Breast Cancer

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.

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

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.

Of four surgical procedures for breast cancer that have been determined to be of low value because they yield no meaningful clinical benefit, two continue to be utilized. In fact, the use of two of these procedures has increased in the United States, new research shows.

“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.

The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.

“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.

The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.

These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.

“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”

“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”

The study was published on Feb. 3 in JAMA Surgery.

For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.

The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.

The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.

Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).

Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”

Two of the four low-value procedures increased in use during the study period.

Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.

In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
 

Patterns at hospitals vary

The authors of the study also examined hospital factors, which can heavily influence choice of procedure.

These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.

Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.

Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.

However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).

Dr. Dossett said the lack of consistency was somewhat unexpected.

“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
 

Evidence may or may not influence trends

The authors speculate on why the low-value designation is in some cases being ignored.

The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.

However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.

Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.

Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.

“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.

Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.

“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.

“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”

“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.

“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”

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

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

Of four surgical procedures for breast cancer that have been determined to be of low value because they yield no meaningful clinical benefit, two continue to be utilized. In fact, the use of two of these procedures has increased in the United States, new research shows.

“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.

The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.

“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.

The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.

These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.

“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”

“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”

The study was published on Feb. 3 in JAMA Surgery.

For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.

The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.

The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.

Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).

Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”

Two of the four low-value procedures increased in use during the study period.

Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.

In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
 

Patterns at hospitals vary

The authors of the study also examined hospital factors, which can heavily influence choice of procedure.

These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.

Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.

Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.

However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).

Dr. Dossett said the lack of consistency was somewhat unexpected.

“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
 

Evidence may or may not influence trends

The authors speculate on why the low-value designation is in some cases being ignored.

The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.

However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.

Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.

Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.

“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.

Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.

“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.

“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”

“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.

“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”

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

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

Of four surgical procedures for breast cancer that have been determined to be of low value because they yield no meaningful clinical benefit, two continue to be utilized. In fact, the use of two of these procedures has increased in the United States, new research shows.

“This is the first study to [evaluate] all four of the low-value breast cancer procedures at the same time and try to draw some conclusions on practice patterns across facilities,” said senior author Lesly A. Dossett, MD, MPH, Center for Health Outcomes and Policy, the University of Michigan, Ann Arbor.

The two low-value procedures that have increased in use are contralateral prophylactic mastectomy for average-risk women with unilateral cancer and sentinel lymph node biopsy for clinically node-negative women aged 70 years and older with hormone receptor–positive (HR+) cancer.

“This suggests that formal efforts to reduce low value care through dissemination of guidelines, education of patients or providers, or alignment of incentives will be necessary to achieve full deimplementation,” she told this news organization.

The researchers emphasize that the providing of services that have no clinically meaningful benefit is a national epidemic, costing the United States more than $100 billion dollars annually.

These trends are notable and likely reflect a broad range of factors, commented Katharine Yao, MD, chief of the division of surgical oncology at the NorthShore University HealthSystem, Evanston, Ill.

“I think the better message here is not so much that facilities are doing too many low-value procedures but more that these procedures are still being performed, and the trends show increased rates over the years – why is that?”

“Perhaps there are other factors here we need to explore: why do these procedures persist, and why, despite the Choosing Wisely campaign, [do] they continue to increase?” she said in an interview. “Maybe there is something we can learn here about patient and physician preferences that perhaps we should be paying more attention to.”

The study was published on Feb. 3 in JAMA Surgery.

For the analysis, Dr. Dossett and her colleagues evaluated surgical data from the National Cancer Database. They examined data from more than 1,500 surgical facilities and from surgeries involving 920,256 women in the United States who were diagnosed with breast cancer between 2004 and 2016.

The team focused on four procedures that have been determined to be of low value by Choosing Wisely, a campaign of the American Board of Internal Medicine Foundation, on the basis of recommendations of the American College of Surgeons, the Society for Surgical Oncology, and the American Society for Breast Surgeons.

The results show that, for two of the four low-value procedures, use declined significantly over the study period. These two procedures were axillary lymph node dissection for limited nodal disease, for patients undergoing lumpectomy and radiotherapy, and lumpectomy re-excision for patients whose surgical margins were close but were negative for invasive cancer.

