Division of Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, IL.
Department of Internal Medicine, University of New Mexico, Albuquerque, NM.
Clin Lung Cancer. 2018 Nov;19(6):531-543. doi: 10.1016/j.cllc.2018.08.011. Epub 2018 Aug 22.
Unsuccessful KRAS-specific treatment approaches in non-small-cell lung cancer (NSCLC) might reflect underlying disease heterogeneity. We sought to define clinical "syndromes" within advanced KRAS mutant NSCLC to improve future clinical trials and create a clinical framework for future molecular development.
To test a series of a priori hypotheses regarding KRAS-mutant NSCLC clinical syndromes, we conducted a multi-institutional retrospective medical record review. Survival probabilities were estimated using the Kaplan-Meier model. Between-group differences were assessed using the log-rank test. Multivariate Cox regression analyses and Wilcoxon rank sum testing were used to assess progression-free survival and overall survival (OS) differences.
Among 218 patients with advanced KRAS-mutant NSCLC, OS and progression-free survival with first-line chemotherapy did not differ by intrathoracic versus extrathoracic spread, smoking intensity, or the specific KRAS mutation. Metastatic disease at diagnosis resulted in significantly worse OS than recurrent, unresectable disease (median OS, 14.6 vs. 40.9 months; P = .001). Among the patients with metastatic disease at diagnosis, nonscalp, soft tissue metastases (syndrome X; 6% of cases; 95% confidence interval [CI], 2.5%-10.1%) signified a poor prognosis (median OS, 7.5 vs. 15.9 months for the controls; P = .021). The response to first-line chemotherapy (syndrome Y; 41% of cases; 95% CI, 32.3%-50.6%) signified a good prognosis (median OS, 26.7 vs. 11.9 months; P = .002). The overlap between these 2 syndromes was minimal (2 of 111). Multivariate analysis confirmed these observations. The hazard ratio for death for syndromes X and Y was 2.64 (95% CI, 1.13-6.14) and 0.45 (95% CI, 0.28-0.76), respectively.
Chemotherapy-responsive disease and nonscalp, soft tissue spread might represent distinct clinical syndromes within KRAS-mutant NSCLC. The molecular biology underlying this heterogeneity warrants future studies.
非小细胞肺癌（NSCLC）中 KRAS 特异性治疗方法的失败可能反映了潜在的疾病异质性。我们试图在晚期 KRAS 突变 NSCLC 中定义临床“综合征”，以改善未来的临床试验并为未来的分子开发创建临床框架。
为了检验关于 KRAS 突变 NSCLC 临床综合征的一系列先验假设，我们进行了一项多机构回顾性病历审查。使用 Kaplan-Meier 模型估计生存概率。使用对数秩检验评估组间差异。使用多变量 Cox 回归分析和 Wilcoxon 秩和检验评估无进展生存期和总生存期（OS）差异。
在 218 例晚期 KRAS 突变 NSCLC 患者中，一线化疗的 OS 和无进展生存期不因胸内与胸外播散、吸烟强度或特定 KRAS 突变而不同。诊断时转移性疾病的 OS 明显差于复发性、不可切除疾病（中位 OS，14.6 与 40.9 个月；P=.001）。在诊断时患有转移性疾病的患者中，非头皮、软组织转移（综合征 X；占病例的 6%；95%置信区间 [CI]，2.5%-10.1%）预示预后不良（中位 OS，7.5 与对照组的 15.9 个月；P=.021）。一线化疗的反应（综合征 Y；占病例的 41%；95%CI，32.3%-50.6%）预示着良好的预后（中位 OS，26.7 与 11.9 个月；P=.002）。这两种综合征之间的重叠很小（111 例中有 2 例）。多变量分析证实了这些观察结果。综合征 X 和 Y 的死亡风险比分别为 2.64（95%CI，1.13-6.14）和 0.45（95%CI，0.28-0.76）。
化疗反应性疾病和非头皮、软组织播散可能代表 KRAS 突变 NSCLC 中的不同临床综合征。这种异质性的分子生物学值得进一步研究。
