Comparison of the Prevalence of Pathogenic Variants in Cancer Susceptibility Genes in Black Women and Non-Hispanic White Women With Breast Cancer in the United States

Key Points

Question  Is there a difference in the prevalence of germline pathogenic variants in cancer susceptibility genes in US Black women compared with non-Hispanic White women with breast cancer?

Findings  In this case-control study of 3946 Black and 25 287 non-Hispanic White women with breast cancer from population-based studies, there was no difference in prevalence of germline pathogenic variants.

Meaning  Changes to guidelines related to genetic testing for women with breast cancer should not be based on race alone.

Importance  The prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes in US Black women compared with non-Hispanic White women with breast cancer is poorly described.

Objective  To determine whether US Black and non-Hispanic White women with breast cancer have a different prevalence of PVs in 12 cancer susceptibility genes.

Design, Setting, and Participants  Multicenter, population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Participants were Black and non-Hispanic White women diagnosed with breast cancer, unselected for family history or age at diagnosis. Data were collected from June 1993 to June 2020; data analysis was performed between September 2020 and February 2021.

Main Outcomes and Measures  Prevalence of germline PVs in 12 established breast cancer susceptibility genes.

Results  Among 3946 Black women (mean [SD] age at diagnosis, 56.5 [12.02] y) and 25 287 non-Hispanic White women (mean [SD] age at diagnosis, 62.7 [11.14] y) with breast cancer, there was no statistically significant difference by race in the combined prevalence of PVs in the 12 breast cancer susceptibility genes evaluated (5.65% in Black vs 5.06% in non-Hispanic White women; P = .12). The prevalence of PVs in CHEK2 was higher in non-Hispanic White than Black patients (1.29% vs 0.38%; P < .001), whereas Black patients had a higher prevalence of PVs in BRCA2 (1.80% vs 1.24%; P = .005) and PALB2 (1.01% vs 0.40%; P < .001). For estrogen receptor–negative breast cancer, the prevalence of PVs was not different except for PALB2, which was higher in Black women. In women diagnosed before age 50 years, there was no difference in overall prevalence of PVs in Black vs non-Hispanic White women (8.83% vs 10.04%; P = .25), and among individual genes, only CHEK2 PV prevalence differed by race. After adjustment for age at diagnosis, the standardized prevalence ratio of PVs in non-Hispanic White relative to Black women was 1.08 (95% CI, 1.02-1.14), and there was no longer a statistically significant difference in BRCA2 PV prevalence.

Conclusions and Relevance  This large population-based case-control study revealed no clinically meaningful differences in the prevalence of PVs in 12 breast cancer susceptibility genes between Black and non-Hispanic White women with breast cancer. The findings suggest that there is not sufficient evidence to make policy changes related to genetic testing based on race alone. Instead, all efforts should be made to ensure equal access to and uptake of genetic testing to minimize disparities in care and outcomes.

In the US, Black women are more likely to be diagnosed with breast cancer before age 50 years or with estrogen receptor (ER)–negative and triple-negative breast cancer (TNBC) than non-Hispanic White women. It remains unclear whether these disparities are related to racial differences in germline genetic pathogenic variants (PVs) in breast cancer susceptibility genes and if race should inform strategies for genetic testing. Our recent report based on, to our knowledge, the largest population of Black patients with breast cancer¹ from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium² demonstrates the validity of the current breast cancer testing panels in Black women; however, the prevalence and type of germline PVs in Black compared with non-Hispanic White women with breast cancer from the general population are currently ill defined. Several studies have suggested that patients of African ancestry with breast cancer are more likely than non-Hispanic White patients to have a PV in a cancer susceptibility gene. However, these studies have been limited by either sample size or ascertainment (eg, ascertained based on young onset or through clinical testing laboratories).^3-13 In the present study, we set out to determine whether there were racial differences in the prevalence of PVs in breast cancer susceptibility genes between US Black and non-Hispanic White women from population-based studies in the CARRIERS consortium.

