晚期胃癌的传统化疗方案中位生存期约为9-11个月。结合疗法虽然能提高生存率，但毒性也随之增加。基因表达谱的研究揭示了胃癌独特的分子表型，其中受体酪氨酸激酶的表达变化为药物研发提供了新的途径。HER2阳性的胃癌患者使用曲妥珠单抗治疗已显示出显著的生存获益。未来可能的策略包括使用新型抗HER2药物如帕妥珠单抗和T-DM1，以及双EGFR/HER2阻断剂拉帕替尼。然而，针对EGFR通路的治疗在未选择的患者群体中尚未取得成功。贝伐珠单抗在大型全球试验中未能达到预期效果，但在某些地区显示出疗效差异，提示可能需要进行区域分层研究。未来临床试验的关键将是精确选择患者亚群，如针对MET/HGF和FGFR轴的新型靶向药物。期望这些分子定义的治疗策略能带来比现有标准疗法更显著的生存改善。
摘要：
For patients with advanced gastric cancer, traditional double or triplet cytotoxic chemotherapy regimens result in a median survival of 9–11months. As combination therapy is associated with increased survival, but also increased toxicity in a patient population whose performance status often compromised by their malignancy, development of more effective and less toxic treatment choices is mandated. Emerging data from gene expression profiling suggests that differences in pathological appearance and clinical behavior may be due the presence of unique molecular phenotypes. Characterization of the gastric cancer genomic landscape reveals the presence of multiple alterations in expression of receptor tyrosine kinases, which in conjunction with their ligands and downstream effector molecules represent potentially druggable pathways for future drug development. Treatment of HER2 positive gastric cancer with trastuzumab has led to significant gains in overall survival, and further manipulation of this pathway using the novel anti- HER2 directed agents pertuzumab and T-DM1 in addition to dual EGFR / HER2 blockade with lapatinib may yield positive results. In contrast, targeting of the EGFR pathway in combination with chemotherapy in unselected patients has not been fruitful to date, with no significant gains over standard chemotherapy yet demonstrated. Similarly, use of the anti-angiogenic monoclonal antibody bevacizumab was not successful in a large global randomized trial; however intriguing regional variations were seen with respect to efficacy of this drug, leading to calls for a second, regionally stratified study. Careful selection of patient subsets will become a key factor in future clinical trials, as novel targeted agents such as those targeting the MET/HGF and FGFR axes move forward into clinical development. It is hoped that treatment of patients in such molecularly defined groups is will lead to significant gains in survival compared to current treatment paradigms.
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