Germline pathogenic variants (GPVs) in the cancer predisposition genesBRCA1,BRCA2,MLH1,MSH2,MSH6,BRIP1,PALB2,RAD51DandRAD51Care identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV inBRCA1,BRCA2,MLH1,MSH2andMSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV inBRIP1,PALB2,RAD51DandRAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition ofRAD51Cand RAD51Das OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management ofBRIP1,PALB2,RAD51DandRAD51Ccarriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.

ObjectiveTo describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories.DesignLaboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years’ missing data.ResultsIndividual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed.ConclusionThe NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

Background: Second primary cancer (SPC) incidence is rising among breast cancer (BC) survivors, but these risks remain unclear. We estimated SPC risks for male and female BC survivors using large-scale electronic health record data from a linkage of National Cancer Registration and Analysis Service data and Hospital Episode Statistics surgical records in England. Material and Methods: We used a retrospective cohort study design comprising 763,578 female and 4,795 male BC survivors first diagnosed with BC between 1995-2018. We calculated overall and site-specific SPC standardized incidence ratios (SIRs) by comparing observed and expected SPC counts for 19 cancer sites. Study participants were followed from one year after the first BC diagnosis until either a SPC diagnosis (excluding ipsilateral breast and non-melanoma skin cancers), death, migration, relevant surgical procedures, or the end of 2019. Expected SPC counts were calculated using year-, age- and sex-specific cancer incidence rates in the general English population. We stratified the SIRs by age group, sex, and cancer site. We estimated Kaplan-Meier absolute risks of site-specific SPCs and assessed the influence of age at first BC diagnosis using Cox proportional hazards models. Results: There were 68,550 and 720 incident SPCs among female and male BC survivors, respectively. There was a significant increased risk of all SPCs combined for female BC survivors (SIR: 1.19, 95%CI: 1.18-1.20). There were significant increased risks for SPC at all sites combined, all non-breast sites combined, and at 12 further specific sites for females and at 2 specific sites for males. Among females, the increase was greatest for contralateral breast (SIR: 1.82, 95%CI: 1.79-1.85) and uterine cancers (SIR: 1.80, 95%CI: 1.76-1.85). The risk at all sites combined was higher for women first diagnosed with BC before age 50 (SIR: 1.89, 95%CI: 1.85-1.92) compared to women diagnosed with BC at age 50 or over (SIR: 1.11, 95%CI: 1.10-1.12). The largest associations were observed for contralateral breast (SIR: 3.19, 95%CI: 3.11-3.29) and uterine (SIR: 1.77, 95%CI: 1.73-1.82) SPCs in the younger and older age groups, respectively. Increasing age at first female BC diagnosis was associated with decreasing CBC absolute risks, but significantly increased absolute risks of all other SPCs. Male BC survivors were at increased risk of contralateral breast (SIR: 42.39, 95%CI: 28.39-60.89) and prostate (SIR: 1.29, 95%CI: 1.13-1.46) SPCs. Conclusions: This is the largest study to date to assess SPC risks following BC in either men or women. SPC risks were significantly increased, both in combination and at specific sites. These findings could help guide clinical management, such as screening recommendations, for BC survivors. Further analysis is underway to investigate the effects of chemotherapy, radiotherapy, hormonal therapy, comorbidities, or germline BC susceptibility. Citation Format: Isaac Allen, Tameera Rahman, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Hend Hassan, Catherine Huntley, Lucy Loong, Yvonne Walburga, Katrina Lavelle, Eva Morris, Steven Hardy, Beth Torr, Diana Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Second primary cancer risks for female and male breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3057.

Introduction: Breast cancer is the most common cancer in women. Women with personal history of breast cancer are at increased risk of second primary cancers including ovarian cancer. Bilateral salpingo-oophorectomy (BSO) is a well-established option for ovarian cancer risk reduction. However, the benefit of ovarian cancer risk reduction should be balanced against the health sequelae caused by the premature estrogen loss. We examined the associations between BSO after breast cancer diagnosis and long-term health outcomes, using large-scale linked electronic health records. Methods: We selected women diagnosed with invasive breast cancer before the age of 75 between 1995 and 2019 using data from the National Cancer Registration Dataset (NCRD), which describes all cancers registered in England. These women were linked to the Hospital Episode Statistics (HES) Admitted Patient Care (APC) dataset to identify the delivery of BSO, while the use of hormonal replacement therapy (HRT) was identified from the community dispensed prescriptions dataset. Long-term outcomes (e.g., ischemic heart disease) were selected from HES, and the NCRD provided data on second cancer diagnosis and all-cause mortality. Multiple imputation was used to impute missing data on stage, grade, hormonal receptor status and ethnicity. Women were followed from the date of breast cancer diagnosis to development of an outcome of interest or censoring or end of data collection. Multivariable Cox regression was used to examine the associations, with BSO modeled as a time-dependent covariate. The analysis was stratified by patient age at BSO (<55 and ≥55 years). Results: The study included 566,731 women, with median follow up time 8.40 (IQR: 4.4-14.5) years. Of those, 23,881 women had BSO after their breast cancer diagnosis. BSO before the age of 55 was not associated with all-cause mortality (hazard ratio (HR):1.03, 95%CI:0.98-1.08), while BSO after the age of 55 was associated with a small reduction in the risk of all-cause mortality (HR:0.93, 95%CI:0.89-0.99). BSO before and after the age of 55 was associated with increased risk of ischemic heart disease with HRs of 1.23(95%CI:1.07-1.41) and 1.13(95%CI:1.02-1.25), respectively. There was no association between BSO and cerebrovascular events (HR:0.97, 95%CI:0.82-1.15, for BSO under age 55, HR:0.96, 95%CI:0.87-1.07, for BSO after age 55). Ongoing analyses are investigating the associations stratified by the severity of cardiovascular outcome (fatal/non-fatal) and the use of HRT, and the associations with second cancers and neuropsychiatric outcomes. Conclusion: BSO after 55 does not appear to be associated with detrimental health effects in women diagnosed with breast cancer. Further examination of the associations between BSO and other long-term health outcomes and the influence of HRT in younger women is needed. Citation Format: Hend Hassan, Tameera Rahman, Andrew Bacon, Craig Knott, Isaac Allen, Catherine Huntley, Lucy Loong, Yvonne Walburga, Katrina Lavelle, Eva Morris, Steven Hardy, Bethany Torr, Diana M Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Long-term health outcomes of bilateral salpingo-oophorectomy in women with personal history of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 988.