more in men. Both types of headache have a variety of effective treatment as detailed above.

Acute migraine headache attacks

A recent review in the Journal of Neuro-Ophthalmology by Konstantinos Spingos and colleagues (including me as the senior author) details typical and new treatments for migraine. We all know about the longstanding options, including the 7 triptans and ergots, as well as over-the-counter analgesics, which can be combined with caffeine, nonsteroidal anti-inflammatory drugs; and many use the 2 categories of medication that I no longer use for migraine, butalbital-containing medications, and opioids.

Now 2 gepants are available—small molecule calcitonin gene-related peptide (CGRP) receptor antagonists. These medications are thought to be a useful alternative for those in whom triptans do not work or are relatively contraindicated due to coronary and cerebrovascular problems and other cardiac risk factors like obesity, smoking, lack of exercise, high cholesterol, and diabetes. Ubrogepant was approved by the FDA in 2019, and rimegepant soon followed in 2020.

• Ubrogepant: In the ACHIEVE trials, approximately 1 in 5 participants who received the 50 mg dose were pain-free at 2 hours. Moreover, nearly 40% of individuals who received it said their worst migraine symptom was resolved at 2 hours. Pain relief at 2 hours was 59%
• Rimegepant: Like ubrogepant, about 20% of trial participants who received the 75 mg melt tablet dose of rimegepant were pain-free at 2 hours. Thirty-seven percent reported that their worst migraine symptom was gone at 2 hours. Patients began to return to normal functioning in 15 minutes.

In addition to gepants, there is 1 ditan approved, which stimulates 5-HT_1F receptors. Lasmiditan is the first medication in this class to be FDA-approved. It, too, is considered an alternative in patients in whom triptans are ineffective or when patients should not take a vasoconstrictor. In the most recent phase 3 study, the percentage of individuals who received lasmiditan and were pain-free at 2 hours were 28% (50 mg), 31% (100 mg) and 39% (200 mg). Relief from the migraine sufferers’ most bothersome symptom at 2 hours occurred in 41%, 44%, and 49% of patients, respectively. Lasmiditan is a Class V controlled substance. It has 18% dizziness in clinical trials. After administration, patients should not drive for 8 hours, and it should only be used once in a 24-hour period.

Non-pharmaceutical treatment options for acute migraine include nerve stimulation using electrical and magnetic stimulation devices, and behavioral approaches such as biofeedback training and mindfulness.  The Nerivio device for the upper arm is controlled by a smart phone app and seems to work as well as a triptan in some patients with almost no adverse events. Just approved in February is the Relivion device which is worn like a tiara on the head and stimulates the frontal branches of the trigeminal nerve as well as the 2 occipital nerves in the back of the head.

Acute care of cluster headache attacks

In 2011, Ashkenazi and Schwedt published a comprehensive table in Headache outlining the treatment options for acute cluster headache. More recently, a review in CNS Drugs by Brandt and colleagues presented the choices with level 1 evidence for efficacy. They include:

• Sumatriptan, 6 mg subcutaneous injection, or 20 mg nasal spray
• Zolmitriptan, 5 or 10 mg nasal spray
• Oxygen, 100%, 7 to 12 liters per minute via a mask over the nose and mouth

The authors recommend subcutaneous sumatriptan 6 mg and/or high-flow oxygen at 9- to 12- liters per minute for 15 minutes. Subcutaneous sumatriptan, they note, has been shown to achieve pain relief within 15 minutes in 75% of patients who receive it. Moreover, one-third report pain freedom. Oxygen’s efficacy has long been established, and relief comes with no adverse events. As for mask type, though no significant differences have been observed in studies, patients appear to express a preference for the demand valve oxygen type, which allows a high flow rate and is dependent on the user’s breathing rate.

Lidocaine intranasally has been found to be effective when triptans or oxygen do not work, according to a review in The Lancet Neurology by Hoffman and May. The medication is dripped or sprayed into the ipsilateral nostril at a concentration of between 4% and 10%. Pain relief is typically achieved within 10 minutes. This review also reports efficacy with percutaneous vagus nerve stimulation with the gammaCore device and neurostimulation of the sphenopalatine ganglion, though the mechanisms of these approaches are poorly understood. 

Evolving therapies for acute cluster headache include the aforementioned CGRP receptor-antagonists. Additionally, intranasal ketamine hydrochloride is under investigation in an open-label, proof-of-concept study; and a zolmitriptan patch is being evaluated in a double-blind, placebo-controlled trial.

Attacks of migraine occur in 12% of the adult population, 3 times more in women than men and are painful and debilitating. Cluster attacks are even more painful and occur in about 0.1% of the population, somewhat more in men. Both types of headache have a variety of effective treatment as detailed above.

Adding everolimus to adjuvant hormone therapy for early ER+, HER2- breast cancer does not offer any benefit over hormone therapy alone, according to results of the phase 3 UNIRAD study.

At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.

These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.

The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.

“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.

“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.

She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.

Study details

The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.

The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.

The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.

Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.

“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.

Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.

Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.

The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:

• Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
• Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
• Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).

With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
 

Problems interpreting data

There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.

For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.

In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.

Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.

Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.

Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.

With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.

“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”

Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”

Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”

Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.

The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.

Adding everolimus to adjuvant hormone therapy for early ER+, HER2- breast cancer does not offer any benefit over hormone therapy alone, according to results of the phase 3 UNIRAD study.

At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.

These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.

The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.

“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.

“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.

She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.

Study details

The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.

The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.

The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.

Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.

“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.

Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.

Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.

The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:

• Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
• Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
• Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).

With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
 

Problems interpreting data

There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.

For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.

In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.

Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.

Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.

Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.

With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.

“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”

Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”

Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”

Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.

The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.

Adding everolimus to adjuvant hormone therapy for early ER+, HER2- breast cancer does not offer any benefit over hormone therapy alone, according to results of the phase 3 UNIRAD study.

At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.

These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.

The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.

“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.

“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.

She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.

Study details

The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.

The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.

The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.

Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.

“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.

Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.

Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.

The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:

• Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
• Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
• Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).

With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
 

Problems interpreting data

There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.

For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.

In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.

Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.

Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.

Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.

With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.

“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”

Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”

Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”

Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.

The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.

Axillary adenopathy, or swelling under the armpit, has been reported by women after receiving the Pfizer-BioNTech and Moderna COVID-19 vaccines, but it is also a common symptom of breast cancer.

Clinicians should therefore consider recent COVID-19 vaccination history in the differential diagnosis of patients who present with unilateral axillary adenopathy, according to a new article.

“We noticed an increasing number of patients with swollen lymph nodes on just one side/one underarm who presented for routine screening mammography or ultrasound, and some women who actually felt these swollen nodes,” said author Katerina Dodelzon, MD, assistant professor of clinical radiology at Weill Cornell Medicine, New York.

“Historically, swollen lymph nodes on just one side are relatively rare and are an uncommon occurrence on screening mammography – seen only 0.02%-0.04% of the time – and is a sign that alerts a radiologist to exclude the presence of breast malignancy on that side,” she added.

In an article published in Clinical Imaging, Dr. Dodelzon and colleagues described four cases involving women who received a COVID-19 vaccine and then sought breast screening. In describing these cases, the authors sought “to inform the medical community to consider this benign and self-resolving diagnosis in the setting of what can be alarming presentation of unilateral axillary adenopathy.”

They hope they will decrease unnecessary biopsies and help reassure patients.

Adenopathy has been reported in association with other vaccines, such as the bacille Calmette-Guérin vaccine, influenza vaccines, and the human papillomavirus vaccine, commented Jessica W. T. Leung, MD, president of the Society of Breast Imaging.

“It’s too early to say if there is something different about the COVID-19 vaccines,” said Dr. Leung, who is also professor of diagnostic radiology and deputy chair of breast imaging at the University of Texas MD Anderson Cancer Center, Houston.

“The two vaccines that are currently in use – Pfizer and Moderna – are both mRNA vaccines, and it is unknown if those will give a stronger immune response,” she said. “If the Johnson & Johnson and AstraZeneca vaccines do become available, it will be interesting to see if they elicit as strong a response, since they are not mRNA vaccines. At this time, we have no data to say one way or the other.”

Dr. Leung also noted that these latest vaccine reactions may be getting more attention because “it is COVID-19 related, and everything related to COVID-19 gets more attention.

“It may also be more noticeable because of the large number of people getting vaccinated within a short period of time in an effort to contain the pandemic, and this is not the case with the other vaccines,” she said.
 

New recommendations from SBI

The SBI recently issued recommendations to clinicians that women who experience axillary adenopathy and who have recently been vaccinated on the same side on which the adenopathy occurs be followed for a few weeks to see whether the lymph nodes return to normal, rather than undergo biopsy.

“Many practices are now routinely inquiring about history of recent vaccination and on which side it was given,” Dr. Dodelzon said. She emphasized that women should feel empowered to share that history if they are not asked.

