# paper.pdf ## Metadata - PDFFormatVersion=1.7 - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - CreationDate=D:20260410184841+05'30' - Creator=PTC Arbortext Layout Developer 12.1.6202/W-x64 - Custom.EPSprocessor=PStill version 1.84.42 - Custom.WPS-ARTICLEDOI=10.1002/cncr.70402 - Custom.WPS-JOURNALDOI=10.1002/(ISSN)1097-0142 - Custom.WPS-PROCLEVEL=3 - ModDate=D:20260410191208+05'30' - Producer=PDFlib+PDI 9.3.1p6 (C++/Win64) - Title=Clinicopathologic characteristics of early‐onset breast cancer among unselected young Black women - Trapped=False - xmp:createdate=2026-04-10T18:48:41+05:30 - xmp:creatortool=PTC Arbortext Layout Developer 12.1.6202/W-x64 - xmp:modifydate=2026-04-10T19:12:08+05:30 - xmp:metadatadate=2026-04-10T19:12:08+05:30 - pdf:producer=PDFlib+PDI 9.3.1p6 (C++/Win64) - pdf:trapped=False - pdfx:wps-articledoi=10.1002/cncr.70402 - pdfx:wps-journaldoi=10.1002/(ISSN)1097-0142 - pdfx:wps-proclevel=3 - pdfx:epsprocessor=PStill version 1.84.42 - jav:journal_article_version=VoR - prism:doi=10.1002/cncr.70402 - dc:format=application/pdf - dc:title=Clinicopathologic characteristics of early‐onset breast cancer among unselected young Black women - xmpmm:documentid=uuid:d722a900-9688-4561-a10c-d9f9c4f4be40 - xmpmm:instanceid=uuid:15685661-0eb0-46fb-b23d-2bc928c41bfa ## Contents ### Page 1 Received: 13 February 2026- Revised: 18 March 2026- Accepted: 19 March 2026 DOI: 10.1002/cncr.70402O R I G I N A L A R T I C L EClinicopathologic characteristics of early-onset breast cancer among unselected young Black womenHeather K. Beasley PhD, MS1 | Tiana Shah BS1 | Rory J. Tinker MD2 |Anne Weidner MPH1 | Lindsay Venton BS1 | Chunling Hu MD, PhD3 |Mya L. Roberson PhD, MSPH4 | Brian D. Lehmann PhD1 | Fergus J. Couch PhD3 |Sonya Reid MD, MPH1 | Kelly Metcalfe RN, PhD5 | Tuya Pal MD11Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA2Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA5Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, CanadaCorrespondenceTuya Pal, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA. Email: tuya.pal@vumc.orgFunding informationU.S. Department of Defense, Grant/Award Number: DOD/BCRP BC201286; American Association for Cancer Research, Grant/ Award Number: 22-20-73-ROBE; Burroughs Wellcome Fund, Grant/Award Number: G-1022376; Susan G. Komen, Grant/Award Number: SAC210105; Nashville Wine Auction; Breast Cancer Research Foundation, Grant/Award Numbers: BCRF-030-24, HEI-25-011AbstractBackground: Black women are more likely to develop and die from early-onset breast cancer. Hereditary breast cancer (HBC) is strongly associated with early age of onset. Accordingly, HBC characteristics in young Black women were evaluated.Methods: Black women diagnosed with invasive breast cancer at age 50 years or younger between 2005 and 2018 were recruited through the state cancer registries in Florida and Tennessee. Participants were asked to complete a questionnaire, sign medical records releases, and donate a saliva sample for free genetic testing to identify HBC germline pathogenic or likely pathogenic variant (GPV). Women with sporadic versus hereditary breast cancer were compared, based on age distribution, clinical characteristics, and family cancer history.Results: Among 686 participants with confirmed genetic testing, 15.3% had GPVs in breast and/or ovarian cancer predisposition genes, including BRCA1 (7.7%), BRCA2(4.5%), PALB2 (0.9%), and ATM (0.7%), with 1.5% in other genes. Compared to the sporadic group, triple-negative breast cancers were overrepresented among BRCA1carriers (23.6% vs. 75.5%; p < .001), and family history of breast cancer was significantly more frequent among BRCA1, BRCA2, and PALB2 carriers (all p < .05). The majority of breast cancers occurred by age 40 years in BRCA1 carriers (52.8%), compared to other genes, where age was more evenly distributed.Conclusion: Among unselected young Black women with breast cancer, our findings demonstrate that the highest frequency of HBC GPVs are in BRCA1, BRCA2, andPALB2, with identification of distinct histopathologic and demographic character- istics across HBC genes, underscoring the critical need for genetic testing in all populations.K E Y W O R D SBlack women, breast cancer, breast cancer age distribution, breast cancer characteristics, germline pathogenic/likely pathogenic variants, hereditary breast cancer, registry-based studyThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro- vided the original work is properly cited. © 2026 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.Cancer. 