Senter, Leigha

PURPOSE The Lynch syndrome (LS) genes, MLH1 , MSH2 , MSH6 , and PMS2 , are considered to be some of the highest-priority genes to be tested for population genomic screening, with the aim to prevent and detect cancers early in those with a higher risk for such diagnoses. The objective of this study was to determine the risk of cancer associated with pathogenic variants in MLH1 , MSH2 , MSH6 , or PMS2 in the general population to build evidence-based guidelines for population genomic screening METHODS This retrospective case-control study uses Helix Research Network data from 230,159 participants across nine US health systems. Variant interpretation was performed following the American College of Medical Genetics and Association for Molecular Pathology guidelines. Clinical diagnoses were identified from electronic health records and claims data for 11 cancer types associated with LS, including colorectal and endometrial cancers. RESULTS Individuals with pathogenic variants in MLH1 , MSH2 , and MSH6 showed substantial risk for LS-related cancers compared with those without pathogenic variants. Conversely, individuals with pathogenic variants in PMS2 had no increase in risk for all 11 LS-associated cancers with hazard ratio (HR) of 1.0 (95% CI, 0.6 to 1.8) compared with those without a pathogenic variant. There was a small increase in risk when restricting the analysis to colorectal cancer with an HR of 3.5 (1.7-7.4). This increase in colorectal cancer risk was predominantly observed after age 60 years, 10 years after US Preventive Services Task Force guidelines recommend starting colonoscopies for the average population. Up to age 60 years, 2.6% of individuals with PMS2 pathogenic variants were diagnosed with colorectal cancer, closer to the general population (0.7%) than those with MLH1 (37.3%), MSH2 (28.9%), or MSH6 (6.7%) pathogenic variants. For 100,000 individuals screened for PMS2 , 854 additional colonoscopies would be performed, which would prevent or detect early 3.2 colorectal cancers. CONCLUSION This analysis across nine health systems highlights the clinical phenotypes of PMS2 pathogenic germline variants in the entire population.

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.

Importance Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. Objective To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Design, Setting, and Participants Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Exposures Entrance into an MRI surveillance program. Main Outcomes and Measures Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. Results A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P &amp;lt; .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. Conclusion and Relevance Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

AbstractBackgroundThe purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant.MethodsParticipants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow‐up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow‐up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan–Meier method.ResultsThere were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk‐reducing mastectomy and bilateral salpingo‐oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%.ConclusionWomen with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.

307 Background: In the US, more than 12,000 people die from ovarian cancer annually. Although new treatments have recently become available, ovarian cancer care delivery remains suboptimal. The Association of Community Cancer Centers (ACCC) developed a series of initiatives to improve the quality of care for patients with ovarian cancer. In Phase I, ACCC evaluated the needs of cancer programs, conducted 3 quality improvement (QI) workshops, and developed expert-driven Quality of Care recommendations to aid cancer programs in self-assessment and quality improvement. In Phase II, ACCC invited programs to self-assess their level of care using the Quality of Care recommendations. Methods: In 2022, ACCC surveyed 7 ovarian cancer programs across the US. Developed by a multidisciplinary expert steering committee, the 26-question survey assessed the patient populations served, services provided, diagnostic evaluations performed, access to molecular testing, and a self-assessment of quality care delivery and interest in conducting QI projects related to self-identified needs. The survey was administered in Qualtrics and summarized using descriptive statistics. Results: Surveys were completed by 1 community, 2 comprehensive community, 2 hospital-associated, 1 academic comprehensive, and 1 NCI-designated comprehensive cancer programs. The median annual ovarian cases was 40 [range: 2 to 68]. The 7 programs serve diverse racial/ethnic distribution of patients with ovarian cancer ranging from 55% Black to 60% Asian and 30% Pacific Islander. Five programs have a multidisciplinary team for ovarian cancer. All 5 multidisciplinary teams included gynecologic oncology and pathology; 3 teams also included medical oncology and or radiology colleague(s). Sites assessed their level of care for 7 domains of quality care from 1 (lowest) to 5 (highest). The average score was 4.0 for Care Coordination and Patient Education, Treatment Planning, and Disease Surveillance. Diagnosis and Initial Management scored on average 3.8, Equity in Care 3.25, Prevention and Screening 3.25, and Quality of Life 3.2. Sites ranked areas of interest for future QI projects (1 = area of most interest, 7 = area of least interest). The highest ranked domains were Care Coordination and Patient Education as well as Diagnosis and Initial management (average rankings 2.8). These were followed by Quality of Life (average 3.0), Prevention and Screening (Average 3.8), Treatment Planning (Average 4.4), Equity in Care (Average 5.0), and Disease Surveillance (Average 6.2). Conclusions: This assessment will be used to identify 4 additional sites for Phase II QI workshops. Findings from these projects will be combined, summarized, and disseminated to inform future education opportunities and QI initiatives. This initiative aims to help organize and standardize the care of patients with ovarian cancer and improve patient care coordination.

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.

256 Background: Ovarian cancer is the leading cause of gynecologic cancer mortality in the US. Given the high burden of disease and complexities in the provision of quality care, a multidisciplinary team approach is critical to optimal care delivery. In 2019, the Association of Community Cancer Centers (ACCC) launched a multiphase, stakeholder-driven initiative to improve care for this patient population. Results of a national survey of cancer programs to identify the needs of patients are reported here. Methods: A 20 question survey was developed by an expert steering committee including gynecologic oncologists, pathologists, genetic counselors, a nurse navigator, and cancer center administrators. The instrument was designed to collect data about cancer programs, key ovarian cancer patient needs, and barriers to and opportunities for improving ovarian cancer care. The online survey was open for participation for 4 weeks using the Qualtrics platform and distributed via email to ACCC and Society of Gynecologic Oncology members. Results: We received 26 total responses from Comprehensive Community (26%), NCI-Designed Comprehensive (22%), Academic Comprehensive (22%), and Integrated Network (13%) Cancer Programs. Annual ovarian cancer cases ranged from 22 to 190 (median: 50.5). 85% of programs has a multidisciplinary team for ovarian cancer and 61% were part of a referral network. On average, programs has 1.5 phase II and 2 phase III clinical trials currently available for ovarian cancer (all programs had at least 1 trial available). Palliative care and comprehensive symptom management was integrated into the first appointment (15%), integrated at the time of recurrence (4%), and most frequently, available by consult (81%). We assessed genetic testing practices at each program. Aggregated across programs, 79% of patients received germline multipanel testing, 71% germline BRCA only, 50% somatic multigene, and 51% somatic BRCA only. The frequency of consultations included: genetic counseling (75%), nurse navigation (75%), social work (50%), dietetics (40%), financial counseling (25%). Genetic evaluations were typically ordered by Gynecologic Oncology (88%), genetic counseling (4%), or both (8%). When asked what topic they would choose for a quality improvement project, genetic testing and counseling was the most frequent choice (46%), followed by clinical trials enrollment and availability (23%), multidisciplinary team care (19%), education on best practices (15%), palliative care (15%), and ancillary services (15%). Conclusions: Multidisciplinary care for ovarian cancer was common across a range of cancer programs but integration of palliative care, social work, dietetics, and financial counseling could be improved. Expanding clinical trials and genetic testing and counseling were the most frequently identified opportunities to improve ovarian cancer care.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.