A therapeutic algorithm guiding subsequent therapy selection after CDK4/6 inhibitors’ failure: A review of current and investigational treatment for HR+/Her2- breast cancer

The first-line combination therapies utilizing cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) have significantly impacted the course of hormone receptor positive (HR+)/Human Epidermal Growth Factor Receptor 2 negative (HER2-) advanced breast cancer (ABC). However, resistance often emerges, leading to a molecularly different disease. Estrogen receptor one (ESR1) gene mutations, driving resistance to aromatase inhibitors (AIs), may guide the use of fulvestrant or emerging oral selective estrogen receptor degraders (SERDs) like elacestrant. The dynamic nature of ESR1 mutations suggests potential guidance for continuing CDK4/6i therapy beyond progression. Targeting mutations like breast cancer gene 1 and 2 (BRCA 1/2) with Poly (ADP-ribose) polymerase (PARP) inhibitors or the PI3K/AKT/mTOR pathway provides therapeutic options. The advent of antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) and novel agents targeting Trophoblast cell surface antigen-2 (Trop-2) introduces further complexity, underscoring the need for early intervention targeting specific genomic alterations in metastatic BC.