2026;e70402. wileyonlinelibrary.com/journal/cncr- 1 of 9https://doi.org/10.1002/cncr.70402 ### Page 2 INTRODUCTIONBlack women experience disproportionately higher incidence and mor- tality from early-onset breast cancer, in part because of higher preva- lence of aggressive triple-negative breast cancer (TNBC).1,2 Both early-onset breast cancer and TNBC are associated with worse breast cancer outcomes1 and a higher risk of having hereditary breast cancer (HBC).1,3HBC accounts for approximately 5% to 10% of all breast cancers,4,5 most commonly because of germline pathogenic or likely pathogenic variants (GPVs) in BRCA1 and BRCA2. Additional genes, including those of high (e.g., PALB2, TP53, PTEN) and moderate (e.g., ATM, CHEK2, RAD51C, RAD51D, BARD1) penetrance also contribute.4,5Most studies evaluating HBC genes have focused primarily on women of European ancestry,4,5 partly because of low genetic testing rates among populations with other ancestry of geographic origin.6This underuse of genetic testing has been consistently observed across clinical settings, which persists even among women who meet estab- lished criteria for testing based on age at diagnosis, tumor subtype, and even family history.7,8 Consequently, there remains limited ability to accurately assess frequencies of GPVs by gene and associated clini- copathologic characteristics. Importantly, the disparity in genetic testing rates in combination with the earlier age at diagnosis and higher rates of TNBC among Black women underscore the importance of characterizing HBCs among young Black women. Current data suggest that women of African ancestry have fre- quencies of inherited breast cancers comparable to,9–11 or poten- tially higher than,12–17 those observed among women of European ancestry. Prior efforts, predominantly in women of European ancestry, show that HBC GPV frequency increases with younger age at breast cancer diagnosis, and is higher among those with TNBC.18Furthermore, histopathologic patterns vary by gene, with the ma- jority of breast cancers observed in BRCA1, RAD51C, RAD51D, andBARD1 carriers being TNBC.18 Although BRCA2 and PALB2 carriers are more likely to have TNBC compared to sporadic cases, the ma- jority of breast cancers are hormone receptor (HR)–positive (estro- gen receptor [ER])–positive and/or progesterone receptor [PR]– positive) and HER2-negative, with increased risks for high-grade disease.18 ATM and CHEK2 carriers with breast cancer predomi- nantly have high-grade ER-positive disease.18In this study, we evaluated the demographic and clinicopathologic characteristics of HBC in a cancer registry-based collection of young Black women with breast cancer, including distribution of GPVs across HBC genes. Among carriers of GPVs, we assessed family history of breast and ovarian cancer, distribution of age at diagnosis, and immunohistochemistry-based clinical subtypes by gene.METHODS Study cohortEligible participants were Black women diagnosed with invasive breast cancer, ≤age 50 years, between 2005 and 2018, living in Florida or Tennessee at the time of diagnosis. Registry-based recruitment was initiated on approval by the Institutional Review Boards (IRB) at Vanderbilt University (IRB #170233) and the De- partments of Health in Florida (IRB #2011-05-VBU) and Tennes- see (IRB #2019-0139). Per previously described state-mandated