Current evidence and treatment strategies of CDK4/6 inhibitors in HR+/HER2- young breast cancer

Abstract Breast cancer (BC) in young women is associated with more aggressive tumor biology, increased risk of recurrence, as well as worse prognosis, with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) subtype accounting for 54–61% of cases. While cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have become the standard treatment in both HR+/HER2- advanced BC (ABC) and early BC (EBC), their application in young BC (YBC) poses distinct challenges. Unlike postmenopausal patients, YBC frequently face premenopausal endocrine milieu, fertility preservation concerns, treatment-induced ovarian dysfunction, and long-term psychosocial burdens. In the adjuvant setting, key unanswered questions include whether adjuvant CDK4/6i can replace chemotherapy (CT) in intermediate-risk disease, how to sequence CDK4/6i with poly (ADP-ribose) polymerase inhibitors (PARPi) in breast cancer susceptibility gene ( BRCA )-mutated young patients, and how to time adjuvant therapy around fertility preservation. In the advanced setting, critical issues remain regarding the integration of CDK4/6i in BRCA or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA )-mutated patients, the timing of CDK4/6i initiation, the benefit of cross-line switching after progression, and whether CDK4/6i-based regimens can defer CT in visceral crisis. Moreover, patient-reported outcomes (PROs) and quality-of-life (QoL) data are critically lacking, which are essential for shared decision-making given the extended treatment trajectory. Future research must prioritize biomarker-driven strategies, head-to-head comparisons of CDK4/6i plus ovarian function suppression (OFS) versus CT, and integration of multidisciplinary team (MDT) care and PROs assessments. Addressing these unmet needs will be pivotal to advancing personalized, holistic management and improving long-term outcomes in YBC.