Julie Lecarpentier, on behalf of GENEPSO, Catherine Noguès, Emmanuelle Mouret-Fourme, Bruno Buecher, Marion Gauthier-Villars, Dominique Stoppa-Lyonnet, Valérie Bonadona, Jean-Pierre Fricker, Pascaline Berthet, Olivier Caron, Isabelle Coupier, Pascal Pujol, Laurence Faivre, Paul Gesta, François Eisinger, Véronique Mari, Laurence Gladieff, Alain Lortholary, Elisabeth Luporsi, Dominique Leroux, Laurence Venat-Bouvet, Christine M. Maugard, Chrystelle Colas, Julie Tinat, Christine Lasset, Nadine Andrieu

Background: Mutations in BRCA1/2 confer a high risk of breast cancer (BC), but literature values of this risk vary. A genotype-phenotype correlation has been found in both genes and the effect of reproductive factors differs according to mutation location. We hypothesize that such a variation may exist for other factors related to estrogen exposure. Methods: We used a weighted Cox regression model to assess variation in BC risk with these factors using location of mutation in homogeneous BC risk region of BRCA1/2 in the GENEPSO study. Results: We found that late age at menarche reduced BC risk by 31% and that among BRCA1 carriers, a long or a short menstrual cycle increased risk (by 35% and 48%, respectively). Among premenopausal women, overweight was associated with a 39% decrease in BC risk while underweight was associated with an increased risk (hazard ratio [HR]=2.09). A natural menopause, mainly after age 50, was associated with a high BC risk (HR=2.46) and a significant interaction between menopause status and the location of mutations was found leading up to 10% variation in absolute risk according to the age at menopause. Conclusions: As observed in the general population, late menarche, long or short menstrual cycle, over- or under-weight, and being post-menopausal were associated with BC risk in BRCA1/2 carriers. The association with the menopause was observed only when the mutation was located in the "high-risk" zones. Impact: Taking into account modifier factors, location of mutation might be important for the clinical management of BRCA1/2 carriers.