Breast cancer cases among self-reported Black or non-Hispanic White patients were drawn from population-based studies from the CARRIERS consortium, including 7 prospective cohort studies (Black Women’s Health Study [BHWS], the Cancer Prevention Study II [CPSII], the California Teachers Study [CTS], the Multiethnic Cohort Study [MEC], the Nurses’ Health Study [NHS], the Nurses’ Health Study II [NHSII], and the Women’s Health Initiative [WHI]), 2 case-cohort studies (the Cancer Prevention Study-3 [CPS3] and the Mayo Mammography Health Study [MMHS]), and 3 case-control studies (the Mayo Clinic Breast Cancer Study [MCBCS], the Women’s Circle of Health Study [WCHS], and the Wisconsin Women’s Health Study [WWHS]), as described previously.^1,2 Studies enriched with early-onset disease or breast cancer family history were excluded to limit bias. Institutional review boards at the Mayo Clinic and all contributing sites approved the research. All participants provided written informed consent.

A customized amplicon-based QIASeq panel consisting of 1733 target regions in 37 cancer predisposition genes was designed for sequencing of germline DNA samples to an average of greater than 20× coverage in more than 99% of the target regions. Twelve established breast cancer predisposition genes were evaluated: ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53. Pathogenic variants were classified as previously described.^1,2

The prevalence of PVs in each gene was compared between Black and non-Hispanic White patients using Fisher exact test. The comparisons were first performed in all breast cancer cases combined, and then stratified by age younger than 50 years vs 50 years and older; tumor ER status; and separately for women with TNBC. To account for the differences in the age at diagnosis distribution between studies, the expected prevalence of PVs in non-Hispanic White patients was calculated by standardizing the age distribution (≤40, 41-50, 51-60, 61-70, ≥71 years) of non-Hispanic White patients to that of Black patients, with 95% CIs estimated using the method by Fay and Feuer.¹⁴ Indirect standardized prevalence ratios and 95% CIs were estimated to compare the adjusted prevalence estimates. Data were collected from June 1993 to June 2020; data analysis was performed between September 2020 and February 2021. Analyses were performed in R, version 3.6.3 (R Foundation); a P value less than .05 was considered statistically significant, and all tests were 2-sided.

Table 1 summarizes the characteristics of Black and non-Hispanic White women with breast cancer in the CARRIERS consortium population-based studies. In comparison to non-Hispanic White women, Black women were more likely to be diagnosed at a younger age and with ER-negative disease and TNBC, less likely to have a first-degree relative with breast cancer, but more likely to have a family history of ovarian cancer (all P < .001) (supporting data in Table 1).

Of the 3946 Black women, 223 (5.65%) had a PV in 1 of the 12 established breast cancer susceptibility genes, compared with a prevalence of 1279 of 25 287 (5.06%) in non-Hispanic White women (P = .12) (Table 2). Non-Hispanic White women with breast cancer were more likely to have PVs in CHEK2 than Black women (1.29% vs 0.38%; P < .001). Of the CHEK2 PVs detected, the majority were CHEK2 1100delC, with 227 of 325 (70%) in non-Hispanic White women and 9 of 15 (60%) in Black women. Black women with breast cancer were more likely than non-Hispanic White women to have PVs in BRCA2 (1.80% vs 1.24%; P = .005) and PALB2 (1.01% vs 0.40%; P < .001). There was no difference by race in the prevalence of PVs in ATM or BRCA1 or in the other breast cancer susceptibility genes analyzed (BARD, CDH1, NBN, NF1, RAD51C, RAD51D, and TP53), although for all genes, except ATM and BRCA1, numbers were small.

Among women with ER-positive breast cancer, Black women were more likely than non-Hispanic White women to have BRCA2 PVs (1.56% vs 1.05%; P = .04) and less likely to have CHEK2 PVs (0.46% vs 1.36%; P < .001). However, the overall prevalence of PVs was not different (4.38% in both groups; P > .99) (Table 3).

For ER-negative breast cancer or TNBC, there was a statistically significant difference between Black patients vs non-Hispanic White patients for PALB2 only (ER-negative breast cancer: 1.83% vs 0.95%; P = .04; TNBC: 2.79% vs 1.23%; P = .05) (Table 3). The overall prevalence of PVs was not different (9.28% in Black women vs 8.08% in non-Hispanic White women; P = .28): more than 75% of PVs seen in ER-negative breast cancer were in BRCA1, BRCA2, or PALB2 (81.3% in Black women and 77.0% non-Hispanic White women).

In women diagnosed before age 50 years, there was no difference in prevalence of PVs in Black vs non-Hispanic White women (8.83% vs 10.04%; P = .25). Among individual genes, only CHEK2 PV differed by race (Table 3).