“Letting your mammography technologist or breast imager know that you have recently been vaccinated, and on which side, will provide the breast imager more accurate context within which to interpret the results,” she said.

In addition, the SBI recommends that, if feasible, women schedule routine screening mammography either before the first dose of the COVID-19 vaccine or 4-6 weeks after the second dose to avoid a false-positive finding.

“We want to emphasize that screening mammography is very important, and if possible, to schedule it around the vaccine,” commented Dr. Leung. “But that may not be possible, as most of us don’t have a choice when to get the vaccine.”

If it is not possible to reschedule either the mammogram or the vaccine, Dr. Leung recommends that women inform the facility that they have recently received a COVID-19 vaccine. “Currently, we recommend a follow-up in 4-12 weeks,” she said. “The swelling could subside sooner, perhaps even within 1-2 weeks, but we generally recommend waiting at least 4 weeks to capture the majority of women.”
 

Differences between the vaccines?

The frequency with which axillary adenopathy occurs as a side effect differs with the two COVID-19 vaccines, according to reports from the Centers for Disease Control and Prevention.

For the Moderna vaccine, axillary adenopathy ipsilateral to the vaccination arm was the second most frequently reported local reaction, with 11.6% of recipients aged 18-64 years reporting it after the first dose, and 16.0% reporting it after the second. The average duration of this adenopathy was 1-2 days.

For the Pfizer-BioNTech COVID-19 vaccine, the CDC notes that reports of adenopathy were imbalanced between the vaccine and placebo groups and concluded that adenopathy was plausibly related to the vaccine.

The average duration of adenopathy was approximately 10 days.

Adenopathy was reported within 2-4 days after vaccination for both vaccine groups, the CDC noted.

However, details from the cases reported by Dr. Dodelzon and colleagues paint a somewhat different picture. For example, in case 1, the patient self-detected unilateral axillary adenopathy 9 days after receiving the first dose of the Pfizer-BioNTech vaccine. In case 3, the time between receiving the Moderna vaccine and detection of adenopathy was 13 days.

In both of these cases, the time was much longer than the average duration of 1-2 days noted by the CDC. The authors suggest that in taking the patient’s vaccination history, radiologists understand that the side effect may occur up to several weeks following the COVID-19 vaccination.

In cases 2 and 4, the axillary adenopathy was incidentally noted during mammography, so it is unclear when the onset of this reaction occurred after receiving the COVID-19 vaccine.

The authors and Dr. Leung have disclosed no relevant financial relationships.

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

Axillary adenopathy, or swelling under the armpit, has been reported by women after receiving the Pfizer-BioNTech and Moderna COVID-19 vaccines, but it is also a common symptom of breast cancer.

Clinicians should therefore consider recent COVID-19 vaccination history in the differential diagnosis of patients who present with unilateral axillary adenopathy, according to a new article.

“We noticed an increasing number of patients with swollen lymph nodes on just one side/one underarm who presented for routine screening mammography or ultrasound, and some women who actually felt these swollen nodes,” said author Katerina Dodelzon, MD, assistant professor of clinical radiology at Weill Cornell Medicine, New York.

“Historically, swollen lymph nodes on just one side are relatively rare and are an uncommon occurrence on screening mammography – seen only 0.02%-0.04% of the time – and is a sign that alerts a radiologist to exclude the presence of breast malignancy on that side,” she added.

In an article published in Clinical Imaging, Dr. Dodelzon and colleagues described four cases involving women who received a COVID-19 vaccine and then sought breast screening. In describing these cases, the authors sought “to inform the medical community to consider this benign and self-resolving diagnosis in the setting of what can be alarming presentation of unilateral axillary adenopathy.”

They hope they will decrease unnecessary biopsies and help reassure patients.

Adenopathy has been reported in association with other vaccines, such as the bacille Calmette-Guérin vaccine, influenza vaccines, and the human papillomavirus vaccine, commented Jessica W. T. Leung, MD, president of the Society of Breast Imaging.

“It’s too early to say if there is something different about the COVID-19 vaccines,” said Dr. Leung, who is also professor of diagnostic radiology and deputy chair of breast imaging at the University of Texas MD Anderson Cancer Center, Houston.

“The two vaccines that are currently in use – Pfizer and Moderna – are both mRNA vaccines, and it is unknown if those will give a stronger immune response,” she said. “If the Johnson & Johnson and AstraZeneca vaccines do become available, it will be interesting to see if they elicit as strong a response, since they are not mRNA vaccines. At this time, we have no data to say one way or the other.”

Dr. Leung also noted that these latest vaccine reactions may be getting more attention because “it is COVID-19 related, and everything related to COVID-19 gets more attention.

“It may also be more noticeable because of the large number of people getting vaccinated within a short period of time in an effort to contain the pandemic, and this is not the case with the other vaccines,” she said.
 

New recommendations from SBI

The SBI recently issued recommendations to clinicians that women who experience axillary adenopathy and who have recently been vaccinated on the same side on which the adenopathy occurs be followed for a few weeks to see whether the lymph nodes return to normal, rather than undergo biopsy.

“Many practices are now routinely inquiring about history of recent vaccination and on which side it was given,” Dr. Dodelzon said. She emphasized that women should feel empowered to share that history if they are not asked.

“Letting your mammography technologist or breast imager know that you have recently been vaccinated, and on which side, will provide the breast imager more accurate context within which to interpret the results,” she said.

In addition, the SBI recommends that, if feasible, women schedule routine screening mammography either before the first dose of the COVID-19 vaccine or 4-6 weeks after the second dose to avoid a false-positive finding.

“We want to emphasize that screening mammography is very important, and if possible, to schedule it around the vaccine,” commented Dr. Leung. “But that may not be possible, as most of us don’t have a choice when to get the vaccine.”

If it is not possible to reschedule either the mammogram or the vaccine, Dr. Leung recommends that women inform the facility that they have recently received a COVID-19 vaccine. “Currently, we recommend a follow-up in 4-12 weeks,” she said. “The swelling could subside sooner, perhaps even within 1-2 weeks, but we generally recommend waiting at least 4 weeks to capture the majority of women.”
 

Differences between the vaccines?

The frequency with which axillary adenopathy occurs as a side effect differs with the two COVID-19 vaccines, according to reports from the Centers for Disease Control and Prevention.

For the Moderna vaccine, axillary adenopathy ipsilateral to the vaccination arm was the second most frequently reported local reaction, with 11.6% of recipients aged 18-64 years reporting it after the first dose, and 16.0% reporting it after the second. The average duration of this adenopathy was 1-2 days.

For the Pfizer-BioNTech COVID-19 vaccine, the CDC notes that reports of adenopathy were imbalanced between the vaccine and placebo groups and concluded that adenopathy was plausibly related to the vaccine.

The average duration of adenopathy was approximately 10 days.

Adenopathy was reported within 2-4 days after vaccination for both vaccine groups, the CDC noted.

However, details from the cases reported by Dr. Dodelzon and colleagues paint a somewhat different picture. For example, in case 1, the patient self-detected unilateral axillary adenopathy 9 days after receiving the first dose of the Pfizer-BioNTech vaccine. In case 3, the time between receiving the Moderna vaccine and detection of adenopathy was 13 days.

In both of these cases, the time was much longer than the average duration of 1-2 days noted by the CDC. The authors suggest that in taking the patient’s vaccination history, radiologists understand that the side effect may occur up to several weeks following the COVID-19 vaccination.

In cases 2 and 4, the axillary adenopathy was incidentally noted during mammography, so it is unclear when the onset of this reaction occurred after receiving the COVID-19 vaccine.

The authors and Dr. Leung have disclosed no relevant financial relationships.

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

Axillary adenopathy, or swelling under the armpit, has been reported by women after receiving the Pfizer-BioNTech and Moderna COVID-19 vaccines, but it is also a common symptom of breast cancer.

Clinicians should therefore consider recent COVID-19 vaccination history in the differential diagnosis of patients who present with unilateral axillary adenopathy, according to a new article.

“We noticed an increasing number of patients with swollen lymph nodes on just one side/one underarm who presented for routine screening mammography or ultrasound, and some women who actually felt these swollen nodes,” said author Katerina Dodelzon, MD, assistant professor of clinical radiology at Weill Cornell Medicine, New York.

“Historically, swollen lymph nodes on just one side are relatively rare and are an uncommon occurrence on screening mammography – seen only 0.02%-0.04% of the time – and is a sign that alerts a radiologist to exclude the presence of breast malignancy on that side,” she added.

In an article published in Clinical Imaging, Dr. Dodelzon and colleagues described four cases involving women who received a COVID-19 vaccine and then sought breast screening. In describing these cases, the authors sought “to inform the medical community to consider this benign and self-resolving diagnosis in the setting of what can be alarming presentation of unilateral axillary adenopathy.”

They hope they will decrease unnecessary biopsies and help reassure patients.

