Couch, F. J.

Abstract Background: Pathogenic variants (PVs) in PALB2 are known to confer high-to-moderate risk for breast cancer. However, breast cancer risk estimates for PALB2 PVs for different populations are not well defined and associations with other cancers are still unclear. Using data from a large clinical genetic testing cohort we have established cancer-specific risks associated with PALB2 PVs. Methods: We analyzed the associations of PALB2 PVs with breast, ovarian, prostate, and pancreatic cancers in individuals tested at Ambry Genetics. Cancer-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated by comparing PV carrier frequencies in cancer cases to population controls from AllofUs matched by sex and adjusting for age and genetic ancestry and gnomAD v4.1 matched by sex and adjusting for ancestry. Two-sided p-values are reported. Results: Of 1,119,667 individuals tested, 357,109 had breast cancer, 37,468 ovarian cancer, 22,112 pancreatic cancer and 32,738 prostate cancer. PALB2 PVs were observed in 0.79% of breast cancer cases, 0.30% of ovarian cancer cases, 0.78% of pancreatic cancer cases, and 0.47% of prostate cancer cases, with mean age at diagnosis of 54.2 years for breast, 60.1 years for ovarian, 62.8 years for pancreatic and 66.7 years for prostate. Whereas only 2.4% of breast cancer cases with PVs had a personal history of ovarian or pancreatic, 13.4% of ovarian cases and 33.3% of pancreatic cases had a history of breast cancer. Analysis of PV types found that frameshift PVs accounted for 50% of PVs, nonsense for 30%, canonical splice sites for 5% and copy number variants for 8-9% of cases in all cancer types. Among 10,077 individuals with multiple primary cancers, PALB2 PVs were detected in 0.65% of cases, with the highest frequencies observed in combinations of breast and pancreatic cancer (1.87%) and pancreatic and prostate cancer (0.79%). To refine estimates of risks for breast cancer, association studies were performed separately with GnomAD v4.1 and AllofUs controls. PALB2 PVs were consistently associated with high risks of breast cancer with lower 95%CI above 4 (GnomADv.4.1 OR=6.85, 95%CI=5.94-7.96, p=3.05x10-145; AllofUs OR=5.65, 95%CI=4.83-6.65, p=2.54x10-155). This was significantly different and increased over breast cancer risk estimates from the CARRIERS and BRIDGES population-based studies (OR=4.67, 95%CI=3.73-5.85, p=3.95x10-27) and the UK Biobank population-based study (OR=3.87, 95%CI=3.09-4.83, p=4.62x10-27). Similarly, high risks of pancreatic cancer were confirmed (GnomADv.4.1 OR=5.14, 95%CI=4.15-6.32, p=3.38x10-52; AllofUs OR=5.59, 95%CI=3.92-7.85, p=2.78x10-18). Importantly, associations between PALB2 PVs and moderate risks of both ovarian cancer (GnomADv.4.1 OR=2.68, 95%CI=2.11-3.40, p=5.94x10-16; AllofUs OR=2.15, 95%CI=1.62-2.85, p=2.97x10-7) and prostate cancer (enriched for aggressive disease) (GnomADv.4.1 OR=2.45, 95%CI=2.01-2.97, p=1.52x10-19) were observed. Conclusions: This large-scale study provides robust estimates of PALB2 PV prevalence and associated cancer risks in a U.S. clinical genetic testing population. The findings provide refined risk estimates for breast and pancreatic cancers but also establish that PALB2 PVs confer increased risk for ovarian and prostate cancers. These results help clarify ongoing uncertainty, particularly for ovarian and prostate cancer, and highlight the importance of PALB2 in broader hereditary cancer risk assessment and multigene panel testing. Citation Format: Y. Y. Tan, C. Hu, H. Huang, N. J. Boddicker, W. Chen, M. Kaul, T. J. Rao, A. N. Monteiro, T. Pesaran, R. Karam, S. M. Domchek, S. Yadav, M. E. Richardson, F. J. Couch. Cancer-specific risks associated with germline PALB2 pathogenic variants from a large clinical genetic testing cohort [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF5-01.

