Department of Medical Oncology, London Regional Cancer Program, London Health Sciences Centre, London, ON.
Curr Oncol. 2012 Jun;19(Suppl 1):S33-44. doi: 10.3747/co.19.1149.
New drugs such as pemetrexed, the epidermal growth factor receptor (egfr) tyrosine kinase inhibitors, and the Alk inhibitor crizotinib have recently enabled progress in the management of advanced non-small-cell lung cancer (nsclc). More drugs, especially Met inhibitors, will follow. However, the benefits of these agents are not uniform across the spectrum of nsclc, and optimizing their utility requires some degree of subgrouping of nsclc by the presence or absence of certain biomarkers.The biomarkers of current or imminent value are EGFR and KRAS mutational status, ALK rearrangements, and MET immunohistochemistry. As a predictor of benefit for anti-egfr monoclonal antibodies, EGFR immunohistochemistry is also of potential interest.Some of the foregoing biomarkers (EGFR, ALK, MET) are direct drivers of the malignant phenotype. As such, they are, quite rationally, the direct targets of inhibitory drugs. However, KRAS, while definitely a driver, has resisted attempts at direct pharmacologic manipulation, and its main value might lie in its role as part of an efficient testing algorithm, because KRAS mutations appear to exclude EGFR and ALK mutations. The indirect value of KRAS in determining sensitivity to other targeted agents or to pemetrexed remains controversial. The other biomarkers (EGFR, ALK, MET) may also have indirect value as predictors of sensitivity to chemotherapy in general, to pemetrexed specifically, and to radiotherapy and molecularly targeted agents.These biomarkers have all enabled the co-development of new drugs with companion diagnostics, and they illustrate the paradigm that will govern progress in oncology in the immediate future. However, in nsclc, the acquisition of sufficient biopsy material remains a stubborn obstacle to the evolution of novel targeted therapies.
新型药物如培美曲塞、表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，以及 Alk 抑制剂克唑替尼，最近已能推进晚期非小细胞肺癌（NSCLC）的治疗进展。更多的药物，尤其是 Met 抑制剂，将会问世。然而，这些药物的疗效并非在 NSCLC 患者中完全一致，因此需要根据特定生物标志物的存在与否，对 NSCLC 进行一定程度的亚组分类。目前或即将具有价值的生物标志物包括 EGFR 和 KRAS 突变状态、ALK 重排以及 MET 免疫组化。作为抗 EGFR 单克隆抗体疗效的预测指标，EGFR 免疫组化也具有潜在的意义。
上述部分生物标志物（EGFR、ALK、MET）是恶性表型的直接驱动因素。因此，它们作为抑制性药物的直接靶点，是相当合理的。然而，KRAS 虽然是明确的驱动因素，但一直难以通过直接药物干预来控制，其主要价值可能在于其作为高效检测算法一部分的作用，因为 KRAS 突变似乎排除了 EGFR 和 ALK 突变。KRAS 在确定对其他靶向药物或培美曲塞的敏感性方面的间接价值仍然存在争议。其他生物标志物（EGFR、ALK、MET）也可能具有预测对化疗、培美曲塞、放疗和分子靶向药物敏感性的间接价值。
这些生物标志物都使得新药物与伴随诊断共同开发成为可能，并且它们说明了将在不久的将来主导肿瘤学进展的范例。然而，在 NSCLC 中，获取足够的活检材料仍然是新型靶向治疗发展的一个顽固障碍。