procedures,17 recruitment methods consisted of initial contact by mail, and, if no response, a phone call to explain the study and determine interest in participation. All participants provided writ- ten consent to participate in the study, and all research proced- ures were conducted in accordance with the Helsinki Declaration. Participants were asked to provide informed consent, sign a medical records and tissue/tumor release, provide a saliva sample for HBC testing, and complete a questionnaire, which collected data on sociodemographic, epidemiologic, and lifestyle factors. Clinical data were collected on all eligible participants who self-reported Black race, which included those of African American, Afro Caribbean, and other/mixed descent within the recruitment time frame.Clinical and demographic variablesClinical data included age at diagnosis, tumor size, stage, histologic subtype, immunohistochemical (IHC) subtype, and grade. Clinical receptor status (ER, PR, and HER2) was obtained from pathology reports or other medical records, supplemented by cancer registry data and self-reported questionnaire data. ER and PR positivity was defined as 1% or greater, whereas values <1% were classified as negative. Breast tumors were stratified on receptor status into the following clinical subtypes: HR+ (ER+ and/or PR+)/HER2–; HER2+; and TNBC (ER–, PR–, and HER2–). For participants who reported genetic testing before study enrollment, genetic test re- ports and medical records were requested to confirm results.Germline testing for HBCThe focus of the current analyses was on genes involved in he- reditary breast and/or ovarian cancer, including ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, RAD51C, RAD51D, andTP53. All of these genes are considered established breast cancer predisposition genes,3–5 other than BRIP1, which is an established ovarian cancer predisposition gene with limited strength of evi- dence to support an association with breast cancer.3,19,20 For par- ticipants who provided a saliva sample for germline testing through the study, genes were sequenced using dual bar-coded QIA-seq (Qiagen) multiplex amplicon-based analysis on a custom panel, as previously described.5 All study participants were offered genetic testing through the study regardless of whether they had prior clinical testing performed previously, as part of their care. In- dividuals were considered to have a GPV if they had a loss-of-function variant or a variant previously classified as a GPV in the ClinVar database.2 of 9 - BREAST CANCER FEATURES IN YOUNG BLACK WOMEN ### Page 3 West African ancestryA saliva sample was collected using an Oragene Self-Collection kit (DNA Genotek, Inc.) and shipped to the investigators for genomic DNA (gDNA) extraction. NanoDrop and Qubit technologies were used for gDNA quantification and quality assessment. gDNA samples were stored at –80°C before genotyping. Samples were genotyped on either the Infinium OncoArray-500K (Illumina, Inc.) or Expanded Multi-Ethnic Genotyping Array (MEGAEX) (Illumina, Inc.). Standard sample- and variant-level quality control procedures were per- formed. Ancestry proportions for each individual were estimated from multilocus single nucleotide polymorphism genotype data using the maximum likelihood-based ADMIXTURE method,21 using the Globe13 calculator from the Dodecad Ancestry project22 as refer- ence, as described in previously published work.23Statistical analysisParticipant characteristics and HBC GPV results were summarized with descriptive statistics, and those with GPVs in HBC genes were compared to sporadic cases based on demographic, clinical, and his- topathological variables. Continuous variables were summarized with means and SDs and compared using Wilcoxon rank-sum tests. Cat- egorical variables were summarized using frequencies and percent- ages and compared using Pearson chi-squared tests when number of carriers was 5 or more, and Fisher exact tests