Optimizing therapeutic approaches for HR+/HER2- advanced breast cancer: clinical perspectives on biomarkers and treatment strategies post-CDK4/6 inhibitor progression

Abstract

This review offers an expert perspective on biomarkers, CDK4/6 inhibitor efficacy, and therapeutic approaches for managing hormone receptor-positive (HR+), human epidermal growth factor receptor-negative (HER2-) advanced breast cancer (ABC), particularly after CDK4/6 inhibitor progression. Key trials have demonstrated that combining CDK4/6 inhibitors with endocrine therapy (ET) significantly improves progression-free survival (PFS), with median durations ranging from 14.8 to 26.7 months, and overall survival (OS), with median durations reaching up to 53.7 months. Actionable biomarkers, such as PIK3CA and ESR1 mutations, have emerged as pivotal tools to guide second-line treatment decisions, enabling the use of targeted therapies like alpelisib and elacestrant and emphasizing the important role of biomarkers in guiding the selection of therapy. This overview aims to provide clinicians with a practical and up-to-date framework to inform treatment decisions and improve patient care in the context of this challenging disease. Additionally, we review emerging biomarkers and novel treatment strategies to address this difficult clinical landscape.

Keywords: CDK4/6 inhibitors; HR+/HER2-; advanced breast cancer; biomarkers; prognosis.

Figure 1

Management of endocrine-sensitive or de novo luminal ABC patients. For luminal ABC, endocrine-sensitive with or without targeted therapy remains the mainstay of treatment. Prior lines of therapy should be exhausted before initiating CT. Preferred therapeutic options are represented for women harboring specific gene mutations or without identified mutations. AI: Aromatase inhibitor; BRCA: breast cancer gene; CDK4/6i: cyclin-dependent kinase 4/6 inhibitors; CT: chemotherapy; ERS1: estrogen receptor 1; ET: endocrine therapy; ERBB2: v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; mut: mutated; PD: progressive disease; PFS: progression-free survival; SG: Sacituzumab govitecan; T-DXd: trastuzumab deruxtecan; wt: wild type; ABC: advanced breast cancer.

Figure 2

Management of endocrine-resistant luminal ABC patients. Similar to the endocrine-sensitive scenario, endocrine-resistant with or without targeted therapy remains a core treatment approach. Prior lines of therapy should be used before initiating CT. Preferred therapeutic options are represented for women harboring specific gene mutations or without identified mutations. All therapies included are evidence-based unless otherwise noted. AI: Aromatase inhibitor; BRCA: breast cancer gene; CDK4/6i: cyclin-dependent kinase 4/6 inhibitors; CT: chemotherapy; ERS1: estrogen receptor 1; ET: endocrine therapy; ERBB2: v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; mut: mutated; PD: progressive disease; PFS: progression-free survival; SG: Sacituzumab govitecan; T-DXd: trastuzumab deruxtecan; wt: wild type; ABC: advanced breast cancer.