Gender-specific endocrine, metabolic and cardiovascular risks in BRCA-carriers: the BEYOND- CANCER study.

Carrying a germline pathogenic or likely pathogenic variant (P/LPV) in the BRCA1 or BRCA2 gene is associated with a substantially increased lifetime risk of breast, ovarian, pancreatic, and prostate cancer. Beyond this well-established oncological predisposition, emerging evidence suggests that BRCA P/LPV carriers may also experience a spectrum of non-oncological health issues, which can impact overall health status and potentially modulate their cancer risk. Reported associations include reduced ovarian reserve, a higher likelihood of premature menopause, increased risk of osteoporosis, cardiovascular disease, insulin resistance, dyslipidemia, and metabolic syndrome. However, most available studies are limited to preclinical models or retrospective cohorts, often without distinguishing BRCA1 from BRCA2 carriers or accounting for gender-specific differences between men and women. The present study aims to systematically assess endocrine, metabolic, and cardiovascular risks in both female and male carriers of BRCA1 and BRCA2 P/LPVs, compared with a control cohort of BRCA wild-type individuals. The endocrine profile will be evaluated through the serum AMH level, serum estradiol (E2), testosterone (tst), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), a spermiogram test, a testicular ultrasound (US) or a transvaginal US, parathyroid hormone (PTH), 25-OH vitamin D, C-terminal telopeptide, serum calcium and phosphate. The metabolic profile will be characterized using the validated MEDI-LITE, AUDIT, and IPAQ questionnaires. Moreover, patients will undergo a DEXA body composition scan, an abdominal US and blood samples will be collected to assess fasting blood glucose, HbA1c, insulin, insulin-like growth factor 1 (IGF-1), and C-peptide levels, kidney function, liver function, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides apoprotein A1, apoprotein B and lipoprotein A. The cardiovascular risk will be assessed through an electrocardiogram, transthoracic echocardiogram and an US of the supra-aortic trunks. Overall, this study seeks to clarify key determinants of global health status in a population at high genetic risk for cancer, while also providing new insights into the biological mechanisms that may contribute to the modulation of their cancer risk.