Abstract Background: International guidelines recommend that all patients (pts) with metastatic breast cancer (mBC) are offered testing for germline BRCA1/BRCA2 mutations (gBRCAm) and other biomarkers to aid treatment decisions. This retrospective study describes real-world testing patterns for germline/tumor (g/t)BRCAm and other biomarkers among US pts with HER2-negative [HER2−] mBC. Methods: Data were captured from US pts aged ≥18 years with HER2− mBC from January 12, 2018, to March 31, 2024, in the deidentified, electronic health record-derived Flatiron Health Research Database. Demographics, clinical characteristics, and testing patterns for g/tBRCAm and other actionable biomarkers were examined. Testing rates, test timing, and biomarker status were described across subgroups defined by demographics (including age, race, and ethnicity), tumor subtype (hormone receptor-positive [HR+]/HER2− mBC or triple-negative mBC [mTNBC]), and disease stage at mBC diagnosis (recurrent/de novo). Results: The BRCA testing rate among pts with mBC increased from 2018 (48%) to 2023 (62%); the overall testing rate was 19,820/34,379 (58%): 5880 pts (17%) received a gBRCA test only, 7285 (21%) received a tBRCA test only, and 6655 (19%) received both gBRCA and tBRCA tests. BRCA testing rates were numerically lower in pts with HR+/HER2− mBC (56%) versus mTNBC (68%), and in pts aged >65 years (HR+/HER2− mBC, 48%; mTNBC, 62%) versus ≤65 years (HR+/HER2− mBC, 64%; mTNBC, 74%; Table). The proportion of pts who received a test before initiation of first-line (1L) therapy was lower among pts with HR+/HER2− mBC than with mTNBC (recurrent, 60% vs 81%; de novo, 37% vs 57%). Among tested pts, 1067/15,168 (7%) with HR+/HER2− mBC and 494/4539 (11%) with mTNBC had a positive result for g/tBRCAm; 365/1067 (34%) pts with g/tBRCAm HR+/HER2− mBC and 138/494 (28%) pts with g/tBRCAm mTNBC were aged >65 years. Among 528 pts with gBRCAm HR+/HER2− mBC, co-mutations in PIK3CA, ESR1, PTEN, and AKT1 were identified in 48 (9%), 38 (7%), 20 (4%), and 3 (<1%) pts, respectively. Among pts diagnosed with gBRCAm HR+/HER2− mBC in 2020-2023 (median follow-up: 15 months), 175/371 (47%) did not receive a test for PIK3CA mutations at any time, and 48/97 (49%) pts diagnosed in 2023 (median follow-up: 6 months) did not receive a test for ESR1 mutations. In 2021-2023, 72/256 (28%) pts with g/tBRCAm mTNBC had tumors with programmed cell death-ligand 1 (PD-L1) combined positive score ≥10; 88 (34%) pts did not receive a PD-L1 test. Conclusions: Although BRCA testing rates increased from 2018 to 2023, 38% of US pts diagnosed with HER2− mBC in 2023 did not receive any BRCA test. BRCA testing rates were low among pts with HR+/HER2− mBC and/or aged >65 years, suggesting that many g/tBRCAm remained undetected. Wider and timelier testing for germline and tumor biomarkers is warranted to identify pts who are eligible for targeted therapies. Citation Format: S. Yadav, Q. Li, Z. Tan, K. E. Mishkin, J. F. Hayes, X. Xu, F. J. Couch. Real-world biomarker testing patterns in US patients with HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-08.

Abstract Background: Young BRCA carriers may undergo breast conserving surgery (BCS) or mastectomy with or without contralateral risk reducing mastectomy at the time of an index breast cancer diagnosis. A variety of factors may influence surgical decision making. Methods: The BRCA BCY Collaboration (NCT03673306) is an international, hospital-based, retrospective cohort study conducted at 109 centres across 5 continents including women with germline pathogenic or likely pathogenic variants (PV) in BRCA1/2 diagnosed between 2000 and 2020 with invasive stage I-III breast cancer prior to or at age 40 years. The primary objective of the present analysis was to evaluate surgical management in these patients. Breast surgery was defined as BCS, unilateral mastectomy, or bilateral mastectomy administered as part of primary treatment for a first diagnosis of invasive breast cancer. Multivariable logistic regression was used to determine factors associated with receipt of bilateral mastectomy. Results: Of 5660 eligible BRCA1/2 carriers, 4715 had unilateral stage I-III breast cancer with surgical treatment details available. The median age of the cohort was 35 years (IQR, 31-38 years). Overall, 1805 (38.3%) patients underwent BCS, 1752 (37.2%) underwent unilateral mastectomy, and 1158 (24.6%) underwent bilateral mastectomy. The proportion of young BRCA1/2 carriers undergoing BCS decreased over the study period (55.7% in 2000 vs. 27.0% in 2020), whereas the use of bilateral mastectomy significantly increased (8.0% in 2000 vs. 44.4% in 2020). Bilateral mastectomy was more common in women who had genetic testing performed before (57.0%) or within 6 months of a breast cancer diagnosis (38.5%), compared to those tested after diagnosis (5.1%, p<0.001). On