HR+/HER2-乳腺癌新型靶向药物的有效性研究进展

Advances in the Efficacy of Novel Targeted Therapeutics for HR+/HER2- Breast Cancer

摘要: HR+/HER2-乳腺癌占全部乳腺癌约70%，内分泌治疗是其系统性治疗的基石，但原发或继发耐药长期制约患者预后。近年来，以CDK4/6抑制剂、PI3K/AKT/mTOR通路抑制剂及口服选择性雌激素受体降解剂(SERD)为代表的新型靶向药物相继完成关键性随机对照试验并获批应用，深刻改变了该亚型的治疗格局。本文按作用机制分类，系统综述上述药物在晚期一线与后线解救治疗及早期辅助强化治疗中的有效性证据，同时纳入PALLAS、PENELOPE-B、IPATunity130等阴性结果研究以完整呈现证据全貌。现有证据表明，CDK4/6抑制剂联合内分泌治疗已在晚期一线和二线治疗中确立总生存获益，其中瑞波西利辅助强化治疗在高危早期患者中亦取得突破；基于PIK3CA、AKT通路变异及ESR1突变等分子标志物检测的精准靶向治疗进一步克服了内分泌耐药；循环肿瘤DNA动态监测指导下的早期换药策略为治疗决策提供了新范式。未来仍需围绕耐药机制深入解析、优势人群精准筛选、药物使用时机优化及本土创新药物持续研发等方向开展研究，以进一步延长患者生存并改善生活质量。

Abstract: HR+/HER2- breast cancer accounts for approximately 70% of all breast cancer cases, with endocrine therapy serving as the cornerstone of systemic treatment; however, primary or acquired endocrine resistance remains a major limitation on patient prognosis. In recent years, novel targeted agents—represented by CDK4/6 inhibitors, PI3K/AKT/mTOR pathway inhibitors, and oral selective estrogen receptor degraders (SERDs)—have completed pivotal randomized controlled trials and received regulatory approval, profoundly reshaping the therapeutic landscape of this subtype. This review systematically summarizes the efficacy evidence for these agents, classified by mechanism of action, in first-line and subsequent-line advanced disease as well as early adjuvant intensification, while incorporating negative trials including PALLAS, PENELOPE-B, and IPATunity130 to present a complete picture. Current evidence demonstrates that CDK4/6 inhibitors combined with endocrine therapy have established overall survival benefits in advanced first-line and second-line settings, with ribociclib also achieving a breakthrough in adjuvant intensification for high-risk early-stage patients. Precision-targeted therapies guided by molecular biomarkers such as PIK3CA, AKT pathway alterations, and ESR1 mutations have further overcome endocrine resistance. Furthermore, early treatment-switch strategies guided by dynamic circulating tumor DNA monitoring offer a novel paradigm for clinical decision-making. Future research should focus on in-depth elucidation of resistance mechanisms, precise identification of optimal beneficiary populations, optimization of drug timing and sequencing, and continued development of domestically innovated agents, so as to further prolong patient survival and improve quality of life.