First-line Chemotherapy Responsiveness and Patterns of Metastatic Spread Identify Clinical Syndromes Present Within Advanced KRAS Mutant Non–Small-cell Lung Cancer With Different Prognostic Significance

Wade T. Iams, Hui Yu, Yu Shyr, Tejas Patil, Leora Horn, Caroline McCoach, Karen Kelly, Robert C. Doebele, D. Ross Camidge

Research output: Contribution to journalArticle


Background: 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. Patients and Methods: 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. Results: 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. Conclusion: 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. In the present multicenter study, we performed a retrospective medical record review of 218 patients. We identified 2 distinct clinical cohorts with KRAS mutant, recurrent, metastatic or de novo metastatic non–small-cell lung cancer: patients with nonscalp, soft tissue metastases with a uniquely poor prognosis and patients with disease responsive to first-line chemotherapy with a uniquely good prognosis. A deeper molecular understanding of these cohorts is needed.

Original languageEnglish (US)
Pages (from-to)531-543
Number of pages13
JournalClinical Lung Cancer
Issue number6
StatePublished - Nov 1 2018



  • Chemotherapy-responsive
  • KRAS clinical syndromes
  • Metastatic
  • Soft tissue metastasis

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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