multivariable analysis, compared to those tested after diagnosis, earlier genetic testing remained the strongest predictor of bilateral mastectomy receipt (testing prior to diagnosis: OR 20.7 [95% CI 15.3-28.1]; testing at diagnosis: OR 6.8 [95% CI 5.4-8.7]). Other predictors of bilateral mastectomy receipt included geographic region, later year of diagnosis, smaller tumor size, node negative disease, and neoadjuvant treatment. In subgroup analysis including 2327 patients who had genetic testing performed before or within 6 months of diagnosis, 42.0% underwent bilateral mastectomy, with the lowest rates reported in Asia/Africa (26.1%) and the highest rates reported in North America (66.4%, p<0.001). In adjusted subgroup analyses, BRCA1 PV, later year of diagnosis, smaller tumor size, node negative disease, neoadjuvant treatment, and geographic region remained independently associated with bilateral mastectomy. Conclusions: In this large, international study of young affected BRCA carriers, geographic region and timing of genetic testing strongly impacted surgical management. These data support early genetic testing for young women with breast cancer to help optimize local therapy decisions. Citation Format: S. M. Wong, E. Blondeaux, V. Delucchi, F. Coussy, R. Bernstein Molho, S. Linn, A. Di Meglio, A. Kwong, K. Pogoda, E. Agostinetto, I. Nevelsteen, J. Balmana, H. C. Moore, A. Toss, A. Ferrari, C. Rousset-Jablonski, T. Renaud, K. Phillips, F. A. PeccatorI, M. Agustina Ipina, S. Paluch-Shimon, J. Ryu, W. Kui, M. Lee, R. Fruscio, M. Rozenblit, C. Vernieri, A. Matikas, M. Dieci, F. J. Couch, L. De Marchis, S. E. Hwang, D. Aguilar-y Mendez, D. Can Guven, M. Swain, C. Gianni, S. Spinaci, G. Montagna, M. Lambertini, H. Kim. Surgical management of young BRCA1/2 carriers with early onset breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD12-01.

Abstract Background: Women with a pathogenic variant in the BRCA1 or BRCA2 gene (carriers) are at a high risk of developing ovarian cancer and recommended to undergo bilateral salpingo-oophorectomy at an early age resulting in surgical menopause. Menopausal hormone therapy (MHT) is the most effective way to mitigate the adverse outcomes of early menopause; however, the safety of MHT on breast cancer risk in this population has not been established. Methods: We conducted a prospective matched analysis of MHT use following menopause (predominantly surgical) and breast cancer risk in BRCA carriers using a matched prospective analysis to emulate a randomized clinical trial. Women without a history of any cancer or bilateral mastectomy and who were enrolled in a longitudinal study with detailed data collection were eligible for inclusion. Women who initiated MHT (exposed) after menopause were matched one-to-one to women who had not initiated MHT (unexposed) by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Cox proportional hazards regression to estimate the hazard ratios (HR) and 95%CIs (CI) of incident breast cancer associated with MHT use. Results: After a mean follow-up of 5.6 years from the date of first MHT use in the exposed woman, there were 87 incident breast cancer cases in the exposed group (12·9%) and 128 cases in the unexposed group (18·9%) (P = 0·002). Compared to their unexposed match, women who used estrogen (E) experienced a significant decrease in the risk of breast cancer (HR = 0·37; 95%: CI 0·24-0·57). There was no protective (or adverse) effect associated with the use of E plus progestogen (E+P) (HR = 0·94; 95%CI 0·54-1·63), with progestogen alone (P) (HR = 1·14; 95%CI: 0·21-6·22) or with tibolone (HR = 0·57; 95%CI: 0·19-1·69). There were no diagnoses of breast cancer in the 43 women who used a CEE + bazedoxifene. Findings were similar for carriers of either gene mutation. Conclusion: To our knowledge, this represents the largest prospective report of MHT use and breast cancer risk in BRCA1 and BRCA2 carriers. Our findings showed no increase in the risk of breast cancer with the use of MHT, irrespective of gene mutation or formulation. These findings provide an evidence-based approach for the management of women at high-risk of breast cancer who are facing the acute and chronic effects of early surgical menopause. The safe use of MHT by BRCA carriers will continue to be an important research topic as formulations continue to evolve. Citation Format: J. Kotsopoulos, M. Seca, G. Jacek, T. Huzarski, P. Møller, R. H. Kim, C. Singer, B. Karlan, A. Aeilts, T. Ramon y Cajal, T. Pal, A. Eisen, L. Bordeleau, W. Foulkes, N. Tung, F. Couch, S. Neuhausen, D. Zakalik, C. Cybulski, O. Olopade, K. Metcalfe, R. Fruscio, P. Sun, J. Lubinski, S. Narod, Hereditary Breast Cancer Clinical Study Group. Menopausal Hormone Therapy and the Risk of Breast Cancer in Women with a Pathogenic Variant in BRCA1 or BRCA2 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS3-01.