The next era of treatment for hormone receptor-positive, HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies
Cette étude passe en revue les mécanismes d'action des thérapies endocriniennes, des inhibiteurs de CDK4/6 et des inhibiteurs de la voie de signalisation PI3K/mTOR, puis fait le point sur les essais cliniques évaluant l'intérêt de combiner ces trois traitements chez les patientes atteintes d'un cancer du sein HR+
Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients. Addition of phosphatidylinositol-3 kinase (PI3K) or mechanistic target of rapamycin (mTOR) inhibitors to combined CDK4/6 and endocrine inhibitor regimens may help prolong CDK4/6 inhibitor sensitivity. Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, and endocrine therapy have shown encouraging signs of clinical activity. However, further research is needed to help understand the extent of treatment benefit from triplet therapy and where this strategy will fit in the treatment sequence for patients with HR+ breast cancer. In this review, we describe the mechanisms of action of endocrine therapy, CDK4/6 inhibitors, and PI3K/mTOR inhibitors, and discuss the rationale underlying triplet combinations of these agents as treatments for HR+ breast cancer. We also summarize clinical trials that are investigating triplet combinations comprising a CDK4/6 inhibitor, a PI3K/mTOR inhibitor, and endocrine therapy.