Ferro Antonella, Campora Michela, Caldara Alessia, De Lisi Delia, Lorenzi Martina, Monteverdi Sara, Mihai Raluca, Bisio Alessandra, Dipasquale Mariachiara, Caffo Orazio, Ciribilli Yari
Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy.
Department of Pathology, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy.
J Clin Med. 2024 Jun 20;13(12):3611. doi: 10.3390/jcm13123611.
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 ( mutations or HER2 low status) or by inhibiting pathways weakened through germline 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.
雌激素受体（ER）阳性乳腺癌（BC）是最常见的BC亚型。针对ER信号通路的内分泌治疗（ET）仍然是激素受体（HR）阳性BC早期或晚期治疗的主要选择，包括不同策略，如抑制雌激素生成或通过选择性雌激素受体调节剂（SERM）或选择性雌激素受体降解剂（SERD）直接阻断ER通路。然而，对于肿瘤学家来说，原发性或获得性内分泌耐药的发生仍然是一个挑战。新型ET与靶向药物如细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂联合使用，显著提高了长期疗效，从而改变了转移性BC（MBC）的治疗方案，最近也改变了早期高危BC辅助治疗的策略。目前，克服对CDK4/6抑制剂联合ET的耐药性是一项尚未满足的医疗需求，对于采用这种联合治疗方案后仍继续进展的患者，最佳治疗方案也存在分歧。通过肿瘤和/或液体活检对复发和/或转移病灶进行基因组分析发现，肿瘤在生长过程中的基因变化可能预测对特定药物的反应或耐药性，通过靶向改变的ER依赖途径（新型口服SERD和新一代抗雌激素药物）或替代的ER非依赖信号通路，如PI3K/AKT/mTOR或酪氨酸激酶受体（突变或HER2低表达状态）或通过抑制因种系突变而减弱的途径，为每位患者建议最佳治疗策略。这些药物正在作为单一分子以及与其他靶向治疗联合进行研究，为克服或避免治疗失败提供了有前景的手段，并提出了越来越个性化的治疗方法。本综述通过探索基于CDK4/6抑制剂和ET联合治疗失败后的临床证据和基因组分析的潜在策略，对转移性HR/HER2 BC的ET和其他靶向治疗提出了新的见解。
