Summary Metastatic luminal breast cancer remains an incurable disease; however, survival outcomes have improved substantially in recent years due to the development of novel endocrine-based and targeted therapeutic strategies aimed at overcoming endocrine resistance. Nevertheless, therapeutic decision-making after disease progression on CDK4/6 inhibition represents a major clinical challenge. Treatment selection after progression is guided by multiple factors, including prior treatment duration, tumor biology, metastatic pattern, molecular alterations, and patient preferences. The clinical definitions of primary and secondary endocrine resistance remain useful in daily practice and are increasingly complemented by biomarker-driven concepts, such as the detection of acquired ESR1 mutations. Alongside ESR1 mutations, alterations in the PI3K/AKT/mTOR pathway, germline BRCA 1/2 or PALB2 mutations, changes in estrogen receptor expression, emergence of RB1 mutations, and intra-tumoral heterogeneity contribute to endocrine and CDK4/6 inhibitor resistance and inform subsequent treatment strategies. Recent clinical trials have expanded therapeutic options across different molecular subgroups, including oral selective estrogen receptor degraders, PI3K/AKT inhibitors, PARP inhibitors, and antibody–drug conjugates. Combination strategies and biomarker-guided treatment adaptations are emerging as promising approaches to improve disease control, particularly in patients with endocrine-resistant disease. However, in a substantial proportion of patients, no actionable molecular alteration can be identified, highlighting the continued need for individualized treatment strategies. This review summarizes current evidence and provides a clinically oriented overview of treatment sequencing in metastatic luminal breast cancer, highlighting the importance of integrating clinical characteristics, molecular profiling, and patient preferences in an increasingly complex therapeutic landscape.
Christoph Suppan (Mon,) studied this question.