Adenopathy has been reported in association with other vaccines, such as the bacille Calmette-Guérin vaccine, influenza vaccines, and the human papillomavirus vaccine, commented Jessica W. T. Leung, MD, president of the Society of Breast Imaging.

“It’s too early to say if there is something different about the COVID-19 vaccines,” said Dr. Leung, who is also professor of diagnostic radiology and deputy chair of breast imaging at the University of Texas MD Anderson Cancer Center, Houston.

“The two vaccines that are currently in use – Pfizer and Moderna – are both mRNA vaccines, and it is unknown if those will give a stronger immune response,” she said. “If the Johnson & Johnson and AstraZeneca vaccines do become available, it will be interesting to see if they elicit as strong a response, since they are not mRNA vaccines. At this time, we have no data to say one way or the other.”

Dr. Leung also noted that these latest vaccine reactions may be getting more attention because “it is COVID-19 related, and everything related to COVID-19 gets more attention.

“It may also be more noticeable because of the large number of people getting vaccinated within a short period of time in an effort to contain the pandemic, and this is not the case with the other vaccines,” she said.
 

New recommendations from SBI

The SBI recently issued recommendations to clinicians that women who experience axillary adenopathy and who have recently been vaccinated on the same side on which the adenopathy occurs be followed for a few weeks to see whether the lymph nodes return to normal, rather than undergo biopsy.

“Many practices are now routinely inquiring about history of recent vaccination and on which side it was given,” Dr. Dodelzon said. She emphasized that women should feel empowered to share that history if they are not asked.

“Letting your mammography technologist or breast imager know that you have recently been vaccinated, and on which side, will provide the breast imager more accurate context within which to interpret the results,” she said.

In addition, the SBI recommends that, if feasible, women schedule routine screening mammography either before the first dose of the COVID-19 vaccine or 4-6 weeks after the second dose to avoid a false-positive finding.

“We want to emphasize that screening mammography is very important, and if possible, to schedule it around the vaccine,” commented Dr. Leung. “But that may not be possible, as most of us don’t have a choice when to get the vaccine.”

If it is not possible to reschedule either the mammogram or the vaccine, Dr. Leung recommends that women inform the facility that they have recently received a COVID-19 vaccine. “Currently, we recommend a follow-up in 4-12 weeks,” she said. “The swelling could subside sooner, perhaps even within 1-2 weeks, but we generally recommend waiting at least 4 weeks to capture the majority of women.”
 

Differences between the vaccines?

The frequency with which axillary adenopathy occurs as a side effect differs with the two COVID-19 vaccines, according to reports from the Centers for Disease Control and Prevention.

For the Moderna vaccine, axillary adenopathy ipsilateral to the vaccination arm was the second most frequently reported local reaction, with 11.6% of recipients aged 18-64 years reporting it after the first dose, and 16.0% reporting it after the second. The average duration of this adenopathy was 1-2 days.

For the Pfizer-BioNTech COVID-19 vaccine, the CDC notes that reports of adenopathy were imbalanced between the vaccine and placebo groups and concluded that adenopathy was plausibly related to the vaccine.

The average duration of adenopathy was approximately 10 days.

Adenopathy was reported within 2-4 days after vaccination for both vaccine groups, the CDC noted.

However, details from the cases reported by Dr. Dodelzon and colleagues paint a somewhat different picture. For example, in case 1, the patient self-detected unilateral axillary adenopathy 9 days after receiving the first dose of the Pfizer-BioNTech vaccine. In case 3, the time between receiving the Moderna vaccine and detection of adenopathy was 13 days.

In both of these cases, the time was much longer than the average duration of 1-2 days noted by the CDC. The authors suggest that in taking the patient’s vaccination history, radiologists understand that the side effect may occur up to several weeks following the COVID-19 vaccination.

In cases 2 and 4, the axillary adenopathy was incidentally noted during mammography, so it is unclear when the onset of this reaction occurred after receiving the COVID-19 vaccine.

The authors and Dr. Leung have disclosed no relevant financial relationships.

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

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Patients with metastatic breast cancer (MBC) face an elevated risk of severe illness or dying from COVID-19. Given the slow rollout of the Moderna and Pfizer COVID vaccines and new, more infectious viral variants circulating in the United States, oncologists will face a challenging balancing act for the foreseeable future: sustaining patients› MBC care while safeguarding them from COVID. The scale leans heavily toward continuing treatment, experts say.

“If we stop treatment for metastatic breast cancer, death will occur quickly,” Fatima F. Cardoso, MD, director of the breast unit at Champalimaud Clinical Centre in Lisbon, Portugal, stated this past August in a Medscape perspective.

Joanne Mortimer, MD, director of Women’s Cancer Programs at City of Hope, a comprehensive cancer center near Los Angeles, expressed a similar sentiment. “Having MBC is worse than getting COVID,” she told Medscape. “We can’t stop treating patients with MBC because of concerns of exposure.”

But maintaining treatment does not mean business as usual. Oncologists have had to modify their pre-pandemic practices to some degree, and that degree largely depends on local COVID conditions.

“Weighing the risk of treatment with the risk of contracting the virus means that many places have carried on treating metastatic breast cancer in a more thoughtful, careful way,” said Jill Dietz, MD, president of the American Society of Breast Surgeons. “That means focusing on high-value treatments for patients with the goal of maximizing their outcomes and quality of life while limiting in-person visits and potentially unnecessary elements of care.”

To guide this more careful approach, Dr. Dietz and colleagues from the recently formed COVID-19 Pandemic Breast Cancer Consortium published recommendations in April 2020 to account for different disease types and severities. These recommendations align closely with those from Cardoso and colleagues in Europe, also published last April.

Although issued early in the pandemic when there was greater uncertainty about viral transmission, adverse outcomes, and treatment for COVID-19, these recommendations still hold almost a year later.

“The framework has proven to be timeless in that it can help institutions where they are in the pandemic,” Dr. Dietz said.

The recommendations at play

For MBC, in particular, Dr. Dietz and colleagues focused on patients who need systemic care but whose treatment can be modified to keep them home more. The modifications include prescribing oral agents such as capecitabine, vinorelbine, and cyclophosphamide to minimize visits to the hospital or infusion suite.

To limit adverse events associated with these oral drugs, Dr. Dietz and colleagues also recommended reducing the dose when possible. For instance, research shows that lowering the dose of the CDK4/6 inhibitor palbociclib in patients with HR+/HER2-negative MBC does not diminish efficacy.

When oral agents are not an option, Dr. Dietz and colleagues suggested stretching out the intervals for chemotherapy infusions or injections. Data show that trastuzumab and pertuzumab injections for metastatic HER2-positive tumors «may reasonably be administered at longer intervals,» such as 4 weeks instead of 3 weeks.

The extent to which oncologists have applied these recommendations hinges on two factors: the local severity of COVID-19 cases and institution-specific policies.

For some oncologists, the pandemic has largely left treatment decisions untouched. “COVID-19 has only minimally impacted my practice,” said Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

Dr. Nanda recalled her concerns in the early days of the pandemic. As the nation watched COVID cases surge across New York City, Chicagoans prepared for the worst, fashioning the McCormick Place Convention Center into a field hospital for COVID patients.

“But fortunately, we were never overwhelmed at the University of Chicago and never needed to use the convention center,” Dr. Nanda said. “We did not have to alter or limit the type of therapy patients with MBC could receive.”

The main changes described by Dr. Nanda at the University of Chicago have centered around limiting the flow of traffic within the infusion suite or hospital by implementing prescreening checks to catch patients with COVID symptoms, keeping waiting rooms empty and infusion centers socially distanced, and having patients come in for appointments solo. The university’s home phlebotomy service also came in handy. Implemented before the pandemic, this service allowed patients with MBC to get their labs done at home before coming in for treatment.

“Overall, with social distancing, mask wearing, and limiting who comes in to the clinic, we have been able to keep patients and staff safe without altering treatment-specific decisions,” Dr. Nanda said.

Streamlining the foot traffic in the cancer center also worked well for Lisa A. Carey, MD, chief of the Division of Hematology/Oncology and deputy director of clinical sciences at University of North Carolina-Chapel Hill. “The truth is, oncological principles of care are still in place,” said Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research. “COVID hasn’t altered those; it has only thrown a little wrench in how we deliver that care.”

Kelly McCann, MD, PhD, a hematologist/oncologist in the Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, has had to walk a tighter rope to protect her patients with MBC, as COVID cases began to soar in LA county last fall.

To keep patients with MBC home more, Dr. McCann said many chose oral cytotoxic chemotherapies over infusional therapies. Some patients with HER2-positive MBC, for instance, opted for the oral combination neratinib + capecitabine over a trastuzumab-deruxtecan infusion, and others with triple-negative tumors chose capecitabine over a taxane.

