PDF(Pubmed)
Abstract：
Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2- BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.
摘要：
雌激素受体（ER）阳性乳腺癌（BC）是最常见的BC亚型。针对ER信号的内分泌治疗（ET）仍然是早期或晚期激素受体（HR）阳性BC的主要治疗选择，包括不同的策略，例如抑制雌激素产生或通过SERMs选择性雌激素受体调节剂或SERDs选择性雌激素受体降解剂直接阻断ER途径。然而，从头或获得性内分泌耐药性的发展仍然是肿瘤学家的挑战。新型ET联合靶向药物的使用，如细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂，显著提高了长期结果率，因此改变了转移性BC（MBC）的治疗方法，以及最近对早期高危BC的辅助治疗策略。消除对CDK4/6抑制剂联合ET的耐药性是目前尚未满足的医疗需求，对于这种联合治疗方法后继续进展的患者，存在着关于最佳治疗方案的分歧。通过肿瘤和/或液体活检的复发和/或转移性病变的基因组谱发现的肿瘤沿其生长的遗传变化可以预测对特定药物的反应或抗性。建议通过靶向改变的ER依赖性途径(新型口服SERD和新一代抗雌激素药物)或替代的ER非依赖性信号通路,如PI3K/AKT/mTOR或酪氨酸激酶受体(HER2突变或HER2低状态)或通过抑制通过种系BRCA1/2突变削弱的途径,为每位患者提供最佳治疗策略.这些药物正在作为单分子进行研究，并与其他目标疗法相结合。提供有希望的武器来克服或避免治疗失败，并提出越来越个性化的治疗方法。这篇综述通过探索基于CDK4/6i和ET组合失败后的临床证据和基因组谱分析的潜在策略，提出了对ET和其他靶向治疗的新见解，用于管理转移性HR+/HER2-BC。
