Authors' Affiliations: Departments of Therapeutic Radiology, Medical Oncology, Neurosurgery, Yale University School of Medicine; and Yale Center for Analytic Sciences, Yale University School of Public Health, New Haven, Connecticut.
Clin Cancer Res. 2013 Oct 1;19(19):5523-32. doi: 10.1158/1078-0432.CCR-13-0836. Epub 2013 Jul 29.
Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes.
Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments.
In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred in-field (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P = 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment.
This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.
非小细胞肺癌（NSCLC）包括一系列辐射敏感和辐射耐受的肿瘤。然而，对于细胞辐射反应的分子决定因素知之甚少。我们检查了 NSCLC 颅内转移接受伽玛刀放疗的临床结果，以评估该模型用于确定辐射敏感肿瘤基因型的用途。
在 2005 年至 2012 年期间，239 名 NSCLC 患者被纳入前瞻性伽玛刀数据存储库。81 名患者的表皮生长因子受体（EGFR）、ALK 和 KRAS 突变状态的分子病理学信息可用。79 名患者的 469 个脑转移瘤有局部和远处脑控制的资料。建立修正的 Cox 比例风险模型来评估经连续伽玛刀治疗后治疗病变的局部控制情况。
共有 11%的患者发生了场内复发。没有 EGFR 突变（0/164 个病灶）或 EML4-ALK 易位（0/61 个病灶）的转移患者在场内复发。相比之下，没有这些突变的 19%患者和有 KRAS 突变的 18%患者在场内复发（分别为 10/139 个和 3/105 个病灶）。肿瘤基因型之间的远处脑转移复发率没有显著差异。与其他 NSCLC 患者相比，EGFR 突变和 ALK 易位的肿瘤的预测中位场内局部控制时间明显更长（P<0.001），而远处脑转移时间则相当（P=0.97）。多变量分析表明，EGFR 突变、ALK 易位和转移灶大小是伽玛刀治疗后局部控制的独立预测因素。
这项研究表明，EGFR 激酶结构域突变和 EML4-ALK 易位是辐射敏感的 NSCLC 基因型，并提出了一种新的模型来识别 NSCLC 的辐射敏感亚型。