After adjustment for age at diagnosis, the standardized prevalence ratio of PVs in the 12 genes evaluated was greater than 1.0 in non-Hispanic White women relative to Black women (1.08; 95% CI, 1.02-1.14) (Table 2). Statistically significant differences remained for PALB2, with a higher prevalence of PVs in Black women (standardized prevalence ratio, 0.40; 95% CI, 0.33-0.48), and for CHEK2, with a lower prevalence in Black women (standardized prevalence ratio, 3.35; 95% CI, 3.01-3.74). There was no longer a difference in the prevalence of PVs in BRCA2 (standardized prevalence ratio, 0.91; 95% CI, 0.81-1.01). Four previously nonsignificant genes (ATM, BRCA1, RAD51D, and TP53) became statistically significant after age adjustment. Notably, all but RAD51D appeared to have a higher prevalence of PVs in non-Hispanic White than Black patients after age adjustment (Table 3).

In this large population-based study of women with breast cancer, no clinically meaningful difference in the prevalence or distribution of PVs was seen in US Black compared with non-Hispanic White cases. Although the prevalence of PVs in 3 genes—CHEK2, BRCA2, and PALB2—differed statistically between the 2 populations, the absolute differences were small.

Black women with breast cancer were younger than non-Hispanic White women at diagnosis, more often had TNBC, and more frequently had a family history of ovarian cancer. These factors are incorporated into current guidelines for consideration of genetic testing in breast cancer. Given the validity of the current breast cancer testing panels for Black women as demonstrated in our recent study,¹ we do not see evidence that race should be used as an independent consideration for genetic testing. Because Black women are less likely to undergo breast cancer genetic testing, largely owing to differences in physician recommendations or access to care,^4,15 continued efforts to promote uptake of and reduce barriers for genetic testing for Black women are warranted.

Limitations of this study include missing family history and receptor status data. In addition, despite the large size of the CARRIERS study, the number of women with PVs in genes such as RAD51C and RAD51D was small.

In this study among Black and non-Hispanic White women with breast cancer in the US, we found no difference in the prevalence of PVs in 12 breast cancer susceptibility genes. Black women are more likely to be diagnosed at a younger age or with TNBC; these characteristics are associated with a higher risk of having a PV, particularly in BRCA1, BRCA2, and PALB2, and are already incorporated into current guidelines. The present study findings, from, to our knowledge, the largest population-based sample of Black patients along with non-Hispanic White patients from similar or the same studies, suggest that there is not sufficient evidence to make changes to genetic testing guidelines based on race alone. All efforts should be made to ensure equal access to and uptake of genetic testing to minimize disparities in care and outcomes.

Accepted for Publication: March 24, 2021.

Published Online: May 27, 2021. doi:10.1001/jamaoncol.2021.1492

Corresponding Author: Susan M. Domchek, MD, Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104 (susan.domchek@pennmedicine.upenn.edu).

Author Contributions: Drs Domchek, Couch, and Polley had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Domchek, Yao, and Chen contributed equally to the work.

Concept and design: Domchek, Yao, Hart, Goldgar, Couch, Polley, Palmer.

Acquisition, analysis, or interpretation of data: Domchek, Yao, Chen, Hu, Hart, Nathanson, Ambrosone, Haiman, Couch, Polley, Palmer.

Drafting of the manuscript: Domchek, Yao, Chen, Hart, Couch, Polley.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Yao, Chen, Hart, Goldgar, Polley, Palmer.

Obtained funding: Nathanson, Ambrosone, Couch.

Administrative, technical, or material support: Domchek, Ambrosone, Haiman, Couch.

Supervision: Couch.

Conflict of Interest Disclosures: Dr Domchek reported receiving personal fees from AstraZeneca and Bristol Myers Squibb outside the submitted work. Dr Couch reported receiving personal fees from AstraZeneca, Qiagen, and Ambry Genetics outside the submitted work. Dr Palmer reported receiving grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

