Enhancing Endocrine Therapy Combination Strategies for the Treatment of Postmenopausal HR+/HER2a?? Advanced Breast Cancer

摘要

Breast cancer (BC) is the most common malignancy in women worldwide, with approximately twoa??thirds having hormone receptora??positive (HR+) tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3a??kinase (PI3K), or cyclina??dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as firsta??line therapy for HR+/HERa?? advanced BC with special consideration for the former in ETa??na?ˉve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as seconda??line therapy with special consideration in select firsta??line patients. Although the safety profiles of these combinations are generally predictable and manageable, both everolimus and palbociclib are associated with an increased risk of potentially serious or earlya??onset toxicities requiring individualized a priori adverse event risk stratification, earlier and more rigorous agenta??specific monitoring, and patient education. Although each of these combinations improves progressiona??free survival, none with the exception of anastrazole plus fulvestrant have demonstrated improved overall survival. PI3K catalytica???± mutations assessed from circulating tumor DNA represent the first potentially viable serum biomarker for the selection of ET combinations, and new data demonstrate the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis. Therapeutic ratios of select ET combinations support their use in firsta?? and seconda??line settings, but optimal sequencing has yet to be determined. Implications for Practice. Emerging data show that new endocrine therapy (ET) combinations can improve progressiona??free and overall survival outcomes in patients with hormone receptora??positive, HER2a??negative (HR+/HERa??) advanced breast cancer. Level 1 evidence supports consideration of dual ET regimens, particularly in ETa??na?ˉve patients, or palbociclib plus letrozole as firsta??line therapy, as well as the addition of mTOR or CDK4/6 inhibitors to established ET in the seconda??line setting and in select firsta??line patients. Some combinations are associated with increased risk of classa??specific toxicities that will require individualized risk stratification, earlier and more rigorous agenta??specific monitoring, and patient education. Recent data on a noninvasive biomarker assay that predicts response to a phosphoinositide 3a??kinase inhibitor demonstrates the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis.