Managing relapses during or after adjuvant CDK4/6 inhibitors in HR-positive/HER2-negative early breast cancer: an emerging challenge

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), such as abemaciclib and ribociclib, have recently been incorporated as adjuvant strategy in combination with endocrine therapy (ET) for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer at higher risk of recurrence. However, despite a significant reduction in recurrence rates, a subset of patients still experiences distant metastatic spreading, with nearly 10% recurring during or shortly after adjuvant CDK4/6i completion, as observed in pivotal trials. To date, only one small retrospective study has described this emerging population while ongoing trials are not specifically addressing this scenario, leaving both the efficacy of postrelapse treatments and the biological background largely unknown. As adjuvant CDK4/6i use expands, these patients with resistant disease pose a novel clinical challenge. Therefore, we propose a pragmatic approach for the management and treatment of relapses occurring during or after adjuvant CDK4/6i exposure, also highlighting key unanswered questions, future perspectives and the urgent need for dedicated research efforts.