Background: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. Objective: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. Methods: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. Results: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. Conclusions: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. Trial Registration: ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. International Registered Report Identifier (IRRID): DERR1-10.2196/24414

Background: Risk-reducing salpingo-oophorectomy (RRSO) is advised for female BRCA1/2 germline pathogenic variant (GPV) carriers to reduce tubal/ovarian cancer risk. RRSO may also affect breast cancer (BC) incidence. The aim was to investigate the effect of RRSO on BC incidence and histopathological features in female BRCA1/2 GPV carriers. Methods: Prospectively collected clinical data from BRCA1/2 GPV carriers in our hospital-based data/biobank were linked to the Dutch Nationwide Pathology Databank (PALGA) in January 2022. Multivariable Cox-proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (95% CIs), where the pre-RRSO group was considered the reference group and the primary endpoint was the first primary BC. Histopathological features of BCs pre- and post-RRSO were compared using descriptive statistics. Results: In 1312 women, 164 incident primary BCs were observed. RRSO did not decrease BC risk for BRCA1 GPV (HR: 1.48, 95% CI: 0.91–2.39) or BRCA2 GPV (HR: 0.95, 95% CI: 0.43–2.07) carriers. BCs tended to be smaller post-RRSO (median: 12 mm) than pre-RRSO (15 mm, p: 0.08). There were no statistically significant differences in histopathological features. Conclusions: RRSO did not decrease BC risk or affect BC features in BRCA1/2 GPV in this study, although BCs diagnosed post-RRSO tended to be smaller.

Purpose: CHEK2 c.1100delC is associated with an increased breast cancer risk in women. While this variant is prevalent in the Netherlands (1% in the general population), knowledge of aetiology and prognosis of breast cancer and other tumours in CHEK2 c.1100delC carriers is lacking. The nationwide HEreditary Breast and Ovarian cancer study the Netherlands (Hebon) cohort aims to answer study questions in families with an increased risk of breast cancer and ovarian cancer. While initially focusing on BRCA1/2 -variant families, Hebon gradually expanded to include pathogenic variants in other genes associated with breast and/or ovarian cancer over time. This provides an excellent setting to establish a cohort to ultimately study the impact of CHEK2 c.1100delC on cancer risk prediction and surveillance, breast cancer treatment and prognosis. Participants: We invited all heterozygous and homozygous CHEK2 c.1100delC indexes and tested female relatives. 1802 women were included, of whom 1374 were heterozygotes and 938 were breast cancer cases. Pedigrees were collected from all clinical genetic departments. Furthermore, participants completed a detailed questionnaire on hormonal and lifestyle factors, family history, cancer diagnosis and treatment. Findings to date: Mean age at study inclusion was 53 years. Linkage with the Netherlands Cancer Registry showed a younger age at diagnosis in homozygotes (mean age 41.7 years) and heterozygotes (47.9 years) than non-carriers (51.2 years). Furthermore, carriers were more often diagnosed with grade 2, oestrogen receptor-positive breast cancer and more often developed contralateral breast cancer than non-carriers. Most women consumed alcohol regularly and about half never smoked. Future plans: Further data linkages with the Netherlands Cancer Registry will allow prospective follow-up and breast cancer risk assessment in unaffected women at the time of genetic testing, risk of contralateral breast cancer and survival in patients with breast cancer. Also, linkage with the nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA) allows us to retrieve tumour samples to study tumourigenesis.

Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1 / BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3’-UTR SNP rs78378222-T’s association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28–1.62, P = 1.76 × 10 ⁻⁹ ). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37–1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date – demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.

Background/Objectives: Germline pathogenic variants (GPVs) in PALB2, RAD51C, and RAD51D increase breast cancer (BC) and ovarian cancer (OC) risk. Limited data on clinicopathological characteristics of BC and OC in women with these GPVs hamper guideline development. Therefore, this study aims to describe these characteristics in a consecutive series of female PALB2, RAD51C, and RAD51D GPV carriers. Methods: Women with a PALB2, RAD51C, or RAD51D GPV determined before July 2023 at the University Medical Center Groningen were included. Cancer diagnoses were obtained through linkage with the Dutch Nationwide Pathology Databank (Palga). Median onset age and histopathological subtypes were compared to the data of The Netherlands Cancer Registry (NCR). Results: Among 164 GPV carriers (125 PALB2, 30 RAD51C, and 9 RAD51D), 54 BC and 6 OC cases were identified. The median BC onset age was 52 (n = 50), 71 (n = 3), and 43 years (n = 1) for PALB2, RAD51C, and RAD51D, respectively, compared with 62 years in the NCR. No BC histological subtype differences were observed in PALB2 carriers. The populations of RAD51C and RAD51D carriers were too small to compare to NCR data. No OC cases occurred in PALB2 carriers. The median OC onset age was 66 (n = 4) and 56 years (n = 2) for RAD51C and RAD51D carriers, respectively, versus 67 years in the NCR. All RAD51D carriers had high-grade serous carcinoma, compared to 51.5% in the NCR. Conclusions: Differences in onset age and histological subtypes were observed between GPV carriers and national data. Further research on cancer characteristics is needed to optimize counseling and cancer prevention in these women.

Introduction: Previous studies have suggested an additional increased risk for types of malignancies other than breast and ovarian cancer for female BRCA1/2 GPV carriers, but risk estimates vary widely. The aim of this study was to investigate if female BRCA1/2 GPV carriers have an increased risk of malignancies other than breast and tubal/ovarian cancer at an early age. Methods: Prospectively collected data from female BRCA1/2 GPV carriers in our hospital-based data/biobank were linked to the PALGA Dutch Pathology Database. Incidences of malignancies occurring before 60 years of age were compared to crude rates/100.000 person-years in the Netherlands, stratified by age and calendar time. Standardized incidence ratios (SIRs) were calculated with 95% confidence intervals (95%CIs). Results: In 1347 women, 82 malignancies other than breast and tubal/ovarian cancer were detected in patients under 60 years of age in 37,068 person-years. An increased risk of cancer in general (SIR:2.25, 95%CI:1.78–2.80, p < 0.001), head and neck cancer (SIR:3.17, 95%CI:1.03–7.39, p < 0.05), gastrointestinal cancer (SIR:1.96, 95%CI:1.14–3.13, p < 0.05), and female genital cancer (SIR:2.48, 95%CI:1.61–3.65, p < 0.001) was found. Conclusions: If confirmed in larger, prospective studies that include the role of bias and previous cancer treatment, awareness of the possible increased risks of head and neck, gastrointestinal, and female genital cancer may be used to tailor clinical guidelines for female BRCA1/2 GPV carriers.