Funding/Support: The CARRIERS study was supported by National Institutes of Health (NIH) grants R01CA192393, R01CA225662, and R35CA253187; an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (P50CA116201); and grants from the Breast Cancer Research Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Carriers Consortium Group Information: Mayo Clinic, Rochester, MN: Chunling Hu, PhD; Steven N. Hart, PhD; Rohan Gnanaolivu, MS; Kun Y. Lee, PhD; Jie Na, MS; Jenna Lilyquist, PhD; Siddhartha Yadav, MD; Nicholas J. Boddicker, PhD; Tricia Lindstrom, BS; Janet E. Olson, PhD; Christopher Scott, MS; Celine M. Vachon, PhD; Eric C. Polley, PhD; Fergus J. Couch, PhD. Harvard University T.H. Chan School of Public Health, Boston, MA: Hongyan Huang, PhD; Chi Gao, MSc; David J. Hunter, ScD; Peter Kraft, ScD. Qiagen, Germany: Raed Samara, PhD; Josh Klebba, BS. Roswell Park Comprehensive Cancer Center, Buffalo, NY: Christine B. Ambrosone, PhD; Song Yao, PhD. University of California, Irvine, CA: Hoda Anton-Culver, PhD; Argyrios Ziogas, PhD. UWM Joseph J. Zilber School of Public Health, Milwaukee, WI: Paul Auer, PhD. Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, The State University of New Jersey, New Brunswick, NJ: Elisa V. Bandera, PhD. Beckman Research Institute of City of Hope, Duarte, CA: Leslie Bernstein, PhD; Huiyan Ma, PhD; Susan Neuhausen, PhD; Jeffrey N. Weitzel, MD. Slone Epidemiology Center at Boston University, Boston, MA: Kimberly A. Bertrand, ScD; Julie R. Palmer, ScD; Lynn Rosenberg, ScD. University of Wisconsin–Madison, Madison, WI: Elizabeth S. Burnside, MD, MPH, MS; Irene M. Ong, PhD; Amy Trentham-Dietz, PhD. Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA: Brian D. Carter, MPH; Mia Gaudet, PhD; James M. Hodge, MPH, JD; Eric J. Jacobs, PhD; Alpa V. Patel, PhD. Brigham and Women’s Hospital, Boston, MA: Heather Eliassen, ScD. Keck School of Medicine, University of Southern California, Los Angeles, CA: Christopher Haiman, ScD. University of Oxford, Oxford, UK: David J. Hunter, ScD. Stanford University School of Medicine, Stanford, CA, Esther M. John, PhD; Allison W. Kurian, MD, MSc. Fred Hutchinson Cancer Research Center, Seattle, WA: Charles Kooperberg, PhD; Polly A. Newcomb, PhD, MPH. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI: Loic Le Marchand, PhD, MD. Department of Epidemiology, University of Washington, Seattle, WA: Sara Lindstrom, PhD. National Institute of Environmental Health Sciences, NIH, Durham, NC: Katie M. O’Brien, PhD; Dale P. Sandler, PhD; Jack A. Taylor, MD, PhD; Clarice R. Weinberg, PhD. Weill Cornell Medicine, New York, NY: Rulla Tamimi, ScD. University of Utah, Salt Lake City, UT: David E. Goldgar, PhD. Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA: Susan M. Domchek, MD; Katherine L. Nathanson, MD. Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA: Susan M. Domchek, MD; Katherine L. Nathanson, MD.

Additional Information: Support for the contributing studies was provided by NIH awards (U01CA164974, R01CA098663, R01CA100598, R01CA185623, P01CA151135, R01CA097396, P30CA16056, U01CA164973, U01CA164920, R01CA204819, R01CA77398, U01CA199277, P30CA014520, U01CA82004, R01CA047147, R01CA067264, UM1CA186107, P01CA87969, R01CA49449 U01CA176726 and R01CA67262); National Heart, Lung, and Blood Institute contracts (HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C); National Institute of Environmental Health Sciences intramural awards (Z01-ES044005, Z01-ES049033 and Z01-ES102245); American Cancer Society; Susan G Komen for the Cure (Drs Palmer and Domchek, 2SISTER), Breast Cancer Research Foundation (Drs Couch, Ambrosone, Domchek, Nathanson, and Weitzel), Karin Grunebaum Cancer Research Foundation (Dr Palmer), the University of Wisconsin–Madison Office of the Vice Chancellor for Research and Graduate Education (Dr Trentham-Dietz), The California Breast Cancer Research Fund (contract 97-10500), California Department of Public Health. The UCI Breast Cancer Study component of this research was supported by the NIH (CA58860, CA92044) and the Lon V Smith Foundation (LVS39420).