At City of Hope, Mortimer has had a different experience of LA county’s COVID surge. Because the center only treats patients with cancer, “we have not had huge numbers of patients with COVID or had to significantly modify our practice outside of screening patients who come in and doing fewer scans compared to pre-COVID,” she said. With these precautions, “we have had no internal transmission of COVID within our institution.”

Still, patients with MBC have gotten COVID, and treating both illnesses does complicate decision-making. In some cases, Mortimer has postponed cancer treatment for patients who can delay for a few weeks while they recover from COVID. But patients who need to continue MBC treatment receive care in a separate unit, and Mortimer considers prescribing Eli Lilly’s recently approved antibody therapy bamlanivimab to treat COVID symptoms. “For each situation, we can always page our infectious disease experts to address any concerns or questions,” Dr. Mortimer said.

The MBC and COVID toll

The biggest hurdle for patients with MBC has been less about treatment decisions and more about handling the psychological toll of the pandemic, according to Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai in New York City.

“These are my personal observations, but I’ve seen how much more stressful it is to have metastatic breast cancer during the pandemic,” said Dr. Shapiro, who worries that fear of COVID may fuel or exacerbate patients’ depression and anxiety. “Patients can’t have family and friends by their side during infusions or appointments, and many feel isolated because of the risk of exposure.”

Because most patients with MBC still need in-person care such as exams, blood draws, or chemotherapy infusions, Dr. McCann has found that many of her patients “are afraid to come to a medical center and have been delaying appointments, imaging, and procedures.”

The psychological toll of treating breast cancer during the pandemic has touched oncologists as well. A recent survey found that burnout scores were significantly higher among physicians whose patients experienced delays in care, including chemotherapy or specialty consultations.

Getting patients vaccinated will improve protection and hopefully lessen fears surrounding COVID infection and transmission. Preliminary recommendations from the National Comprehensive Cancer Network›s COVID-19 Vaccination Advisory Committee state that patients with cancer «should be prioritized for vaccination.»

Dr. McCann agreed. “I’ve recommended COVID-19 vaccination to all of my patients with MBC,” she said. But because a lot of these therapies suppress the immune system to some degree, “I’ll recommend a period of time for vaccination in which the immune system is expected to have recovered, such as in the days prior to a dose of chemotherapy.”

Overall, according to Dr. Carey, institutional responses to treating MBC during the pandemic have been very similar: The key has been that “no one is keeping secrets,” she said. “Our global oncology community is sharing and adopting best practices. Our focus has been doing right by our patients.”

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

Patients with metastatic breast cancer (MBC) face an elevated risk of severe illness or dying from COVID-19. Given the slow rollout of the Moderna and Pfizer COVID vaccines and new, more infectious viral variants circulating in the United States, oncologists will face a challenging balancing act for the foreseeable future: sustaining patients› MBC care while safeguarding them from COVID. The scale leans heavily toward continuing treatment, experts say.

“If we stop treatment for metastatic breast cancer, death will occur quickly,” Fatima F. Cardoso, MD, director of the breast unit at Champalimaud Clinical Centre in Lisbon, Portugal, stated this past August in a Medscape perspective.

Joanne Mortimer, MD, director of Women’s Cancer Programs at City of Hope, a comprehensive cancer center near Los Angeles, expressed a similar sentiment. “Having MBC is worse than getting COVID,” she told Medscape. “We can’t stop treating patients with MBC because of concerns of exposure.”

But maintaining treatment does not mean business as usual. Oncologists have had to modify their pre-pandemic practices to some degree, and that degree largely depends on local COVID conditions.

“Weighing the risk of treatment with the risk of contracting the virus means that many places have carried on treating metastatic breast cancer in a more thoughtful, careful way,” said Jill Dietz, MD, president of the American Society of Breast Surgeons. “That means focusing on high-value treatments for patients with the goal of maximizing their outcomes and quality of life while limiting in-person visits and potentially unnecessary elements of care.”

To guide this more careful approach, Dr. Dietz and colleagues from the recently formed COVID-19 Pandemic Breast Cancer Consortium published recommendations in April 2020 to account for different disease types and severities. These recommendations align closely with those from Cardoso and colleagues in Europe, also published last April.

Although issued early in the pandemic when there was greater uncertainty about viral transmission, adverse outcomes, and treatment for COVID-19, these recommendations still hold almost a year later.

“The framework has proven to be timeless in that it can help institutions where they are in the pandemic,” Dr. Dietz said.

The recommendations at play

For MBC, in particular, Dr. Dietz and colleagues focused on patients who need systemic care but whose treatment can be modified to keep them home more. The modifications include prescribing oral agents such as capecitabine, vinorelbine, and cyclophosphamide to minimize visits to the hospital or infusion suite.

To limit adverse events associated with these oral drugs, Dr. Dietz and colleagues also recommended reducing the dose when possible. For instance, research shows that lowering the dose of the CDK4/6 inhibitor palbociclib in patients with HR+/HER2-negative MBC does not diminish efficacy.

When oral agents are not an option, Dr. Dietz and colleagues suggested stretching out the intervals for chemotherapy infusions or injections. Data show that trastuzumab and pertuzumab injections for metastatic HER2-positive tumors «may reasonably be administered at longer intervals,» such as 4 weeks instead of 3 weeks.

The extent to which oncologists have applied these recommendations hinges on two factors: the local severity of COVID-19 cases and institution-specific policies.

For some oncologists, the pandemic has largely left treatment decisions untouched. “COVID-19 has only minimally impacted my practice,” said Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

Dr. Nanda recalled her concerns in the early days of the pandemic. As the nation watched COVID cases surge across New York City, Chicagoans prepared for the worst, fashioning the McCormick Place Convention Center into a field hospital for COVID patients.

“But fortunately, we were never overwhelmed at the University of Chicago and never needed to use the convention center,” Dr. Nanda said. “We did not have to alter or limit the type of therapy patients with MBC could receive.”

The main changes described by Dr. Nanda at the University of Chicago have centered around limiting the flow of traffic within the infusion suite or hospital by implementing prescreening checks to catch patients with COVID symptoms, keeping waiting rooms empty and infusion centers socially distanced, and having patients come in for appointments solo. The university’s home phlebotomy service also came in handy. Implemented before the pandemic, this service allowed patients with MBC to get their labs done at home before coming in for treatment.

“Overall, with social distancing, mask wearing, and limiting who comes in to the clinic, we have been able to keep patients and staff safe without altering treatment-specific decisions,” Dr. Nanda said.

Streamlining the foot traffic in the cancer center also worked well for Lisa A. Carey, MD, chief of the Division of Hematology/Oncology and deputy director of clinical sciences at University of North Carolina-Chapel Hill. “The truth is, oncological principles of care are still in place,” said Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research. “COVID hasn’t altered those; it has only thrown a little wrench in how we deliver that care.”

Kelly McCann, MD, PhD, a hematologist/oncologist in the Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, has had to walk a tighter rope to protect her patients with MBC, as COVID cases began to soar in LA county last fall.

To keep patients with MBC home more, Dr. McCann said many chose oral cytotoxic chemotherapies over infusional therapies. Some patients with HER2-positive MBC, for instance, opted for the oral combination neratinib + capecitabine over a trastuzumab-deruxtecan infusion, and others with triple-negative tumors chose capecitabine over a taxane.

At City of Hope, Mortimer has had a different experience of LA county’s COVID surge. Because the center only treats patients with cancer, “we have not had huge numbers of patients with COVID or had to significantly modify our practice outside of screening patients who come in and doing fewer scans compared to pre-COVID,” she said. With these precautions, “we have had no internal transmission of COVID within our institution.”

Still, patients with MBC have gotten COVID, and treating both illnesses does complicate decision-making. In some cases, Mortimer has postponed cancer treatment for patients who can delay for a few weeks while they recover from COVID. But patients who need to continue MBC treatment receive care in a separate unit, and Mortimer considers prescribing Eli Lilly’s recently approved antibody therapy bamlanivimab to treat COVID symptoms. “For each situation, we can always page our infectious disease experts to address any concerns or questions,” Dr. Mortimer said.

The MBC and COVID toll

The biggest hurdle for patients with MBC has been less about treatment decisions and more about handling the psychological toll of the pandemic, according to Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai in New York City.

“These are my personal observations, but I’ve seen how much more stressful it is to have metastatic breast cancer during the pandemic,” said Dr. Shapiro, who worries that fear of COVID may fuel or exacerbate patients’ depression and anxiety. “Patients can’t have family and friends by their side during infusions or appointments, and many feel isolated because of the risk of exposure.”

Because most patients with MBC still need in-person care such as exams, blood draws, or chemotherapy infusions, Dr. McCann has found that many of her patients “are afraid to come to a medical center and have been delaying appointments, imaging, and procedures.”

The psychological toll of treating breast cancer during the pandemic has touched oncologists as well. A recent survey found that burnout scores were significantly higher among physicians whose patients experienced delays in care, including chemotherapy or specialty consultations.