Axillary lymph node dissection declined from 63% in 2004 to 14% in 2016. The steepest reduction was seen soon after data from the Z0011 study were published in 2010. The rates for this procedure halved in the following year, from 62% in 2010 to 31% in 2011 (P < .001).

Likewise, reoperation rates after lumpectomy dropped from 19% in 2004 to 15% in 2016. The sharpest decline, from 18% in 2013 to 16% in 2014, corresponded to the publishing of the SSO/ASTRO consensus statement, which designated a negative margin as having “no tumor on ink.”

Two of the four low-value procedures increased in use during the study period.

Rates of contralateral prophylactic mastectomy increased nearly 2.5-fold among women with unilateral breast cancer undergoing mastectomy, from 11% in 2004 to 26% in 2016, despite SSO guidelines issued in 2007 recommending that the procedure not be used for women at average risk.

In addition, rates of sentinel lymph node biopsy among women aged 70 years and older with clinically node-negative HR+ breast cancer increased from 78% in 2004 to 87% in 2012. There was no significant decline in the use of this procedure, even after the CALGB 9343 trial from the Cancer and Leukemia Group B showed no survival benefit in 2013.
 

Patterns at hospitals vary

The authors of the study also examined hospital factors, which can heavily influence choice of procedure.

These results showed that the greatest reductions of the low-value breast cancer procedures occurred at academic research programs and high-volume surgical facilities. Elsewhere, the rates varied widely.

Interfacility rates of axillary lymph node dissection ranged from 7% to 47%; lumpectomy reoperation rates ranged from 3% to 62%; contralateral prophylactic mastectomy rates ranged from 9% to 67%; and sentinel lymph node biopsy rates ranged from 25% to 97%.

Being an outlier for use of one procedure did not necessarily translate to nonconformity for others. Factors such as a hospital’s volume of breast cancer cases or the type of facility did not appear to influence rates of axillary lymph node dissection or lumpectomy reoperation.

However, the rates of contralateral prophylactic mastectomy were significantly higher in high-volume centers and integrated network cancer programs, compared with community cancer programs (23% vs. 2%; P < .001).

Dr. Dossett said the lack of consistency was somewhat unexpected.

“We expected we would find some facilities were constantly good or bad at deimplementation or that there would be stronger associations between certain facility characteristics and performance,” she said. “That really wasn’t the case, and most facilities had mixed performance.”
 

Evidence may or may not influence trends

The authors speculate on why the low-value designation is in some cases being ignored.

The evidence regarding the risk for lymphedema related to axillary lymph node dissection procedure appears to have helped reduce its use, they note.

However, surgeons have been much less convinced of benefits in omitting sentinel lymph node biopsy, either because they are unfamiliar with the recommendations to avoid the procedure, or they may feel the procedure adds only minimal time and risk to a patient’s operation, the authors explain.

Patients may be convinced to opt to omit sentinel lymph node biopsy if they are properly counseled regarding the risks and benefits of the procedure, Dr. Dossett commented.

Dr. Yao added that, for elderly patients, age can play an important role in sentinel node biopsy.

“Patients’ life expectancy has increased over the years, and node status may impact adjuvant therapy decisions for these patients, even chemotherapy decisions,” she said.

Pressure to continue to perform contralateral prophylactic mastectomy is believed to be significantly patient driven, Dr. Dossett noted.

“I ultimately think the best way to reduce contralateral prophylactic mastectomy is to encourage women with small cancers to undergo breast-conserving surgery, i.e., lumpectomy, instead of mastectomy,” she explained.

“Once the decision for mastectomy is made, there is often a great deal of momentum towards a contralateral prophylactic mastectomy.”

“Contralateral prophylactic mastectomy is a personal preference that many surgeons are willing to do for their patients,” Dr. Yao explained.

“Although no survival benefit has been demonstrated for this procedure, patients find many other benefits that have nothing to do with survival.”

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

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

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

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.

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

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.

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

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.

