Kim, Raymond H

PURPOSE BRCA carriers face high risks of developing both breast and ovarian/fallopian tube cancers (hereafter referred to as ovarian ). Among BRCA carriers with ovarian cancer, it is not clear whether the risk of breast cancer is sufficiently high that risk-reducing mastectomy should be offered. This study aimed to assess the risk of breast cancer BRCA carriers after a diagnosis of ovarian cancer. METHODS We included women with a pathogenic/likely pathogenic variant in BRCA1 or BRCA2 , a diagnosis of ovarian cancer, and no other cancer history and no risk-reducing bilateral mastectomy. Women were followed for incident breast cancer from the date of ovarian cancer diagnosis or the date of baseline questionnaire, whichever came last. The 5-, 10-, and 15-year cumulative risks of breast cancer were compared for women with ovarian cancer and an age-matched set of control women without ovarian cancer. RESULTS A total of 960 participants with ovarian cancer were identified (814 BRCA1 and 146 BRCA2 carriers). After a mean follow-up of 4.9 years, 41 women (4.3%) developed breast cancer, at a mean age at diagnosis of 57.5 years (range, 39-74). Actuarial cumulative breast cancer risks after ovarian cancer were 4.4%, 8.9%, and 11.5% at 5, 10, and 15 years, respectively. Only three breast cancer–related deaths occurred. Among 741 age-matched BRCA carriers without ovarian cancer, actuarial cumulative risks of breast cancer were 20.9%, 38.6%, and 47.2% at 5, 10, and 15 years, respectively. The hazard ratio for breast cancer, after an ovarian cancer diagnosis, compared with no ovarian cancer, was 0.18 ([95% CI, 0.12 to 0.27]; P < .0001). CONCLUSION After ovarian cancer, BRCA carriers have a relatively low risk of breast cancer. Risk-reducing mastectomy should not be recommended routinely, but might be considered for long-term survivors. Magnetic resonance imaging surveillance and/or mammography is a realistic alternative.

Abstract Introduction: Women with a germline pathogenic variant (PV) in PALB2 face a lifetime risk of breast cancer, generally exceeding 40%. We have initiated an international clinical follow up study of women with stage 0 to stage 4 breast cancer and a PALB2 PV to evaluate clinical characteristics and to determine optimal treatments. The objective of the current study was to estimate and to identify factors predictive of contralateral breast cancer (CBC) risk. Methods: Clinical data, including diagnostic, treatment, and follow-up data, were collected by medical record review for eligible women with breast cancer and a germline PV in PALB2. PV carriers were followed every two years to collect information about recurrences, new cancers, and vital status. Data was summarized using descriptive statistics. The risk of CBC was estimated by following women from the date of breast cancer diagnosis until the date of: 1) contralateral breast cancer, 2) contralateral mastectomy, 3) death from any cause, or 4) last follow-up. The cumulative incidence of CBC was calculated with the Kaplan-Meier method. Cox proportional hazards regression was used to identify factors associated with contralateral breast cancer risk. Covariates included age at diagnosis, ER status, grade, nodal status, chemotherapy, radiation therapy, tamoxifen, and bilateral salpingo-oophorectomy (time-dependent). Results: Among 888 PALB2 carriers, the mean age at diagnosis of breast cancer was 49.3 years (range 22 to 83 years). Overall, 36 women (4.1%) were diagnosed with synchronous bilateral breast cancer. 73.6% of the breast cancers were ER-positive, and 29% were lymph node-positive. Patients were followed for a mean of 5.6 years (range 0.3 to 22 years) from date of diagnosis. During the follow-up period, 53 patients were diagnosed with a metachronous CBC. The 15-year risk of metachronous CBC was 26.4% overall; 19.5% for those diagnosed younger than 50 years, and 34.8% for those diagnosed at 50 years or older. In a multivariate analysis, ER status was not significantly associated with CBC risk (RR 1.15, 95%CI 0.45-2.93, p=0.77). Bilateral salpingo-oophorectomy (BSO) was associated with a significant reduction in the risk of CBC (RR 0.17, 95%CI 0.04-0.70, p=0.02). In the follow-up period, 47 women were diagnosed with another incident cancer, including seven with pancreatic cancer and three with ovarian cancer Conclusion: The high 15-year risk of contralateral breast cancer suggests that bilateral mastectomy should be considered for primary surgical intervention. Moreover, bilateral salpingo-oophorectomy (BSO) significantly reduces the risk of CBC and should be considered post-treatment. Citation Format: K. Metcalfe, A. Stachowski, F. Couch, M. Marabelli, S. Wong, S. Domchek, A. Aeilts, A. Eisen, R. Kim, T. Ramon y Cajal, R. Fruscio, S. Yadav, C. Hoey, S. Karamali, P. Sun, J. Lubinski, S. Narod, T. Pal. Contralateral Breast Cancer Risk in Women with PALB2-Associated 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 PD4-11.