were used when ex- pected counts were smaller than 5. Percentages were determined using only known counts for each variable, excluding any unknown values. For gene-specific comparisons, each HBC gene was inde- pendently compared with sporadic cases. Fisher exact tests were used for these comparisons, with Monte Carlo simulation applied when expected counts were small. Additional analyses stratified by HBC genes compared to spo- radic cases included age at diagnosis, tumor size, tumor grade, stage, histology, IHC subtype, West African genetic ancestry, and family history of breast and ovarian cancer. All statistical tests were two-sided, and p values <.05 were considered statistically significant.RESULTSA total of 785 women with invasive breast cancer were included in this study (Table 1). The mean age at diagnosis was 42.3 years (21–50 years). More than 25% of women had TNBC, and most presented with nonmetastatic disease (96.4%), invasive ductal carcinoma (81.5%), and high-grade tumors (57.6%) (Table 1). Of those with confirmed germline testing (n = 686), GPVs were detected in 105 (15.3%) participants (Figure 1) in one of the following breast and/or ovarian cancer predisposition genes: BRCA1 (n = 53), BRCA2 (n = 31),PALB2 (n = 6), ATM (n = 5), BRIP1 (n = 4), CHEK2 (n = 3), RAD51CT A B L E 1 Description of the study population.Characteristic Total cohortN = 785 No. %Age at diagnosis≤40 264 33.6 41–45 224 28.5 46–50 297 37.8 Histology Ductal 627 81.5 Lobular 47 6.1 Mixed 15 2.0 Other 80 10.4 Unknown 16 Tumor grade Grade I 74 9.9 Grade II 244 32.5 Grade III 432 57.6 Unknown 35 Stage Localized 294 38.9 Regional 434 57.5 Distant 27 3.6 Unknown 30 Subtype HR+, HER2– 374 52.3 HER2+ 146 20.4 TNBC 195 27.3 Unknown 70 First-degree family history of breast cancer No 553 77.8 Yes 158 22.2 Unknown 74 Second-degree family history of breast cancer No 423 59.5 Yes 288 40.5 Unknown 74 First-degree family history of ovarian cancer No 686 96.6 Yes 24 3.4 Unknown 75(Continues)BEASLEY ET AL. - 3 of 9 ### Page 4 (n = 2), and RAD51D (n = 1). The mean percentage of West African ancestry by gene ranged from 61% in CHEK2 carriers to 79% inRAD51D carriers (Table 2). To determine gene-specific clinicopathological associations, we compared clinical characteristics of the sporadic group (n = 581) with each gene-specific group for which there were five or more GPV carriers identified (i.e., BRCA1, BRCA2, PALB2, and ATM), as presented in Table 3. Compared to sporadic cases, women with BRCA1 GPVs were significantly more likely to be diagnosed at a younger age (p < .01) and have high-grade disease (p < .01). Additionally, BRCA1carriers were significantly more likely to report a family history of breast cancer among first- and second-degree relatives (p < .001), whereas BRCA2 and PALB2 carriers were more likely to report family history of breast cancer among second degree relatives (p = .02 and .03, respectively) when compared to sporadic cases. Most breast cancers (52.8%) were diagnosed at or below age 40 years in BRCA1 carriers, whereas other HBC genes had similar dis- tributions across age groups (Table 4). TNBCs were overrepresented among BRCA1 carriers (75.5%) compared to sporadic cases (23.6%) (Table 5). Among HR+/HER2– breast cancers and TNBCs, the pro- portion with HBC GPVs were 35/329 (10.6%) and 50/176 (28.4%), respectively. ER status varied by HBC gene, with the majority ofBRCA1-associated tumors being ER-negative (73.6%), whereasBRCA2- and PALB2-associated tumors were predominantly ER+(58.1% and 66.7%, respectively). ATM- and CHEK2-associated tumors were all ER+. The distributions of ER+ and ER– tumors across gene groups are presented in Table 5. Among ER+ and ER– breast cancers, the proportion with HBC GPVs were 48/429 (11.2%) and 57/236 (24.2%), respectively.DISCUSSIONThis study is among the largest to characterize HBC in comparison to sporadic breast cancers within a registry-based sample of young Black women diagnosed