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

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

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

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

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

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

An artificial intelligence (AI) diagnostic system based on neural networks may assist in the diagnosis of COVID-19, according to a pilot study.

The system, called CXR-Net, was trained to differentiate SARS-CoV-2 chest x-rays (CXRs) from CXRs that are either normal or non–COVID-19 lung pathologies, explained Abdulah Haikal, an MD candidate at Wayne State University, Detroit.

Mr. Haikal described CXR-Net at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S11-04).

CXR-Net is a two-module pipeline, Mr. Haikal explained. Module I is based on Res-CR-Net, a type of neural network originally designed for the semantic segmentation of microscopy images, with the ability to retain the original resolution of the input images in the feature maps of all layers and in the final output.

Module II is a hybrid convolutional neural network in which the first convolutional layer with learned coefficients is replaced by a layer with fixed coefficients provided by the Wavelet Scattering Transform. Module II inputs patients’ CXRs and corresponding lung masks quantified by Module I, and generates as outputs a class assignment (COVID-19 or non–COVID-19) and high-resolution heat maps that detect the severe acute respiratory syndrome–-associated lung regions.

“The system is trained to differentiate COVID and non-COVID pathologies and produces a highly discriminative heat map to point to lung regions where COVID is suspected,” Mr. Haikal said. “The Wavelet Scattering Transform allows for fast determination of COVID versus non-COVID CXRs.”
 

Preliminary results and implications

CXR-Net was piloted on a small dataset of CXRs from non–COVID-19 and polymerase chain reaction–confirmed COVID-19 patients acquired at a single center in Detroit.

Upon fivefold cross validation of the training set with 2,265 images, 90% accuracy was observed when the training set was tested against the validation set. However, once 1,532 new images were introduced, a 76% accuracy rate was observed.

The F1 scores were 0.81 and 0.70 for the training and test sets, respectively.

“I’m really excited about this new approach, and I think AI will allow us to do more with less, which is exciting,” said Ross L. Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, who led a discussion session with Mr. Haikal about CXR-Net.

One question raised during the discussion was whether the technology will help health care providers be more thoughtful about when and how they image COVID-19 patients.

“The more data you feed into the system, the stronger and more accurate it becomes,” Mr. Haikal said. “However, until we have data sharing from multiple centers, we won’t see improved accuracy results.”

Another question was whether this technology could be integrated with more clinical parameters.

“Some individuals are afraid that AI will replace the job of a professional, but it will only make it better for us,” Mr. Haikal said. “We don’t rely on current imaging techniques to make a definitive diagnosis, but rather have a specificity and sensitivity to establish a diagnosis, and AI can be used in the same way as a diagnostic tool.”

Mr. Haikal and Dr. Levine disclosed no conflicts of interest. No funding sources were reported in the presentation.

An artificial intelligence (AI) diagnostic system based on neural networks may assist in the diagnosis of COVID-19, according to a pilot study.

The system, called CXR-Net, was trained to differentiate SARS-CoV-2 chest x-rays (CXRs) from CXRs that are either normal or non–COVID-19 lung pathologies, explained Abdulah Haikal, an MD candidate at Wayne State University, Detroit.

Mr. Haikal described CXR-Net at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S11-04).

CXR-Net is a two-module pipeline, Mr. Haikal explained. Module I is based on Res-CR-Net, a type of neural network originally designed for the semantic segmentation of microscopy images, with the ability to retain the original resolution of the input images in the feature maps of all layers and in the final output.

Module II is a hybrid convolutional neural network in which the first convolutional layer with learned coefficients is replaced by a layer with fixed coefficients provided by the Wavelet Scattering Transform. Module II inputs patients’ CXRs and corresponding lung masks quantified by Module I, and generates as outputs a class assignment (COVID-19 or non–COVID-19) and high-resolution heat maps that detect the severe acute respiratory syndrome–-associated lung regions.

“The system is trained to differentiate COVID and non-COVID pathologies and produces a highly discriminative heat map to point to lung regions where COVID is suspected,” Mr. Haikal said. “The Wavelet Scattering Transform allows for fast determination of COVID versus non-COVID CXRs.”
 

