下一代肿瘤不可知靶点即将出现
Next-generation tumor-agnostic targets on the horizon.
肿瘤不可知药物开发将肿瘤学重新聚焦于共享的分子依赖性而非组织来源,从而能够针对跨肿瘤的罕见可操作驱动因素进行高效开发。
英文原题:Breast cancer chemotherapy in transition: predictive markers, resistance mechanisms, and new treatment approaches.
Breast cancer chemotherapy in transition: predictive markers, resistance mechanisms, and new treatment approaches.
乳腺癌仍然是全球女性中最常被诊断的恶性肿瘤,尽管治疗取得了实质性进展,但仍是癌症相关死亡的主要原因。
乳腺癌仍然是全球女性中最常被诊断的恶性肿瘤,尽管治疗取得了实质性进展,它仍是癌症相关死亡的主要原因。化疗仍然是治疗的核心组成部分,尤其在高风险早期乳腺癌、三阴性乳腺癌(TNBC)、HER2阳性疾病以及部分激素受体阳性肿瘤中。在过去二十年中,化疗在乳腺癌中的作用已从大体统一的细胞毒性方法演变为由肿瘤生物学、反应动力学和残留疾病负担指导的更精细策略。新辅助化疗变得尤为重要,不仅用于肿瘤降期,还提供了体内化疗敏感性测试,其中病理完全缓解(pCR)可作为侵袭性生物学亚型长期结局的有用标志物。与此同时,对预测性生物标志物如BRCA1/2状态、同源重组缺陷(HRD)、TIL(肿瘤浸润淋巴细胞)(TILs)、Ki-67、内在分子亚型和循环肿瘤DNA(ctDNA)的认识不断增加,改善了患者分层并为更个性化治疗开辟了机会。然而,化疗耐药仍然是主要障碍。耐药通过多种机制产生,包括药物外排、DNA修复增强、凋亡失调、上皮-间质转化、癌症干细胞可塑性、代谢适应以及肿瘤微环境介导的免疫抑制。这些机制限制了持久反应并导致复发,特别是在TNBC和新辅助治疗后的残留疾病中。近期治疗进展集中于通过铂类药物、PARP抑制剂、免疫检查点阻断、新辅助治疗后卡培他滨或曲妥珠单抗-emtansine的升级治疗以及新兴的抗体-药物偶联物来克服耐药性。本综述总结了乳腺癌化疗的进展。
Breast cancer remains the most frequently diagnosed malignancy among women worldwide and continues to be a major cause of cancer-related mortality despite substantial therapeutic progress. Chemotherapy remains a central component of treatment, especially in high-risk early breast cancer, triple-negative breast cancer (TNBC), HER2-positive disease, and selected hormone receptor-positive tumors. Over the last two decades, the role of chemotherapy in breast cancer has evolved from a largely uniform cytotoxic approach to a more nuanced strategy guided by tumor biology, response dynamics, and residual disease burden. Neoadjuvant chemotherapy has become particularly important, not only for tumor downstaging but also for providing an in vivo test of chemosensitivity, with pathologic complete response (pCR) serving as a useful marker of long-term outcome in aggressive biological subtypes. At the same time, increasing knowledge of predictive biomarkers such as BRCA1/2 status, homologous recombination deficiency (HRD), tumor-infiltrating lymphocytes (TILs), Ki-67, intrinsic molecular subtypes, and circulating tumor DNA (ctDNA) has improved patient stratification and opened opportunities for more personalized treatment. However, chemotherapy resistance remains a major obstacle. Resistance arises through multiple mechanisms, including drug efflux, enhanced DNA repair, apoptotic dysregulation, epithelial-mesenchymal transition, cancer stem cell plasticity, metabolic adaptation, and tumor microenvironment-mediated immune suppression. These mechanisms limit durable response and contribute to relapse, particularly in TNBC and residual disease after neoadjuvant therapy. Recent therapeutic advances have focused on overcoming resistance through platinum agents, PARP inhibitors, immune checkpoint blockade, post-neoadjuvant escalation with capecitabine or trastuzumab emtansine, and emerging antibody-drug conjugates. This review summarizes the advancement of chemotherapy in breast cancer.
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