with breast cancer at age 50 years and younger. The overall frequency of HBC GPVs was 15.3%, with the majority occurring in BRCA1 and BRCA2. Among women with BRCA1-related tumors, there was overrepresentation of high-grade tumors and TNBC. A family history of breast cancer was more common among BRCA1, BRCA2, and PALB2 carriers. Finally, among those withBRCA1 GPVs, the majority of breast cancers occurred at or below age 40 years, whereas the age at diagnosis was more evenly distributed up to age 50 years for other gene carriers. The most common genes with GPVs reported in US-based Black women with breast cancer in prior studies were BRCA1 and BRCA2, followed by PALB2,9,10 consistent with our findings. However, there have been mixed results reported among studies focused on the proportions of HBC GPVs among Black women with breast cancer. Emerging data suggest rates of BRCA1 and BRCA2 GPVs among Black women with HBC in the United States,12,13 the Caribbean,14,15and western sub-Saharan Africa16,17 may be higher than that pre- viously reported among predominantly White populations. However, a study of 4000 Black and 25,000 White women across all age groups showed similar overall frequency of GPVs (~5%) in both populations.11 In that study, there was a significantly higher fre- quency of GPVs observed in high penetrance genes (BRCA2 andPALB2) among Black women, whereas a significantly lower frequency of CHEK2 GPVs was observed, likely because of the strong founder effect among individuals of European ancestry. Similarly, we also observed a low frequency of CHEK2 GPVs in our study, with these women having the lowest proportion of West African ancestry compared to the other HBC genes. Consequently, data from our study and others suggest that women of African ancestry with breast cancer have at least similar frequencies of HBC GPVs as individuals of European ancestry, with lower frequencies of CHEK2 GPVs observed. Prior studies, including those conducted in Black women, have reported younger ages of breast cancer diagnosis in women with GPVs in BRCA1 compared to BRCA2.9,10,24 These findings are consistent with our results, where the mean age of breast cancer was lowest in those with GPVs in BRCA1, followed by BRCA2, both of which were lower than PALB2 and CHEK2. Regarding family history of breast cancer, prior studies have reported an association with HBC GPVs.9,25 In fact, a study of 67,692 women with breast cancer, including 13% Black women, reported a significantly higher proportion with BRCA1, BRCA2, and PALB2 GPVs had a family history of breast cancer compared to those with sporadic tu- mors.25 Similarly, among 5054 Black women with breast cancer, family history of breast cancer among women with BRCA1, BRCA2, or PALB2 GPVs was higher compared to those with sporadic tu- mors, with odds ratios of 9.0, 8.0, and 13.6, respectively.9 These findings are consistent with our study, where women with BRCA1,BRCA2, or PALB2 GPVs were significantly more likely to have a first- and/or second-degree relative with breast cancer than spo- radic cases. Prior studies involving predominantly women of European ancestry have reported that the frequency of BRCA1 and BRCA2GPVs decreased with age at breast cancer diagnosis, indicating thatT A B L E 1 (Continued)Characteristic Total cohortN = 785 No. %Second-degree family history of ovarian cancer No 633 89.5% Yes 74 10.5% Unknown 78 Abbreviation: TNBC, triple-negative breast cancer.4 of 9 - BREAST CANCER FEATURES IN YOUNG BLACK WOMEN ### Page 5 hereditary influences are strongest in younger women.18,24 In the two largest studies of Black women with breast cancer that evaluated HBC GPVs,9,10 BRCA1-associated breast cancers occurred at younger ages than BRCA2-associated cancers, whereas PALB2, ATM, andCHEK2 showed age distributions spanning both younger and older groups, similar to our findings. GPV frequencies reported in HR+/HER2– breast cancers and TNBC have been reported as 