Preliminary results and implications

CXR-Net was piloted on a small dataset of CXRs from non–COVID-19 and polymerase chain reaction–confirmed COVID-19 patients acquired at a single center in Detroit.

Upon fivefold cross validation of the training set with 2,265 images, 90% accuracy was observed when the training set was tested against the validation set. However, once 1,532 new images were introduced, a 76% accuracy rate was observed.

The F1 scores were 0.81 and 0.70 for the training and test sets, respectively.

“I’m really excited about this new approach, and I think AI will allow us to do more with less, which is exciting,” said Ross L. Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, who led a discussion session with Mr. Haikal about CXR-Net.

One question raised during the discussion was whether the technology will help health care providers be more thoughtful about when and how they image COVID-19 patients.

“The more data you feed into the system, the stronger and more accurate it becomes,” Mr. Haikal said. “However, until we have data sharing from multiple centers, we won’t see improved accuracy results.”

Another question was whether this technology could be integrated with more clinical parameters.

“Some individuals are afraid that AI will replace the job of a professional, but it will only make it better for us,” Mr. Haikal said. “We don’t rely on current imaging techniques to make a definitive diagnosis, but rather have a specificity and sensitivity to establish a diagnosis, and AI can be used in the same way as a diagnostic tool.”

Mr. Haikal and Dr. Levine disclosed no conflicts of interest. No funding sources were reported in the presentation.

An artificial intelligence (AI) diagnostic system based on neural networks may assist in the diagnosis of COVID-19, according to a pilot study.

The system, called CXR-Net, was trained to differentiate SARS-CoV-2 chest x-rays (CXRs) from CXRs that are either normal or non–COVID-19 lung pathologies, explained Abdulah Haikal, an MD candidate at Wayne State University, Detroit.

Mr. Haikal described CXR-Net at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S11-04).

CXR-Net is a two-module pipeline, Mr. Haikal explained. Module I is based on Res-CR-Net, a type of neural network originally designed for the semantic segmentation of microscopy images, with the ability to retain the original resolution of the input images in the feature maps of all layers and in the final output.

Module II is a hybrid convolutional neural network in which the first convolutional layer with learned coefficients is replaced by a layer with fixed coefficients provided by the Wavelet Scattering Transform. Module II inputs patients’ CXRs and corresponding lung masks quantified by Module I, and generates as outputs a class assignment (COVID-19 or non–COVID-19) and high-resolution heat maps that detect the severe acute respiratory syndrome–-associated lung regions.

“The system is trained to differentiate COVID and non-COVID pathologies and produces a highly discriminative heat map to point to lung regions where COVID is suspected,” Mr. Haikal said. “The Wavelet Scattering Transform allows for fast determination of COVID versus non-COVID CXRs.”
 

Preliminary results and implications

CXR-Net was piloted on a small dataset of CXRs from non–COVID-19 and polymerase chain reaction–confirmed COVID-19 patients acquired at a single center in Detroit.

Upon fivefold cross validation of the training set with 2,265 images, 90% accuracy was observed when the training set was tested against the validation set. However, once 1,532 new images were introduced, a 76% accuracy rate was observed.

The F1 scores were 0.81 and 0.70 for the training and test sets, respectively.

“I’m really excited about this new approach, and I think AI will allow us to do more with less, which is exciting,” said Ross L. Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, who led a discussion session with Mr. Haikal about CXR-Net.

One question raised during the discussion was whether the technology will help health care providers be more thoughtful about when and how they image COVID-19 patients.

“The more data you feed into the system, the stronger and more accurate it becomes,” Mr. Haikal said. “However, until we have data sharing from multiple centers, we won’t see improved accuracy results.”

Another question was whether this technology could be integrated with more clinical parameters.

“Some individuals are afraid that AI will replace the job of a professional, but it will only make it better for us,” Mr. Haikal said. “We don’t rely on current imaging techniques to make a definitive diagnosis, but rather have a specificity and sensitivity to establish a diagnosis, and AI can be used in the same way as a diagnostic tool.”

Mr. Haikal and Dr. Levine disclosed no conflicts of interest. No funding sources were reported in the presentation.