Getting patients vaccinated will improve protection and hopefully lessen fears surrounding COVID infection and transmission. Preliminary recommendations from the National Comprehensive Cancer Network›s COVID-19 Vaccination Advisory Committee state that patients with cancer «should be prioritized for vaccination.»

Dr. McCann agreed. “I’ve recommended COVID-19 vaccination to all of my patients with MBC,” she said. But because a lot of these therapies suppress the immune system to some degree, “I’ll recommend a period of time for vaccination in which the immune system is expected to have recovered, such as in the days prior to a dose of chemotherapy.”

Overall, according to Dr. Carey, institutional responses to treating MBC during the pandemic have been very similar: The key has been that “no one is keeping secrets,” she said. “Our global oncology community is sharing and adopting best practices. Our focus has been doing right by our patients.”

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

Patients with metastatic breast cancer (MBC) face an elevated risk of severe illness or dying from COVID-19. Given the slow rollout of the Moderna and Pfizer COVID vaccines and new, more infectious viral variants circulating in the United States, oncologists will face a challenging balancing act for the foreseeable future: sustaining patients› MBC care while safeguarding them from COVID. The scale leans heavily toward continuing treatment, experts say.

“If we stop treatment for metastatic breast cancer, death will occur quickly,” Fatima F. Cardoso, MD, director of the breast unit at Champalimaud Clinical Centre in Lisbon, Portugal, stated this past August in a Medscape perspective.

Joanne Mortimer, MD, director of Women’s Cancer Programs at City of Hope, a comprehensive cancer center near Los Angeles, expressed a similar sentiment. “Having MBC is worse than getting COVID,” she told Medscape. “We can’t stop treating patients with MBC because of concerns of exposure.”

But maintaining treatment does not mean business as usual. Oncologists have had to modify their pre-pandemic practices to some degree, and that degree largely depends on local COVID conditions.

“Weighing the risk of treatment with the risk of contracting the virus means that many places have carried on treating metastatic breast cancer in a more thoughtful, careful way,” said Jill Dietz, MD, president of the American Society of Breast Surgeons. “That means focusing on high-value treatments for patients with the goal of maximizing their outcomes and quality of life while limiting in-person visits and potentially unnecessary elements of care.”

To guide this more careful approach, Dr. Dietz and colleagues from the recently formed COVID-19 Pandemic Breast Cancer Consortium published recommendations in April 2020 to account for different disease types and severities. These recommendations align closely with those from Cardoso and colleagues in Europe, also published last April.

Although issued early in the pandemic when there was greater uncertainty about viral transmission, adverse outcomes, and treatment for COVID-19, these recommendations still hold almost a year later.

“The framework has proven to be timeless in that it can help institutions where they are in the pandemic,” Dr. Dietz said.

The recommendations at play

For MBC, in particular, Dr. Dietz and colleagues focused on patients who need systemic care but whose treatment can be modified to keep them home more. The modifications include prescribing oral agents such as capecitabine, vinorelbine, and cyclophosphamide to minimize visits to the hospital or infusion suite.

To limit adverse events associated with these oral drugs, Dr. Dietz and colleagues also recommended reducing the dose when possible. For instance, research shows that lowering the dose of the CDK4/6 inhibitor palbociclib in patients with HR+/HER2-negative MBC does not diminish efficacy.

When oral agents are not an option, Dr. Dietz and colleagues suggested stretching out the intervals for chemotherapy infusions or injections. Data show that trastuzumab and pertuzumab injections for metastatic HER2-positive tumors «may reasonably be administered at longer intervals,» such as 4 weeks instead of 3 weeks.

The extent to which oncologists have applied these recommendations hinges on two factors: the local severity of COVID-19 cases and institution-specific policies.

For some oncologists, the pandemic has largely left treatment decisions untouched. “COVID-19 has only minimally impacted my practice,” said Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

Dr. Nanda recalled her concerns in the early days of the pandemic. As the nation watched COVID cases surge across New York City, Chicagoans prepared for the worst, fashioning the McCormick Place Convention Center into a field hospital for COVID patients.

“But fortunately, we were never overwhelmed at the University of Chicago and never needed to use the convention center,” Dr. Nanda said. “We did not have to alter or limit the type of therapy patients with MBC could receive.”

The main changes described by Dr. Nanda at the University of Chicago have centered around limiting the flow of traffic within the infusion suite or hospital by implementing prescreening checks to catch patients with COVID symptoms, keeping waiting rooms empty and infusion centers socially distanced, and having patients come in for appointments solo. The university’s home phlebotomy service also came in handy. Implemented before the pandemic, this service allowed patients with MBC to get their labs done at home before coming in for treatment.

“Overall, with social distancing, mask wearing, and limiting who comes in to the clinic, we have been able to keep patients and staff safe without altering treatment-specific decisions,” Dr. Nanda said.

Streamlining the foot traffic in the cancer center also worked well for Lisa A. Carey, MD, chief of the Division of Hematology/Oncology and deputy director of clinical sciences at University of North Carolina-Chapel Hill. “The truth is, oncological principles of care are still in place,” said Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research. “COVID hasn’t altered those; it has only thrown a little wrench in how we deliver that care.”

Kelly McCann, MD, PhD, a hematologist/oncologist in the Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, has had to walk a tighter rope to protect her patients with MBC, as COVID cases began to soar in LA county last fall.

To keep patients with MBC home more, Dr. McCann said many chose oral cytotoxic chemotherapies over infusional therapies. Some patients with HER2-positive MBC, for instance, opted for the oral combination neratinib + capecitabine over a trastuzumab-deruxtecan infusion, and others with triple-negative tumors chose capecitabine over a taxane.

At City of Hope, Mortimer has had a different experience of LA county’s COVID surge. Because the center only treats patients with cancer, “we have not had huge numbers of patients with COVID or had to significantly modify our practice outside of screening patients who come in and doing fewer scans compared to pre-COVID,” she said. With these precautions, “we have had no internal transmission of COVID within our institution.”

Still, patients with MBC have gotten COVID, and treating both illnesses does complicate decision-making. In some cases, Mortimer has postponed cancer treatment for patients who can delay for a few weeks while they recover from COVID. But patients who need to continue MBC treatment receive care in a separate unit, and Mortimer considers prescribing Eli Lilly’s recently approved antibody therapy bamlanivimab to treat COVID symptoms. “For each situation, we can always page our infectious disease experts to address any concerns or questions,” Dr. Mortimer said.

The MBC and COVID toll

The biggest hurdle for patients with MBC has been less about treatment decisions and more about handling the psychological toll of the pandemic, according to Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai in New York City.

“These are my personal observations, but I’ve seen how much more stressful it is to have metastatic breast cancer during the pandemic,” said Dr. Shapiro, who worries that fear of COVID may fuel or exacerbate patients’ depression and anxiety. “Patients can’t have family and friends by their side during infusions or appointments, and many feel isolated because of the risk of exposure.”

Because most patients with MBC still need in-person care such as exams, blood draws, or chemotherapy infusions, Dr. McCann has found that many of her patients “are afraid to come to a medical center and have been delaying appointments, imaging, and procedures.”

The psychological toll of treating breast cancer during the pandemic has touched oncologists as well. A recent survey found that burnout scores were significantly higher among physicians whose patients experienced delays in care, including chemotherapy or specialty consultations.

Getting patients vaccinated will improve protection and hopefully lessen fears surrounding COVID infection and transmission. Preliminary recommendations from the National Comprehensive Cancer Network›s COVID-19 Vaccination Advisory Committee state that patients with cancer «should be prioritized for vaccination.»

Dr. McCann agreed. “I’ve recommended COVID-19 vaccination to all of my patients with MBC,” she said. But because a lot of these therapies suppress the immune system to some degree, “I’ll recommend a period of time for vaccination in which the immune system is expected to have recovered, such as in the days prior to a dose of chemotherapy.”

Overall, according to Dr. Carey, institutional responses to treating MBC during the pandemic have been very similar: The key has been that “no one is keeping secrets,” she said. “Our global oncology community is sharing and adopting best practices. Our focus has been doing right by our patients.”

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

Novel research from the Concussion Assessment, Research and Education (CARE) Consortium sheds new light on how to effectively reduce the incidence of concussion and head injury exposure in college football.

The study, led by neurotrauma experts Michael McCrea, PhD, and Brian Stemper, PhD, professors of neurosurgery at the Medical College of Wisconsin in Milwaukee, reports data from hundreds of college football players across five seasons and shows concussion incidence and head injury exposure are disproportionately higher in the preseason versus the regular season.

The research also reveals that such injuries occur more often during practices than games.

“We think that with the findings from this paper, there’s a role for everybody to play in reducing injury,” Dr. McCrea said. “We hope these data help inform broad-based policy about practice and preseason training policies in collegiate football. We also think there’s a role for athletic administrators, coaches, and even athletes themselves.”

The study was published online Feb. 1 in JAMA Neurology.
 

