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.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest No conflict CONFLICT OF INTEREST STATEMENT The authors whose names are listed immediately below certify that they have NO affi liations with or involvement in any organization or entity with any fi nancial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-fi nancial interest (such as personal or professional relationships, affi liations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Author names: Serena Astore Ester Oneda Alberto Zaniboni