8.6% and 17.2%, respectively.24 In our study, we observed similar rates in HR+/HER2– breast cancers (10.6%), but higher rates in TNBC (28.4%), likely because of our exclusive focus on young women with breast cancer. The frequency of HBC GPVs reported in prior studies among predominantly White women with breast cancer across all ages has been higher among ER– cases (8.2%) compared to ER+ cases (3.0%).5 Similarly, among Black women with breast cancer across all ages, HBC GPV frequencies have been higher among ER– (8.9%-11.5%) compared to ER+ (5.0%-6.4%) cases.9,10 However, these prior studies did not present HBC GPV prevalence estimates by age, limiting direct comparisons. Therefore, although we also found higher HBC GPV frequencies among ER– cases (24.2%), compared to ER+ cases (11.2%), our observed frequencies are likely higher because of our focus exclu- sively on young women, in which HBC GPVs are enriched compared to older age groups. HBCs exhibit distinct histopathologic patterns that vary by gene, most of which have been studied in European ancestry pop- ulations.18,20 Our findings related to IHC-based subtypes across genes were overall consistent with those reported in prior studies of predominantly women of European ancestry,4,5,18 in which TNBC accounted for the majority of BRCA1-associated breast cancers. The largest study to date to evaluate breast cancer characteristics in HBC was based on 42,680 women with breast cancer.18 Among BRCA1-associated breast cancers in this study, TNBC has accounted for 69.2% in women younger than age 40 years and 59.5% across all ages, which is consistent with our study where TNBC was observed in 75.5%. Furthermore, we observed similar rates of BRCA2-associ- ated breast cancer in HR+/HER2– (55.2%) and TNBC (34.5%) as prior studies that reported enrichment in HR+/HER2– (65%-70%), and TNBC (30%-40%) compared to sporadic cancers.4,5 Similarly,PALB2-associated breast cancers are predominantly ER+/ HER2–,18,20 consistent with our findings, albeit based on a very small sample size, limiting our ability to draw any conclusions. Finally, the majority of ATM-associated breast cancers are HR+,18,24 which is consistent with our study; however, most of these tumors are generally not HER2+, in contrast to our study where 60% of tumors were HER2+. However, these findings are based on a small sample size, and it is possible that the young age of our cohort contributed to this observation.F I G U R E 1 Overview of study population.T A B L E 2 Frequency of germline pathogenic/likely pathogenic variants and West African ancestry.Gene N % of cohort % of carriers Mean %N = 686 N = 105 West African ancestryN = 561aSporadic 581 84.7 N/A 74 Germline 105 15.3 N/A 72BRCA1 53 7.7 50.5% 72BRCA2 31 4.5 29.5% 73PALB2 6 0.9 5.7% 74ATM 5 0.7 4.8% 69BRIP1 4 0.6 3.8% 70CHEK2 3 0.4 2.9% 61RAD51C 2 0.3 1.9% 76RAD51D 1 0.1 1.0% 79 Abbreviation: N/A, not available.a11 BRCA1 carriers, 4 BRCA2 carriers, 2 BRIP1 carriers, 1 CHEK2 carrier, and 107 sporadic cases without ancestry data available.BEASLEY ET AL. - 5 of 9 ### Page 6 Collectively, our data indicate that demographic and clinico- pathologic breast cancer characteristics observed in young Black women are comparable to those seen among White women, highlighting the importance of genetic testing across all populations. Importantly, the underuse of genetic testing among Black women is due to patient, provider, and system-level factors,7 and remains anT A B L E 3 Demographic and clinical characteristics (genes with >5 germline pathogenic/likely pathogenic variants).ATM BRCA1 BRCA2 PALB2 SporadicN = 5 N = 53 N = 31 N = 6 N = 581n (%) p n (%) p n (%) p n (%) p n (%)Age at diagnosis (mean) 42 .91 39 <.01 41 .13 42 .83 43 Tumor size (cm) (mean) 2.7 .71 2.3 .79 2.6 .67 4.8 .17 2.4 Histology 1.00 .15 .80 .37 Ductal 5 (100%) 46 (87%) 24 (77%) 3 (75%) 454 (80%) Lobular - - 3 (10%) 1 (25%) 42 (7%) Mixed - 1 (2%) - - 9 (2%) Other - 6 (11%) 4 (13%) - 64 (11%) Unknown - - - 2 12 Tumor grade 1.00 <.01 .27 1.00 Grade I - - 2 (7%) - 64 (12%) Grade II 2 (40%) 7 (14%) 7 (23%) 2 (40%) 192 (35%) Grade III 3 (60%) 43 (86%) 21 (70%) 3 (60%) 299 (54%) Unknown - 3 1 1 26 Stage .09 .59 .34 1.00 Localized 1 (20%) 17 (33%) 11 (37%) 2 (33%) 228 (40%) Regional 3 (60%) 34 (65%) 17 (57%) 4 (67%) 330 (58%) Distant 1 (20%) 1 (2%) 2 (7%) - 15 (3%) Unknown - 1 1 - 8 First-degree family history of breast cancer 1.00 <.001 .36 1.00 No 4 (80%) 23 (44%) 23 (74%) 5 (83%) 460 (80%) Yes 1 (20%) 29 (56%) 8 (26%) 1 (17%) 112 (20%) Unknown - 1 - - 9 Second-degree family history of breast cancer .66 <.001 .02 .03 No 4 (80%) 16 (31%) 13 (42%) 1 (17%) 362 (63%) Yes 1 (20%) 36 (69%) 18 (58%) 5 (83%) 210 (37%) Unknown - 1 - - 9 First-degree family history of ovarian cancer 1.00 0.30 1.00 .17 No 5 (100%) 47 (90%) 31 (100%) 5 (83%) 557 (98%) Yes - 5 (10%) - 1 (17%) 14 (2%) Unknown - 1 - - 10 Second-degree family history of ovarian cancer 1.00 0.02 .35 .47 No 5 (100%) 41 (79%) 29 (97%) 5 (83%) 514 (90%) Yes - 11 (21%) 1 (3%) 1 (17%) 55 (10%) Unknown - 1 1 - 126 of 9 - BREAST CANCER FEATURES IN YOUNG BLACK WOMEN ### Page 7 unmet clinical need. Consequently, our findings underscore the need to improve testing rates so that all populations may benefit from this information. Our study has several strengths, including the large sample size of unselected Black women diagnosed with breast cancer at or below age 50 years, making it unique compared to other cohorts, which generally are not focused exclusively on young patients with breast cancer. Consequently, our observed frequencies of GPVs need to be inter- preted in the context of our young cohort, and results may not be generalizable to later-onset breast cancers. Furthermore, free genetic testing was offered to all study participants, including those who re- ported prior testing, removing the barrier to access testing and demonstrating that no-cost testing may lead to higher completion of testing. Despite these strengths, there remain some limitations given that participation required consent, which could introduce a selection bias. Moreover, despite our large sample of young Black women, the absolute numbers of those with GPVs for many susceptibility genes remain small, limiting the precision of gene-level estimates and asso- ciated characteristics. Overall, our study is among the largest single studies of unse- lected young Black women with invasive breast cancer to charac- terize HBCs relative to sporadic tumors. Our study identified a high prevalence of HBC GPVs (15.3%), with overrepresentation of TNBCs and HR+/HER2– breast cancers among those with BRCA1 and ATMGPVs, respectively. Family history of breast cancer was more com- mon among women with BRCA1, BRCA2, and PALB2 GPVs, whereas a higher frequency of BRCA1 and BRCA2 GPVs was seen at earlier ages of diagnosis. Our findings contribute to characterization of HBCs in Black women, highlighting the importance of genetic testing in this underserved population. These women have a higher prevalence of early-onset breast cancer yet lower genetic testing rates. Ultimately, there remains a need to address disparities in this undertested population, so those with an HBC GPV can benefit from the latest treatment advances, reduce their risks of future cancer, and share this information with at-risk family members.T A B L E 5 Histopathology-based breast cancer subtypes by germline status.Gene No. HRþ, HER2–, N = 329 (52.0%) HER2þ TNBCpERþER–, N = 236, n (%)N = 128 (20.0%) N = 176 (28.0%) N = 429, n (%)Sporadica,b 581 294 (55.1%) 114 (21.3%) 126 (23.6%) 381 (68.0%) 179 (32.0%) Germline 105 35 (35.4%) 14 (14.1%) 50 (50.1%) 48 (45.7%) 57 (54.2%)BRCA1a 53 8 (16.3%) 4 (8.2%) 37 (75.5%) <.001d 14 (26.4%) 39 (73.6%)BRCA2a 31 16 (55.2%) 3 (10.3%) 10 (34.5%) 0.23d 18 (58.1%) 13 (41.9%)PALB2 6 3 (50.0%) 2 (33.3%) 1 (16.7%) 0.62e 4 (66.7%) 2 (33.3%)ATM 5 2 (40.0%) 3 (60.0%) - 0.07e 5 (100%) -BRIP1c 4 3 (75.0%) - 1 (25.0%) - 3 (75.0%) 1 (25.0%)CHEK2 3 2 (66.7%) 1 (33.3%) - 0.619e 3 (100%) -RAD51C 2 - 1 (50.0%) 1 (50.0%) 0.079e - 2 (100%)RAD51Dc 1 1 (100%) - - - 1 (100.0%) -Abbreviation: TNBC, triple-negative breast cancer.a4 BRCA1 carriers, 2 BRCA2 carriers, and 47 sporadic cases with unknown subtype.b21 sporadic cases with unknown estrogen receptor status.cBRIP1 and RAD51D had insufficient sample size for hypothesis testing.dFisher exact test with Monte Carlo simulation comparing four-category subtype distributions (HR+/HER2−, HR+/HER2+, HR−/HER2+, TNBC) between the indicated germline gene and sporadic cases.eFisher exact test with Monte Carlo simulation comparing binary subtype distributions between the indicated germline gene and sporadic cases, applied when sample size was limited.T A B L E 4 Age distribution by gene.Gene N n ≤ 40 (%) n = 41–45 (%) n = 46–50 (%)Sporadic 581 184 (31.7%) 172 (29.6%) 225 (38.7%) Germline 105 49 (46.6%) 25 (23.8%) 31 (29.5%)BRCA1 53 28 (52.8%) 12 (22.6%) 13 (24.5%)BRCA2 31 12 (38.7%) 11 (35.5%) 8 (25.8%)PALB2 6 3 (50.0%) - 3 (50.0%)ATM 5 2 (40.0%) 1 (20.0%) 2 (40.0%)BRIP1 4 2 (50.0%) - 2 (50.0%)CHEK2 3 1 (33.3%) 1 (33.3%) 1 (33.3%)RAD51C 2 1 (50.0%) - 1 (50.0%)RAD51D 1 - - 1 (100%)BEASLEY ET AL. - 7 of 9 ### Page 8 AUTHOR CONTRIBUTIONS Heather K. Beasley: Writing—original draft; formal analysis; writing—review and editing; conceptualization. Tiana Shah: Writing—original draft; writing—review and editing; conceptualiza- tion. Rory J. Tinker: Formal analysis; methodology; writing—review and editing; conceptualization. Anne Weidner: Writing—review and editing; project administration; data curation; formal analysis. Lind- say Venton: Data curation; writing—review and editing; project administration. Chunling Hu: Writing—review and editing; data curation. Mya L. Roberson: Writing—review and editing. Brian D. Lehmann: Writing—review and editing; formal analysis; supervision.Fergus J. Couch: Writing—review and editing; data curation; funding acquisition; resources. Sonya Reid: Writing—review and editing; funding acquisition; supervision; conceptualization; investigation; resources; data curation; methodology. Kelly Metcalfe: Conceptual- ization; writing—review and editing. Tuya Pal: Conceptualization; investigation; funding acquisition; writing—original draft; project administration; supervision; data curation; writing—review and edit- ing; formal analysis; resources; methodology.ACKNOWLEDGMENTSThe authors are tremendously grateful to all of the study participants who chose to participate in this study, and to the community advisory board members over the years, who have been instrumental in guiding our efforts.CONFLICT OF INTEREST STATEMENTNone.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.ETHICS APPROVAL STATEMENTBlack Women with Breast Cancer: Etiology, Survival, and Treatment Outcomes (BEST) Study (Vanderbilt IRB# 170233)FUNDING STATEMENTThis work has been supported in part by NCI grant R01CA204819 (T.P.), Susan G. Komen SAC210105 (T.P.), Breast Cancer Research Foundation grant HEI-25-011 (T.P., S.R.), Nashville Wine Auction (T.P., S.R.), American Association for Cancer Research in Partnership with Victoria’s Secret and Pelotonia Career Development Award 22-20-73-ROBE (M.L.R.), NIH/NCI grants R35CA253187, U24CA258 058, P50CA116201, and the Breast Cancer Research Foundation BCRF-030-24 (F.C.), DOD/BCRP, BC201286 (B.D.L.), Burroughs Wellcome Fund PDEP, G-1022376, and NIH T32 Training Fellowship 5T32GM7569-49 (H.K.B.).PATIENT CONSENT STATEMENTEligible individuals were recruited through the state cancer registries in Tennessee and Florida as part of the Black Women with Breast Cancer: Etiology, Survival, and Treatment Outcomes (BEST) Study. Existing participants in the BEST Study who meet eligibility criteria, with verified test results and a signed tissue/tumor release form, will be included in the proposed study.ORCIDHeather K. 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