The OFSET trial (NRG-BR009) is a forthcoming phase III study that aims to address the critical question of whether premenopausal women with early-stage, ER-positive/HER2-negative breast cancer truly benefit from cytotoxic chemotherapy outside of its secondary effects, causing ovarian function suppression.64 If OFSET demonstrates that the therapeutic effect of chemotherapy in intermediate-risk premenopausal women is largely attributable to ovarian suppression, it could fundamentally shift treatment strategies. This evidence concerns the gene ESR1 and breast carcinoma.