More injuries in preseason

Concussion is one of the most common injuries in football. Beyond these harms are growing concerns that repetitive HIE may increase the risk of long-term neurologic health problems including chronic traumatic encephalopathy (CTE).

The CARE Consortium, which has been conducting research with college athletes across 26 sports and military cadets since 2014, has been interested in multiple facets of concussion and brain trauma.

“We’ve enrolled more than 50,000 athletes and service academy cadets into the consortium over the last 6 years to research all involved aspects including the clinical core, the imaging core, the blood biomarker core, and the genetic core, and we have a head impact measurement core.”

To investigate the pattern of concussion incidence across the football season in college players, the investigators used impact measurement technology across six Division I NCAA football programs participating in the CARE Consortium from 2015 to 2019.

A total of 658 players – all male, mean age 19 years – were fitted with the Head Impact Telemetry System (HITS) sensor arrays in their helmets to measure head impact frequency, location, and magnitude during play.

“This particular study had built-in algorithms that weeded out impacts that were below 10G of linear magnitude, because those have been determined not likely to be real impacts,” Dr. McCrea said.

Across the five seasons studied, 528,684 head impacts recorded met the quality standards for analysis. Players sustained a median of 415 (interquartile range [IQR], 190-727) impacts per season.

Of those, 68 players sustained a diagnosed concussion. In total, 48.5% of concussions occurred during preseason training, despite preseason representing only 20.8% of the football season. Total head injury exposure in the preseason occurred at twice the proportion of the regular season (324.9 vs. 162.4 impacts per team per day; mean difference, 162.6 impacts; 95% confidence interval, 110.9-214.3; P < .001).

“Preseason training often has a much higher intensity to it, in terms of the total hours, the actual training, and the heavy emphasis on full-contact drills like tackling and blocking,” said Dr. McCrea. “Even the volume of players that are participating is greater.”

Results also showed that in each of the five seasons, head injury exposure per athlete was highest in August (preseason) (median, 146.0 impacts; IQR, 63.0-247.8) and lowest in November (median, 80.0 impacts; IQR, 35.0-148.0). In the studied period, 72% of concussions and 66.9% of head injury exposure occurred in practice. Even within the regular season, total head injury exposure in practices was 84.2% higher than in games.

“This incredible dataset we have on head impact measurement also gives us the opportunity to compare it with our other research looking at the correlation between a single head impact and changes in brain structure and function on MRI, on blood biomarkers, giving us the ability to look at the connection between mechanism of effect of injury and recovery from injury,” said Dr. McCrea.

These findings also provide an opportunity to modify approaches to preseason training and football practices to keep players safer, said Dr. McCrea, noting that about half of the variance in head injury exposure is at the level of the individual athlete.

“With this large body of athletes we’ve instrumented, we can look at, for instance, all of the running backs and understand the athlete and what his head injury exposure looks like compared to all other running backs. If we find out that an athlete has a rate of head injury exposure that’s 300% higher than most other players that play the same position, we can take that data directly to the athlete to work on their technique and approach to the game.

“Every researcher wishes that their basic science or their clinical research findings will have some impact on the health and well-being of the population they’re studying. By modifying practices and preseason training, football teams could greatly reduce the risk of injury and exposure for their players, while still maintaining the competitive nature of game play,” he added.  

Through a combination of policy and education, similar strategies could be implemented to help prevent concussion and HIE in high school and youth football too, said Dr. McCrea.

‘Shocking’ findings

In an accompanying editorial, Christopher J. Nowinski, PhD, of the Concussion Legacy Foundation, Boston, and Robert C. Cantu, MD, department of neurosurgery, Emerson Hospital, Concord, Massachusetts, said the findings could have significant policy implications and offer a valuable expansion of prior research.

“From 2005 to 2010, studies on college football revealed that about two-thirds of head impacts occurred in practice,” they noted. “We cited this data in 2010 when we proposed to the NFL Players Association that the most effective way to reduce the risks of negative neurological outcomes was to reduce hitting in practice. They agreed, and in 2011 collectively bargained for severe contact limits in practice, with 14 full-contact practices allowed during the 17-week season. Since that rule was implemented, only 18% of NFL concussions have occurred in practice.”

“Against this backdrop, the results of the study by McCrea et al. are shocking,” they added. “It reveals that college football players still experience 72% of their concussions and 67% of their total head injury exposure in practice.”

Even more shocking, noted Dr. Nowinski and Dr. Cantu, is that these numbers are almost certainly an underestimate of the dangers of practice.

“As a former college football player and a former team physician, respectively, we find this situation inexcusable. Concussions in games are inevitable, but concussions in practice are preventable,” they wrote.  

“Laudably,” they added “the investigators call on the NCAA and football conferences to explore policy and rule changes to reduce concussion incidence and HIE and to create robust educational offerings to encourage change from coaches and college administrators.”

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

Novel research from the Concussion Assessment, Research and Education (CARE) Consortium sheds new light on how to effectively reduce the incidence of concussion and head injury exposure in college football.

The study, led by neurotrauma experts Michael McCrea, PhD, and Brian Stemper, PhD, professors of neurosurgery at the Medical College of Wisconsin in Milwaukee, reports data from hundreds of college football players across five seasons and shows concussion incidence and head injury exposure are disproportionately higher in the preseason versus the regular season.

The research also reveals that such injuries occur more often during practices than games.

“We think that with the findings from this paper, there’s a role for everybody to play in reducing injury,” Dr. McCrea said. “We hope these data help inform broad-based policy about practice and preseason training policies in collegiate football. We also think there’s a role for athletic administrators, coaches, and even athletes themselves.”

The study was published online Feb. 1 in JAMA Neurology.
 

More injuries in preseason

Concussion is one of the most common injuries in football. Beyond these harms are growing concerns that repetitive HIE may increase the risk of long-term neurologic health problems including chronic traumatic encephalopathy (CTE).

The CARE Consortium, which has been conducting research with college athletes across 26 sports and military cadets since 2014, has been interested in multiple facets of concussion and brain trauma.

“We’ve enrolled more than 50,000 athletes and service academy cadets into the consortium over the last 6 years to research all involved aspects including the clinical core, the imaging core, the blood biomarker core, and the genetic core, and we have a head impact measurement core.”

To investigate the pattern of concussion incidence across the football season in college players, the investigators used impact measurement technology across six Division I NCAA football programs participating in the CARE Consortium from 2015 to 2019.

A total of 658 players – all male, mean age 19 years – were fitted with the Head Impact Telemetry System (HITS) sensor arrays in their helmets to measure head impact frequency, location, and magnitude during play.

“This particular study had built-in algorithms that weeded out impacts that were below 10G of linear magnitude, because those have been determined not likely to be real impacts,” Dr. McCrea said.

Across the five seasons studied, 528,684 head impacts recorded met the quality standards for analysis. Players sustained a median of 415 (interquartile range [IQR], 190-727) impacts per season.

Of those, 68 players sustained a diagnosed concussion. In total, 48.5% of concussions occurred during preseason training, despite preseason representing only 20.8% of the football season. Total head injury exposure in the preseason occurred at twice the proportion of the regular season (324.9 vs. 162.4 impacts per team per day; mean difference, 162.6 impacts; 95% confidence interval, 110.9-214.3; P < .001).

“Preseason training often has a much higher intensity to it, in terms of the total hours, the actual training, and the heavy emphasis on full-contact drills like tackling and blocking,” said Dr. McCrea. “Even the volume of players that are participating is greater.”

Results also showed that in each of the five seasons, head injury exposure per athlete was highest in August (preseason) (median, 146.0 impacts; IQR, 63.0-247.8) and lowest in November (median, 80.0 impacts; IQR, 35.0-148.0). In the studied period, 72% of concussions and 66.9% of head injury exposure occurred in practice. Even within the regular season, total head injury exposure in practices was 84.2% higher than in games.

“This incredible dataset we have on head impact measurement also gives us the opportunity to compare it with our other research looking at the correlation between a single head impact and changes in brain structure and function on MRI, on blood biomarkers, giving us the ability to look at the connection between mechanism of effect of injury and recovery from injury,” said Dr. McCrea.

These findings also provide an opportunity to modify approaches to preseason training and football practices to keep players safer, said Dr. McCrea, noting that about half of the variance in head injury exposure is at the level of the individual athlete.

“With this large body of athletes we’ve instrumented, we can look at, for instance, all of the running backs and understand the athlete and what his head injury exposure looks like compared to all other running backs. If we find out that an athlete has a rate of head injury exposure that’s 300% higher than most other players that play the same position, we can take that data directly to the athlete to work on their technique and approach to the game.

“Every researcher wishes that their basic science or their clinical research findings will have some impact on the health and well-being of the population they’re studying. By modifying practices and preseason training, football teams could greatly reduce the risk of injury and exposure for their players, while still maintaining the competitive nature of game play,” he added.  

