编者按：来自美国加利福尼亚大学的Alan P. Venook博士，在第50届ASCO年会上， 担任“Education Session”、“Special Session”等多专题的主持，并就医学肿瘤学在过去的50年中的进展，为与会者呈现了结直肠癌的最新数据。《肿瘤瞭望》在会议现场就结直肠的诊断和治疗，采访了Alan P. Venook博士。

　　<Oncology Frontier>: Why are BRAF-inhibitors effective in the treatment of BRAF-mutated metastatic melanoma while it fails to do so in the BRAF-mutated colorectal cancers?

　　《肿瘤瞭望》：为什么BRAF抑制剂在治疗BRAF突变的黑色素瘤中起作用，而在BRAF突变的结直肠癌中未见良好获益？

　　Dr Venook: The question is whether pathways make the same difference in each cancer and， in fact， different cancers have different pathways that govern the behavior of the disease. So for whatever reason， BRAF is a driver mutation in melanoma and controlling that BRAF mutation makes a big impact on the disease. The colorectal cancer is just one of a number of mutations that may play a role but isn’t the dominant role. It is informative to know that even in melanoma， BRAF mutations and then treating BRAF mutations with a BRAF-inhibitor makes an impact but not a dramatic impact and not a durable impact. When you combine that BRAF-inhibitor with another agent for example， you get much more bang for your buck. The case is that most cancers are not going to be dominated or be addicted to just one pathway and one mutation. The exception to all of this is GI stromal tumors for example where a c-kit mutation may be treated and may dominate the disease. So it shouldn’t surprise us that one pathway in one cancer is going to behave differently than in another.

　　Venook博士：问题在于在不同的肿瘤中，通路是存在差异的。实际上，不同的肿瘤是通过各自不同的通路来控制疾病的行为。因此不论何种原因，在黑色素瘤中BRAF是驱动突变，并且通过控制BRAF突变可以对疾病产生很大影响。而在结直肠癌中可能是其中某一突变发挥作用，但并非主导作用。通过信息了解到，尽管在黑色素瘤中存在BRAF突变，后续应用BRAF抑制剂治疗BRAF突变已取得了效果，但是并非主要而持久的疗效。当你将BRAF抑制剂与其他的药物进行比较时，你就会有很吃惊的发现。目前的状况是大多数肿瘤不只是靠单一途径和突变介导的。胃肠道间质瘤是一个特例，c-kit突变可能被治疗并且可能在该疾病中占主导地位。所以我们不应该感到惊讶，一个通路在某一肿瘤中的行为与在其他肿瘤中是不同的。

　　<Oncology Frontier>: So for BRAF-mutated colorectal cancers， what kind of therapy strategy would you recommend?

　　《肿瘤瞭望》：对于BRAF突变的结直肠癌患者，您推荐怎样的治疗方案？

　　Dr Venook: What we can say off the bat is that BRAF-mutated colorectal cancer is a bad disease; it is different from the average disease. I presented data yesterday that showed about a 30-month median overall survival for the average patient with metastatic colorectal cancer. This would not apply to the BRAF mutant patients. Some data from previous experience shows about half that survival time with BRAF wild type. What we have done is piggybacked on top of the melanoma group and we have looked at combinations of BRAF-， MAPK- and EGFR-inhibitors and by doing those in combination we are seeing a greater effect. We haven’t cured the disease by a long shot but we are making a difference. On the national level， what we believe is that BRAF mutation patients are different enough that we need the facility to identify these patients at the time of first diagnosis and that they then be treated differently because standard therapies don’t make much of an impact.

　　Venook博士：我们可以肯定BRAF突变的结直肠癌不同于一般的结直肠癌，它是一类较严重的疾病。我本届大会上提出的数据显示转移性结肠癌患者平均的中位生存期约为30个月，这并不适用于BRAF突变的患者。以往的研究数据显示，约一半的生存时间存在BRAF野生型。我们所做的是组建黑色素瘤组，并且发现BRAF、MARK和EGFR抑制剂的联合应用会有较大的获益。我们虽然在一段时间内未能治愈疾病，但是我们有重大突破。从全国水平来看，我们认为BRAF突变的患者有其特殊性，因此在这些患者首次诊断的时候就应将其识别出来，然后给予个体化治疗，因为标准化治疗对这些患者不会产生太大作用。