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.

Background: Carriers of a pathogenic variant (PV) in BRCA1 face a high risk of breast cancer. This study estimated the risk of developing breast cancer according to mutation type and location. Methods: BRCA1 carriers with no personal history of breast cancer or bilateral mastectomy were included. Detailed information on clinical and family history was collected by questionnaire. Survival analysis was used to estimate 15-year cumulative risk according to PV type and location. Results: A total of 3677 BRCA1 carriers were followed for a mean of 7.2 years (range 0.1–15.0 years); 481 incident breast cancers were documented. Overall, the 15-year cumulative incidence was 25%. Risk estimates varied by exon, ranging from 9% (exon 21) to 19% (exon 12) to 36% (exon 15); however, strata were small. Carriers of four founder mutations common in Eastern Europe (c.5263_5264insC, c.181T > G, c.66_67delAG and c.4034delA) experienced a lower-than-expected cancer risk (15.9–24.4%) compared to other PVs (28.8%) (p = 0.02). Conclusions: Although our data suggests some variability in penetrance based on specific BRCA1 PV, this was based on a large number of founder mutations. Breast cancer management strategies should continue to be based on comprehensive risk assessment.

Abstract Background Women with a pathogenic variant in BRCA1 or BRCA2 are at high risk of developing ovarian cancer, and it is often recommended that they undergo bilateral salpingo-oophorectomy at an early age, resulting in surgical menopause. Menopausal hormone replacement therapy (HRT) is an effective way to mitigate the adverse outcomes of early menopause; however, the safety of menopausal HRT on breast cancer risk in this population has not been established. Methods We conducted a prospective matched analysis of HRT use following menopause and breast cancer risk in BRCA carriers. Women who initiated HRT were matched one-to-one with women who had not initiated menopausal HRT by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Menopausal HRT use collected by questionnaire included formulation and mode of administration. Results After a mean of 5.6 years, there were 87 (12.9%) incident breast cancer cases in the 676 exposed women and 128 (18.9%) cases in the 676 unexposed women (P = .002). Compared with unexposed matched control individuals, women who used estrogen alone experienced a statistically significantly decreased risk of breast cancer (hazard ratio = 0.37, 95% CI = 0.24 to 0.57). No protective or adverse effect was associated with the use of estrogen plus progestogen (hazard ratio = 0.94, 95% CI = 0.54 to 1.63). Conclusions Our findings suggest no substantial increase in the risk of breast cancer in BRCA carriers with the use of HRT and that estrogen alone might be protective.

Background: Endometriosis affects an estimated 10% of reproductive-aged women and is associated with increased ovarian cancer risk. While BRCA1/2 mutations are established risk factors for ovarian cancer, their association with endometriosis remains unclear. This study aimed to characterize the prevalence and clinical features of endometriosis within a large cohort of BRCA mutation carriers. Methods: A descriptive analysis was conducted using data from a multi-center longitudinal cohort of women with pathogenic BRCA variants. Reproductive history and related factors were collected through self-reported questionnaires and compared. Results: Among 16,950 BRCA carriers, the prevalence of endometriosis was 2.4%. Compared to BRCA carriers without endometriosis, those with endometriosis were more likely to carry a BRCA2 mutation, have post-secondary education, and experience earlier menarche. BRCA carriers with endometriosis had a lower ovarian cancer prevalence than those without (10% vs. 15%, p < 0.001). Conclusions: This is the first study of this scale to report the prevalence of endometriosis among BRCA mutation carriers, which was lower than previously reported in the general population. The association between endometriosis and ovarian cancer does not appear to be generalizable to this population. Further prospective studies are warranted to clarify this association among BRCA mutation carriers.

