胃癌治疗中最有前景的靶向疗法是什么？

　　Khorana博士：雷莫芦单抗（ramucirumab）和曲妥珠单抗（trastuzumab）获得了批准，是目前此方案中仅有的两种靶向药物。近期最引人注目的数据或许倾向于AMG 337 [一种MET抑制剂]，该药在早期阶段的研究中已在MET-扩增患者中取得了良好的反应。需要注意的是这些数据仅代表早期阶段研究中一个亚组的结果，需要进行进一步验证。在较晚期阶段的试验中，使用单克隆抗体的另一种MET抑制方法失败了。

　　在您看来，为什么贝伐单抗（bevacizumab）失败而雷莫芦单抗（ramucirumab）能成功？还有其他对胃癌治疗前景较好的抗血管生成疗法吗？

　　Khorana博士：尽管这两种药物针对类似的途径，它们与血管生成受体之间的相互作用不同。此外，研究的人群也有些不同。的确，在贝伐单抗的研究中，若对北美患者亚组进行分析，贝伐单抗确实表现出获益。所以可能有与不同地理位置的不同种族和分期有关的我们不完全理解的细微问题存在。

　　EGFR靶向治疗失败背后的原因是什么？

　　Khorana博士：目前还不清楚。EGFR-激活途径可能不像我们之前认为的那么重要。也有可能是存在其他途径，削弱了这些途径的作用。

　　近期分子特征研究在如何最好地治疗胃癌方面有何见解？

　　Khorana博士：我们一直在通过以解剖部位对患者（和治疗）进行归类的方式治疗多种癌症，包括胃癌。但这可能不是归类的最佳方式。以胃癌为例，食管下段癌侵入胃食管交界处患者的病理生理学可能与胃体部肿瘤患者的病理生理学相去甚远，前者可能是由反流/Barrett食管引起，而后者的发生可能与幽门螺杆菌（以及其他影响因素）有关。所以，我们所认为的“胃癌”其实是几种完全不同的癌症的合称，但由于缺乏更好的了解，我们将这些归类到一起并使用类似的治疗方法。癌症基因组图谱项目也同样建议将胃癌划分为四个不同的亚型。这种分子分类方法会为病理生理学（对今后的预防很重要）以及根据表达上调的途径来区分治疗方法提供线索。

　　胃癌靶向治疗的研发中遇到的最大的困难是什么？

　　Khorana博士：缺乏相应的生物标志物来确定哪些患者可从靶向药物治疗中获益，这是一个重大的挑战。没有用以预测雷莫芦单抗治疗获益的生物标志物。同样，MET扩增与免疫组化（竞争性检测方法）^a的问题可能是前述MET定向的抗体失败的潜在原因之一。

　　^a注：几项研究表明，MET-靶向治疗的临床试验中观察到的阴性结果可能与MET像差的测试在困难有关。经免疫组织化学（IHC）检测为MET表达阳性的为数众多的患者并不患有MET扩增的疾病。IHC或MET基因拷贝数可能不是检测患者是否对MET靶向治疗策略潜在敏感的最佳方案。

访谈原文

　　OncLive: What are the most promising targeted therapies for the treatment of gastric cancer?

　　Dr Khorana: Ramucirumab and trastuzumab are， of course， approved and are the only currently available targeted agents in this setting. Probably the most impressive recent data are for AMG 337 [a MET inhibitor] which， in early-phase studies， has shown excellent responses in MET-amplified patients. Note that these data represent only a subgroup of an early-phase study and further validation is necessary. An alternative MET inhibition approach using a monoclonal antibody failed in more advanced-phase trials.

　　In your opinion， why did ramucirumab succeed where bevacizumab failed and are there any other antiangiogenic therapies that hold promise in gastric cancer?

　　Although both drugs target similar pathways， they may interact differently with angiogenic receptors. In addition， the study populations were somewhat different. Indeed， in the bevacizumab study， if only the subgroup of North American patients was analyzed， bevacizumab did appear to provide benefit. So there may be subtle issues related to ethnicity and staging that differ by geographic location and are incompletely understood.

　　What are the reasons behind the failure of EGFR-targeting therapy?

　　It is unclear; EGFR-activated pathways may not be as important as we had previously thought. Or they may be redundant with other pathways.

　　What insights do recent molecular characterization studies offer about how best to treat gastric cancer?

　　We have been treating many cancers， including gastric， by categorizing patients (and treatments) based on anatomic location. This may， however， not turn out to be the best way to categorize.

　　In gastric cancer， for instance， patients with lower esophageal cancer invading into the gastroesophageal junction may have quite different pathophysiology than patients with body tumors—the former are likely caused by reflux/ Barrett esophagus and the latter related to?Helicobacter pylori?(among other influences).

　　So really what we think of as “gastric cancer” is a conglomerate of several different cancers entirely， yet due to a lack of better knowledge we have been grouping these together and treating them similarly. The Cancer Genome Atlas project suggests just as much， dividing gastric cancer into four distinct subtypes. This molecular classification provides clues to pathophysiology (important for prevention in the future) as well as differing approaches to treatment based on which pathways are upregulated.

　　What are the most significant hurdles to the development of targeted therapy in gastric cancer?

　　The lack of appropriate biomarkers to identify patients who benefit from targeted agents is a major challenge. There are no biomarkers to predict therapeutic benefit from ramucirumab. Similarly， issues with MET amplification versus immunohistochemistry (competing assays)a?may have been one of the potential causes for the failure of the MET-directed antibody mentioned previously.

　　aNote: Several studies have suggested that the negative findings observed in trials of MET-targeted therapies may be related to difficulties in testing for MET aberrations. A significant number of patients who test positive for MET expression on immunohistochemistry (IHC) do not have MET-amplified disease. IHC or?MET?gene copy number may not be optimal for detecting patients potentially sensitive to MET-targeting strategies.

　　- See more at: http://www.onclive.com/publications/Oncology-live/2015/march-2015/GI-Specialist-Discusses-Hurdles-in-Targeting-Gastric-Cancers#sthash.ToglQPBm.dpuf