Familial risk of epithelial ovarian cancer after accounting for gynaecological surgery: a population-based study.

Background: Uptake of risk-reducing surgery has increased among women at high risk of epithelial ovarian cancer. We sought to characterise familial risk of epithelial ovarian cancer histotypes in a population-based study after accounting for gynaecological surgeries, including bilateral oophorectomy.

Methods: We compared risk of epithelial ovarian cancer in relatives of 3536 epithelial ovarian cancer cases diagnosed in 1966-2016 and relatives of 35 326 matched controls. We used Cox competing risk models, incorporating bilateral oophorectomy as a competing risk, to estimate the relative risk of ovarian cancer in first-degree (FDR), second-degree (SDR) and third-degree (TDR) relatives from 1966 to 2016. We also estimated relative risks in time periods before (1966-1994, 1995-2004) and after (2005-2016) formal recommendations were made for prophylactic oophorectomy among women with pathogenic variants in .

Results: The relative risks of epithelial ovarian cancer in FDRs, SDRs and TDRs of cases versus controls were 1.68 (95% CI 1.39 to 2.04), 1.51 (95% CI 1.30 to 1.75) and 1.34 (95% CI 1.20 to 1.48), respectively. Relative risks were greatest for high-grade serous, mucinous and 'other epithelial' histotypes. Relative risks were attenuated for case FDRs, but not for SDRs or TDRs, from 2005 onwards, consistent with the timing of recommendations for prophylactic surgery.

Conclusion: Familial risk of epithelial ovarian cancer extends to TDRs, especially for high-grade serous and mucinous histotypes. Distant relatives share genes but minimal environment, highlighting the importance of germline inherited genetics in ovarian cancer aetiology. Increased ovarian cancer risk in distant relatives has implications for counselling and recommendations for prophylactic surgeries that, from our data, appear only to reach FDRs.