Abstract Background: Multi-cancer early detection (MCED) tests are being established as a novel approach to screen for multiple cancer types with one test. A blood-based MCED test using cell-free DNA targeted methylation patterns to detect a shared cancer signal and predict a cancer signal origin (CSO) has demonstrated feasibility. An initial return of results study (PATHFINDER; NCT04241796) reported performance of a refined version of the MCED test, including a 43.1% positive predictive value (PPV), 98.5% negative predictive value (NPV), 99.5% specificity, and 88.0% CSO accuracy. To build on this work, the PATHFINDER 2 study (NCT05155605) will evaluate safety and performance of the MCED test in larger, more diverse populations. Methods: PATHFINDER 2 is a prospective, multicenter, interventional study. Participants ≥50 years of age will be enrolled, with specific targets to improve diversity (age, sex, race/ethnicity) and few exclusions due to comorbid conditions. Exclusion criteria include current clinical suspicion of cancer or recent cancer/treatment (within 3 years). Participants will undergo blood draw for MCED testing, followed by return of results (cancer signal detection and CSO) to the investigator and diagnostic evaluations if a cancer signal is detected. A confirmatory PET-CT scan will be performed when CSO-directed workups do not result in a cancer diagnosis. Participants will be followed for approximately 3 years. Primary endpoints include 1) MCED test safety in terms of diagnostic testing triggered by a positive result (number/type of procedures and adverse events) and 2) test performance (PPV, NPV, specificity, sensitivity, CSO accuracy, cancer detection rate and number needed to screen). Secondary endpoints include participant reported outcomes (eg, anxiety), utilization of guideline-recommended cancer screening, and cancer detection rate of confirmatory PET-CT, amongst others. The study plans to enroll approximately 35,000 participants across North America. Sites were selected based on geographic location, catchment area demographics, and practice setting (academic vs non-academic). Enrollment targets for age, sex and race/ethnicity (White [non-Hispanic] 72%; Hispanic or Latino 11%; African American or Black 11%; Asian, Native Hawaiian or Other Pacific Islander 6%; American Indian/Alaska Native 1%) were derived from US Census data. Strategies to promote diverse recruitment include translation of participant-facing documents across multiple languages, participant and healthcare provider educational material, and site-led community outreach campaigns. MCED testing is an emerging, potentially paradigm-changing strategy in cancer screening, and PATHFINDER 2 is designed to characterize the safety, performance, and clinical implementation of the MCED test as a screening tool in a broad and representative population. Citation Format: Karthik V. Giridhar, Michael J. Demeure, Raymond H. Kim, Justin A. Chen, Shirish Gadgeel, Dax Kurbegov, Margarita Lopatin, Roland Matthews, Marc Matrana, Charles McDonnell, Donald Richards, Benjamin Rybicki, Gretchen Stipec, Nima Nabavizadeh. PATHFINDER 2: A prospective study to evaluate safety and performance of a multi-cancer early detection test in a population setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4784.

ImportancePreventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined.ObjectiveTo evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation.Design, Setting, and ParticipantsIn this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023.ExposuresSelf-reported bilateral oophorectomy (with or without salpingectomy).Main Outcomes and MeasuresAll-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.ResultsThere were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P &amp;lt; .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P &amp;lt; .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy.Conclusions and RelevanceIn this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.

Abstract CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing &gt;3200 variants in &gt;470 genes from &gt;3100 publications.

Abstract Background: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case–control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. Methods: A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n = 4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. Results: In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34–0.55; P &lt; 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87–1.70; P = 0.26). Conclusions: The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. Impact: Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.