Navigating the post-CDK4/6 inhibitor era: a clinical algorithm for hormone receptor-positive metastatic breast cancer

Breast cancer remains the most frequently diagnosed ma­lig­nancy globally, with incidence rates projected to escalate drastically by 2050, creating a substantial bur­den in countries like Romania, where late detection drives high mortality. While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have revolutionized the standard of care for hormone receptor-positive (HR+), HER2-negative me­tas­ta­tic breast cancer (mBC), the inevitable development of resistance creates an unmet clinical need. This review out­lines a clinical algorithm for the post-CDK4/6 inhibitor land­scape, describing a shift from chemotherapy ap­proa­ches to biomarker-guided sequencing. Strategies to ma­xi­mize first-line durability are examined, including the “all-oral triplet” with inavolisib for PIK3CA-mutated tu­mors and molecular interception of estrogen receptor 1 (ESR1) mu­ta­tions via circulating tumor DNA (ctDNA) mo­ni­to­ring. For disease progression, the discussion details evi­dence for targeting the phosphoinositide 3-kinase (PI3K)/AKT/mam­ma­lian target of rapamycin (mTOR) pathway (al­pe­li­sib, capivasertib), ESR1 mutations and germline BRCA mu­ta­tions. Furthermore, it addresses the reclassification of HER2 status, positioning antibody-drug conjugates like trastuzumab deruxtecan as superior alternatives to chemotherapy for HER2-low/ultralow expression. High­light­ing these advancements is essential for clinical prac­tice, as it demonstrates how these novel molecules provide sub­stan­tial gains in progression-free and overall survival, ul­ti­mately delaying cytotoxic chemotherapy and redefining out­comes for patients facing advanced disease.