The impact of conventional chemotherapy regimens and targeted drugs on ovarian function in breast cancer patients

Abstract

Breast cancer is the most common malignancy among women, affecting nearly 1.5 million individuals worldwide every year. While survival rates improve, many reproductive-age survivors confront significant long-term consequences, particularly diminished ovarian reserve, infertility, and premature ovarian insufficiency due to the gonadotoxic effects of chemotherapy. Postponement of pregnancy for five years or more after treatment exacerbates the decline in fertility due to ongoing ovarian aging and depletion of residual ovarian reserve. Women carrying BRCA1/2 mutations may already exhibit reduced ovarian reserve and are more vulnerable to gonadal damage, possibly due to impaired DNA repair mechanisms associated with these mutations. The contribution of other breast cancer susceptibility genes (e.g., ATM, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) to chemotherapy-induced gonadotoxicity remains unclear. Although animal data shows depletion of primordial follicle pool and granulosa cells dysfunction, the ovarian effects of the poly(ADP-ribose) polymerase (PARP) inhibitors in women with and without BRCA mutation are not clear. Immune-check point inhibitors (ICIs) causes immune-mediated destruction of the primordial follicle pool and reduction in ovarian reserve. Cyclin dependent kinase inhibitors appear to be less toxic than ICIs. In this narrative review of the current literature we aimed to provide a comprehensive overview of the molecular mechanisms underlying ovarian toxicity associated with conventional chemotherapy and targeted therapies in breast cancer treatment.