Journal Article
Impaired glucose tolerance in women with BRCA1 versus BRCA2 pathogenic or likely pathogenic variants: Results from a prospective cohort study
Giovanni Grandi; Claudia Piombino; Giovanna Sighinolfi; Elena Barbieri; Marta Venturelli; Chiara Melotti; Rebecca Lippi Bruni; Valentina Grisendi; Riccardo Cuoghi Costantini; Mina Grippa; Emma Zattarin; Elena Tenedini; Elisabetta Razzaboni; Giulia Brigante; Roberto D’Amico; Benedetta Nanni; Renata Menozzi; Laura Cortesi; Massimo Dominici; Antonio La Marca; Angela Toss
Familial Cancer · Vol. 25, Issue 2 · 2026
Abstract
Background Estrogens exert a beneficial effect on metabolism. Women carrying BRCA likely pathogenic/pathogenic variants (LP/PV) are at increased risk of premature menopause and may therefore be at higher risk of developing metabolic disorders later in life. In this single-center prospective cohort study, we investigated whether the specific BRCA mutation ( BRCA 1 vs. BRCA 2) has a differential impact on metabolism in women. Methods Eligible participants were BRCA LP/PV carriers who were premenopausal or underwent menopause –either natural or iatrogenic– within the 5 years prior to enrollment. Blood samples for lipid and glucose panels were obtained every 6 months, for a total of four time points. Body composition variables were evaluated at baseline and at the final follow-up using bioimpedance analysis. Glucose tolerance was assessed using the homeostatic model assessment for insulin resistance (HOMA-IR). Associations between lipid and glucose profile and patient characteristics were evaluated using univariable and multivariable linear regression models. Results Fifty-seven BRCA1 and 58 BRCA2 LP/PV carriers were included in the final analysis. At baseline, BRCA1 LP/PV carriers had a higher body mass index (BMI) (27.3 vs. 24.6 kg/m 2 , p = 0.01) and higher fat mass (27.3 vs. 21.9 kg, p = 0.013) than BRCA2 LP/PV carriers. Insulin levels and HOMA-IR were consistently higher in BRCA1 than in BRCA2 LP/PV carriers at all time points, and this difference was not attributable to age, BMI, menopausal status, risk-reducing salpingo-oophorectomy, previous chemotherapy or use of cholesterol-lowering agents. The lipid profile was similar between the groups, although BRCA1 LP/PV carriers showed a tendency toward a less favorable profile (higher LDL and lower HDL). Conclusions These prospective results suggest that BRCA1 LP/PV carriers might have impaired glucose tolerance and a greater tendency toward insulin resistance compared with BRCA2 LP/PV carriers: this first report needs further independent confirmations from other cohorts.