Through a combination of policy and education, similar strategies could be implemented to help prevent concussion and HIE in high school and youth football too, said Dr. McCrea.

‘Shocking’ findings

In an accompanying editorial, Christopher J. Nowinski, PhD, of the Concussion Legacy Foundation, Boston, and Robert C. Cantu, MD, department of neurosurgery, Emerson Hospital, Concord, Massachusetts, said the findings could have significant policy implications and offer a valuable expansion of prior research.

“From 2005 to 2010, studies on college football revealed that about two-thirds of head impacts occurred in practice,” they noted. “We cited this data in 2010 when we proposed to the NFL Players Association that the most effective way to reduce the risks of negative neurological outcomes was to reduce hitting in practice. They agreed, and in 2011 collectively bargained for severe contact limits in practice, with 14 full-contact practices allowed during the 17-week season. Since that rule was implemented, only 18% of NFL concussions have occurred in practice.”

“Against this backdrop, the results of the study by McCrea et al. are shocking,” they added. “It reveals that college football players still experience 72% of their concussions and 67% of their total head injury exposure in practice.”

Even more shocking, noted Dr. Nowinski and Dr. Cantu, is that these numbers are almost certainly an underestimate of the dangers of practice.

“As a former college football player and a former team physician, respectively, we find this situation inexcusable. Concussions in games are inevitable, but concussions in practice are preventable,” they wrote.  

“Laudably,” they added “the investigators call on the NCAA and football conferences to explore policy and rule changes to reduce concussion incidence and HIE and to create robust educational offerings to encourage change from coaches and college administrators.”

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

Novel research from the Concussion Assessment, Research and Education (CARE) Consortium sheds new light on how to effectively reduce the incidence of concussion and head injury exposure in college football.

The study, led by neurotrauma experts Michael McCrea, PhD, and Brian Stemper, PhD, professors of neurosurgery at the Medical College of Wisconsin in Milwaukee, reports data from hundreds of college football players across five seasons and shows concussion incidence and head injury exposure are disproportionately higher in the preseason versus the regular season.

The research also reveals that such injuries occur more often during practices than games.

“We think that with the findings from this paper, there’s a role for everybody to play in reducing injury,” Dr. McCrea said. “We hope these data help inform broad-based policy about practice and preseason training policies in collegiate football. We also think there’s a role for athletic administrators, coaches, and even athletes themselves.”

The study was published online Feb. 1 in JAMA Neurology.
 

More injuries in preseason

Concussion is one of the most common injuries in football. Beyond these harms are growing concerns that repetitive HIE may increase the risk of long-term neurologic health problems including chronic traumatic encephalopathy (CTE).

The CARE Consortium, which has been conducting research with college athletes across 26 sports and military cadets since 2014, has been interested in multiple facets of concussion and brain trauma.

“We’ve enrolled more than 50,000 athletes and service academy cadets into the consortium over the last 6 years to research all involved aspects including the clinical core, the imaging core, the blood biomarker core, and the genetic core, and we have a head impact measurement core.”

To investigate the pattern of concussion incidence across the football season in college players, the investigators used impact measurement technology across six Division I NCAA football programs participating in the CARE Consortium from 2015 to 2019.

A total of 658 players – all male, mean age 19 years – were fitted with the Head Impact Telemetry System (HITS) sensor arrays in their helmets to measure head impact frequency, location, and magnitude during play.

“This particular study had built-in algorithms that weeded out impacts that were below 10G of linear magnitude, because those have been determined not likely to be real impacts,” Dr. McCrea said.

Across the five seasons studied, 528,684 head impacts recorded met the quality standards for analysis. Players sustained a median of 415 (interquartile range [IQR], 190-727) impacts per season.

Of those, 68 players sustained a diagnosed concussion. In total, 48.5% of concussions occurred during preseason training, despite preseason representing only 20.8% of the football season. Total head injury exposure in the preseason occurred at twice the proportion of the regular season (324.9 vs. 162.4 impacts per team per day; mean difference, 162.6 impacts; 95% confidence interval, 110.9-214.3; P < .001).

“Preseason training often has a much higher intensity to it, in terms of the total hours, the actual training, and the heavy emphasis on full-contact drills like tackling and blocking,” said Dr. McCrea. “Even the volume of players that are participating is greater.”

Results also showed that in each of the five seasons, head injury exposure per athlete was highest in August (preseason) (median, 146.0 impacts; IQR, 63.0-247.8) and lowest in November (median, 80.0 impacts; IQR, 35.0-148.0). In the studied period, 72% of concussions and 66.9% of head injury exposure occurred in practice. Even within the regular season, total head injury exposure in practices was 84.2% higher than in games.

“This incredible dataset we have on head impact measurement also gives us the opportunity to compare it with our other research looking at the correlation between a single head impact and changes in brain structure and function on MRI, on blood biomarkers, giving us the ability to look at the connection between mechanism of effect of injury and recovery from injury,” said Dr. McCrea.

These findings also provide an opportunity to modify approaches to preseason training and football practices to keep players safer, said Dr. McCrea, noting that about half of the variance in head injury exposure is at the level of the individual athlete.

“With this large body of athletes we’ve instrumented, we can look at, for instance, all of the running backs and understand the athlete and what his head injury exposure looks like compared to all other running backs. If we find out that an athlete has a rate of head injury exposure that’s 300% higher than most other players that play the same position, we can take that data directly to the athlete to work on their technique and approach to the game.

“Every researcher wishes that their basic science or their clinical research findings will have some impact on the health and well-being of the population they’re studying. By modifying practices and preseason training, football teams could greatly reduce the risk of injury and exposure for their players, while still maintaining the competitive nature of game play,” he added.  

Through a combination of policy and education, similar strategies could be implemented to help prevent concussion and HIE in high school and youth football too, said Dr. McCrea.

‘Shocking’ findings

In an accompanying editorial, Christopher J. Nowinski, PhD, of the Concussion Legacy Foundation, Boston, and Robert C. Cantu, MD, department of neurosurgery, Emerson Hospital, Concord, Massachusetts, said the findings could have significant policy implications and offer a valuable expansion of prior research.

“From 2005 to 2010, studies on college football revealed that about two-thirds of head impacts occurred in practice,” they noted. “We cited this data in 2010 when we proposed to the NFL Players Association that the most effective way to reduce the risks of negative neurological outcomes was to reduce hitting in practice. They agreed, and in 2011 collectively bargained for severe contact limits in practice, with 14 full-contact practices allowed during the 17-week season. Since that rule was implemented, only 18% of NFL concussions have occurred in practice.”

“Against this backdrop, the results of the study by McCrea et al. are shocking,” they added. “It reveals that college football players still experience 72% of their concussions and 67% of their total head injury exposure in practice.”

Even more shocking, noted Dr. Nowinski and Dr. Cantu, is that these numbers are almost certainly an underestimate of the dangers of practice.

“As a former college football player and a former team physician, respectively, we find this situation inexcusable. Concussions in games are inevitable, but concussions in practice are preventable,” they wrote.  

“Laudably,” they added “the investigators call on the NCAA and football conferences to explore policy and rule changes to reduce concussion incidence and HIE and to create robust educational offerings to encourage change from coaches and college administrators.”

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

Endocrine therapy is the standard of care for estrogen receptor–positive (ER+) breast cancer, but only about half of women respond. At present, there is no method for identifying the women who are likely – and also unlikely – to respond.

But a new approach looks to be useful. It involves a trial of estrogen followed by imaging that measures the function of estrogen receptors in the cancer cells.

This functional testing of estrogen receptors on breast cancer cells was perfectly accurate in predicting endocrine therapy response in 43 postmenopausal women with advanced ER+ disease, say researchers from Washington University, St. Louis, led by Farrokh Dehdashti, MD.

“There is an unmet clinical need to develop more precise predictive biomarkers. The results of this study are extremely promising,” they conclude.  

The study was published online in Nature Communications.

For the study, the women were first infused with a radioactive progestin analog – 21-[18F]fluorofuranylnorprogesterone (FFNP) – that binds progesterone receptors. About 40 minutes later, they had a PET scan to assess its uptake, an indication of progesterone-receptor abundance.

The women were then given three 200-mg doses of estradiol over 24 hours.

The FFNP infusion and PET scan were repeated the next day.

Estradiol will cause cancer cells with functional estrogen receptors to produce more progesterone receptors, so increased uptake of the radioactive analog indicates functional estrogen receptors that will respond to endocrine therapy. If estrogen receptors are not functional, and therefore not amenable to endocrine therapy (ET), estradiol will not upregulate progesterone receptors.

The results proved the theory. FFNP uptake increased more than 6.7% in 28 subjects and a median of 25.4%. All 28 women responded to subsequent ET, including 15 partial responses and 13 women with stable disease at 6 months.

Median survival was not reached after a median follow up of 27.1 months.

