Investigator
Leiden University
Response to Nahshon and Lavie
High-Grade Serous Carcinoma at Risk-Reducing Salpingo-Oophorectomy in Asymptomatic Carriers of BRCA1/2 Pathogenic Variants: Prevalence and Clinical Factors
PURPOSE To investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2-pathogenic variant (PV) carriers. PATIENTS AND METHODS We included BRCA1/2-PV carriers who underwent RRSO between 1995 and 2018 from the Hereditary Breast and Ovarian cancer in the Netherlands study. All pathology reports were screened, and histopathology reviews were performed for RRSO specimens with epithelial abnormalities or where HGSC developed after normal RRSO. We then compared clinical characteristics, including parity and oral contraceptive pill (OCP) use, for women with and without HGSC at RRSO. RESULTS Of the 2,557 included women, 1,624 had BRCA1, 930 had BRCA2, and three had both BRCA1/2-PV. The median age at RRSO was 43.0 years (range: 25.3-73.8) for BRCA1-PV and 46.8 years (27.6-77.9) for BRCA2-PV carriers. Histopathologic review confirmed 28 of 29 HGSCs and two further HGSCs from among 20 apparently normal RRSO specimens. Thus, 24 (1.5%) BRCA1-PV and 6 (0.6%) BRCA2-PV carriers had HGSC at RRSO, with the fallopian tube identified as the primary site in 73%. The prevalence of HGSC in women who underwent RRSO at the recommended age was 0.4%. Among BRCA1/2-PV carriers, older age at RRSO increased the risk of HGSC and long-term OCP use was protective. CONCLUSION We detected HGSC in 1.5% ( BRCA1-PV) and 0.6% ( BRCA2-PV) of RRSO specimens from asymptomatic BRCA1/2-PV carriers. Consistent with the fallopian tube hypothesis, we found most lesions in the fallopian tube. Our results highlight the importance of timely RRSO with total removal and assessment of the fallopian tubes and show the protective effects of long-term OCP.
High-grade serous carcinoma occurring after risk-reducing salpingo-oophorectomy in BRCA1/2 germline pathogenic variant carriers
Abstract Background Risk-reducing salpingo-oophorectomy (RRSO) effectively prevents high-grade serous carcinoma (HGSC) in BRCA1/2 germline pathogenic variant (GPV) carriers. Still, some women develop HGSC after RRSO without pathological findings. This study assessed long-term incidence and risk factors for developing HGSC after RRSO without pathological findings. Methods BRCA1/2 GPV carriers were selected from the Hereditary Breast and Ovarian cancer in the Netherlands (HEBON) cohort. Follow-up data for HGSC after RRSO were obtained from the Dutch Nationwide Pathology Databank (PALGA) and confirmed by histopathological review. Cumulative incidence rates of HGSC were calculated using Kaplan-Meier analyses. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors associated with an increased risk of HGSC after RRSO without pathological findings. Results A total of 2519 women were included, with a median follow-up of 13.4 years (range: 0.0-27.6 years). The 20-year cumulative incidence rate of HGSC was 1.5% (95% CI = 0.0 to 2.1) for BRCA1 and 0.2% (95% CI = 0.0 to 1.4) for BRCA2 GPV carriers. All women who developed HGSC underwent RRSO after the recommended age. Incomplete embedding of the RRSO specimen (HR = 4.2, 95% CI = 1.4 to 12.6), higher age at RRSO (HR per year = 1.1, 95% CI = 1.0 to 1.1), and carrying a BRCA1 GPV (HR = 12.1, 95% CI = 1.6 to 91.2) were associated with increased risk of HGSC. Conclusions In BRCA1/2 GPV carriers, long-term incidence of HGSC after RRSO without pathological findings was low. Strict adherence to guidelines regarding timely RRSO followed by complete specimen embedding can further reduce the risk of HGSC in the years after RRSO.
Evaluation of BRCA1/2 testing rates in epithelial ovarian cancer patients: lessons learned from real-world clinical data
Abstract Identification of somatic and germline BRCA1/2 pathogenic variants in epithelial ovarian cancer (EOC) patients is essential for determining poly-(ADP-ribose)-polymerase (PARP) inhibitor sensitivity and genetic predisposition. In the Netherlands, BRCA1/2 testing changed to a tumor-first approach to efficiently identify both somatic and germline pathogenic variants in all patients. Here, we performed an in-depth evaluation of the first four years of the tumor-first test-pathway. Data of consecutive series of patients diagnosed with EOC in two regions were obtained from the Netherlands Cancer Registry. Tumor and/or germline test data were retrieved from hospital databases. The primary outcome was the percentage of patients completing the BRCA1/2 test-pathway, defined as having a negative tumor test or a referral for a germline test in case of a positive tumor test or no tumor test. Factors associated with test-pathway completion were identified through multivariable logistic regression analysis. In total, 69.8% (757/1085) completed the test-pathway. This was 74.4% in the most recent year. Younger patients, patients diagnosed in year three or four, patients with high-grade serous/high-grade endometrioid carcinoma, advanced stage disease, middle or high socioeconomic status, and patients who underwent surgery or chemotherapy, were more likely to complete the test-pathway. We report inequalities in genetic testing access in EOC patients, which highlight the need for better guideline adherence, particularly in older patients, those with low socioeconomic status, low-grade histotypes, early-stage disease and those without surgery or chemotherapy. Additionally, timely testing of patients, and testing relatives if patients cannot be tested, are crucial to increase test uptake.
