Targeted therapy in gastroesophageal cancers:past,present and future

胃/食管癌的靶向治疗:过去、现在和将来

Gastroesophageal cancer is a significant global problem that frequently presents at an incurable stage and has very poor survival with standard chemotherapy approaches.This review will examine the epidemiology and molecular biology of gastroesophageal cancer and will focus on the key deregulated signaling pathways that have been targeted in the clinic.A comprehensive overview of clinical data highlighting successes and failures with targeted agents will be presented.Most notably,HER2-targeted therapy with the monoclonal antibody trastuzumab has proven beneficial in first-line therapy and has been incorporated into standard practice.Targeting the VEGF pathway has also proven beneficial,and the VEGFR-targeted monoclonal antibody ramucirumab is now approved for second-line therapy.In contrast to these positive results,agents targeting the EGFR and MET pathways have been evaluated extensively in gastroesophageal cancer but have repeatedly failed to show benefit.An increased understanding of the molecular predictors of response to targeted therapies is sorely needed.In the future,improved molecular pathology approaches should subdivide this heterogeneous disease entity to allow individualization of cancer therapy based on integrated and global identification of deregulated signaling pathways.Better patient selection,rational combinations of targeted therapies and incorporation of emerging immunotherapeutic approaches should further improve the treatment of this deadly disease.

胃/食管癌是一个全球难题,发现时经常已处于无法根治的阶段,对其进行标准方案化疗,预后也非常差。本文首先总结胃/食管癌的流行病学及分子生物学特征,然后重点阐述靶向治疗相关的几条关键信号调控通路。同时,本文还对靶向药物的临床应用情况(包括成功与失败的数据)进行了全面回顾。值得一提的是,靶向HER2的单克隆抗体trastuzumab在一线治疗中的获益已获证实,从而作为一项标准治疗应用于临床实践。靶向VEGF的单克隆抗体ramucirumab的疗效也获证实,并被批准用于临床二线治疗。相比这些积极的研究结果,虽然EGFR和MET通路的靶向治疗药物在胃/食管癌中也有着广泛的研究,但其疗效并未获得证实。有必要对预测这些靶向药物疗效的分子标记物进行更深入的研究。未来,基于抑制上述信号通路的相关研究结果而出现的更为可靠的分子病理学方法,或可将胃/食管癌这种异质性疾病进行亚分类,从而实现个体化治疗。精准的病例选择、合理的靶向药物搭配以及免疫治疗药物的联合应用有望进一步提高胃/食管癌的疗效。