Uptake increased no more than 6.7% in 15 subjects and, in fact, fell a median of 0.7% from baseline. None of these women responded to ET. The median survival was 22.6 months.

“We observed 100% agreement between the response to estrogen challenge and the response to hormone therapy. … This method should work for any therapy that depends on a functional estrogen receptor, and it could provide valuable information to oncologists deciding how best to treat their patients,” Dr. Dehdashti said in a press release.

A larger multicenter confirmation trial is in the works.

Oncology needs “to get away from empiric therapies and make therapy more individualized” to save patients from the morbidity and expense of ineffective treatment and wasting time when other options are available, Dr. Dehdashti told this news organization.

“It would be a good thing if we could identify endocrine-resistant patients,” said Charles Shapiro, MD, a professor and director of translational breast cancer research at Mount Sinai Hospital, New York.

However, he wondered “about the exportability to less resource-intensive community settings where most oncology care occurs. This technology, assuming the results are confirmed in a larger study, [needs] a cost-effectiveness analysis” vs. the empiric approach, Dr. Shapiro said in an interview.

The women taking part in this study were a median of 60 years old, and most had metastatic disease. PET imaging extended from the base of the skull to the upper thighs, with data derived from bone, lung, breast, and other tumor sites. ET options included aromatase inhibitors, fulvestrant, and tamoxifen in combination with other agents.

Almost three-quarters of the women had prior systemic treatment, most often a hormone therapy–based regimen. Prior treatment had no effect on FFNP uptake.

There were no adverse events with the radiotracer, but the estradiol made a few women nauseous, among other transient discomforts, the team reported.

The work was funded by the National Cancer Institute and Washington University, St. Louis. Dr. Shapiro and Dr. Dehdashti have disclosed no relevant financial relationships. Several investigators reported consulting fees and/or other ties to a number of companies, including Pfizer, Merck, Avid Radiopharmaceutical, and Radius Health.

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

Endocrine therapy is the standard of care for estrogen receptor–positive (ER+) breast cancer, but only about half of women respond. At present, there is no method for identifying the women who are likely – and also unlikely – to respond.

But a new approach looks to be useful. It involves a trial of estrogen followed by imaging that measures the function of estrogen receptors in the cancer cells.

This functional testing of estrogen receptors on breast cancer cells was perfectly accurate in predicting endocrine therapy response in 43 postmenopausal women with advanced ER+ disease, say researchers from Washington University, St. Louis, led by Farrokh Dehdashti, MD.

“There is an unmet clinical need to develop more precise predictive biomarkers. The results of this study are extremely promising,” they conclude.  

The study was published online in Nature Communications.

For the study, the women were first infused with a radioactive progestin analog – 21-[18F]fluorofuranylnorprogesterone (FFNP) – that binds progesterone receptors. About 40 minutes later, they had a PET scan to assess its uptake, an indication of progesterone-receptor abundance.

The women were then given three 200-mg doses of estradiol over 24 hours.

The FFNP infusion and PET scan were repeated the next day.

Estradiol will cause cancer cells with functional estrogen receptors to produce more progesterone receptors, so increased uptake of the radioactive analog indicates functional estrogen receptors that will respond to endocrine therapy. If estrogen receptors are not functional, and therefore not amenable to endocrine therapy (ET), estradiol will not upregulate progesterone receptors.

The results proved the theory. FFNP uptake increased more than 6.7% in 28 subjects and a median of 25.4%. All 28 women responded to subsequent ET, including 15 partial responses and 13 women with stable disease at 6 months.

Median survival was not reached after a median follow up of 27.1 months.

Uptake increased no more than 6.7% in 15 subjects and, in fact, fell a median of 0.7% from baseline. None of these women responded to ET. The median survival was 22.6 months.

“We observed 100% agreement between the response to estrogen challenge and the response to hormone therapy. … This method should work for any therapy that depends on a functional estrogen receptor, and it could provide valuable information to oncologists deciding how best to treat their patients,” Dr. Dehdashti said in a press release.

A larger multicenter confirmation trial is in the works.

Oncology needs “to get away from empiric therapies and make therapy more individualized” to save patients from the morbidity and expense of ineffective treatment and wasting time when other options are available, Dr. Dehdashti told this news organization.

“It would be a good thing if we could identify endocrine-resistant patients,” said Charles Shapiro, MD, a professor and director of translational breast cancer research at Mount Sinai Hospital, New York.

However, he wondered “about the exportability to less resource-intensive community settings where most oncology care occurs. This technology, assuming the results are confirmed in a larger study, [needs] a cost-effectiveness analysis” vs. the empiric approach, Dr. Shapiro said in an interview.

The women taking part in this study were a median of 60 years old, and most had metastatic disease. PET imaging extended from the base of the skull to the upper thighs, with data derived from bone, lung, breast, and other tumor sites. ET options included aromatase inhibitors, fulvestrant, and tamoxifen in combination with other agents.

Almost three-quarters of the women had prior systemic treatment, most often a hormone therapy–based regimen. Prior treatment had no effect on FFNP uptake.

There were no adverse events with the radiotracer, but the estradiol made a few women nauseous, among other transient discomforts, the team reported.

The work was funded by the National Cancer Institute and Washington University, St. Louis. Dr. Shapiro and Dr. Dehdashti have disclosed no relevant financial relationships. Several investigators reported consulting fees and/or other ties to a number of companies, including Pfizer, Merck, Avid Radiopharmaceutical, and Radius Health.

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

Endocrine therapy is the standard of care for estrogen receptor–positive (ER+) breast cancer, but only about half of women respond. At present, there is no method for identifying the women who are likely – and also unlikely – to respond.

But a new approach looks to be useful. It involves a trial of estrogen followed by imaging that measures the function of estrogen receptors in the cancer cells.

This functional testing of estrogen receptors on breast cancer cells was perfectly accurate in predicting endocrine therapy response in 43 postmenopausal women with advanced ER+ disease, say researchers from Washington University, St. Louis, led by Farrokh Dehdashti, MD.

“There is an unmet clinical need to develop more precise predictive biomarkers. The results of this study are extremely promising,” they conclude.  

The study was published online in Nature Communications.

For the study, the women were first infused with a radioactive progestin analog – 21-[18F]fluorofuranylnorprogesterone (FFNP) – that binds progesterone receptors. About 40 minutes later, they had a PET scan to assess its uptake, an indication of progesterone-receptor abundance.

The women were then given three 200-mg doses of estradiol over 24 hours.

The FFNP infusion and PET scan were repeated the next day.

Estradiol will cause cancer cells with functional estrogen receptors to produce more progesterone receptors, so increased uptake of the radioactive analog indicates functional estrogen receptors that will respond to endocrine therapy. If estrogen receptors are not functional, and therefore not amenable to endocrine therapy (ET), estradiol will not upregulate progesterone receptors.

The results proved the theory. FFNP uptake increased more than 6.7% in 28 subjects and a median of 25.4%. All 28 women responded to subsequent ET, including 15 partial responses and 13 women with stable disease at 6 months.

Median survival was not reached after a median follow up of 27.1 months.

Uptake increased no more than 6.7% in 15 subjects and, in fact, fell a median of 0.7% from baseline. None of these women responded to ET. The median survival was 22.6 months.

“We observed 100% agreement between the response to estrogen challenge and the response to hormone therapy. … This method should work for any therapy that depends on a functional estrogen receptor, and it could provide valuable information to oncologists deciding how best to treat their patients,” Dr. Dehdashti said in a press release.

A larger multicenter confirmation trial is in the works.

Oncology needs “to get away from empiric therapies and make therapy more individualized” to save patients from the morbidity and expense of ineffective treatment and wasting time when other options are available, Dr. Dehdashti told this news organization.

“It would be a good thing if we could identify endocrine-resistant patients,” said Charles Shapiro, MD, a professor and director of translational breast cancer research at Mount Sinai Hospital, New York.

However, he wondered “about the exportability to less resource-intensive community settings where most oncology care occurs. This technology, assuming the results are confirmed in a larger study, [needs] a cost-effectiveness analysis” vs. the empiric approach, Dr. Shapiro said in an interview.

The women taking part in this study were a median of 60 years old, and most had metastatic disease. PET imaging extended from the base of the skull to the upper thighs, with data derived from bone, lung, breast, and other tumor sites. ET options included aromatase inhibitors, fulvestrant, and tamoxifen in combination with other agents.

Almost three-quarters of the women had prior systemic treatment, most often a hormone therapy–based regimen. Prior treatment had no effect on FFNP uptake.

There were no adverse events with the radiotracer, but the estradiol made a few women nauseous, among other transient discomforts, the team reported.

The work was funded by the National Cancer Institute and Washington University, St. Louis. Dr. Shapiro and Dr. Dehdashti have disclosed no relevant financial relationships. Several investigators reported consulting fees and/or other ties to a number of companies, including Pfizer, Merck, Avid Radiopharmaceutical, and Radius Health.

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