KRAS is not a significant prognostic marker in patients with resected NSCLC,... and at this time, it cannot be recommended as a tool to select patients for adjuvant chemotherapy.
—Frances A. Shepherd, MD, FRCPC, and colleagues
KRAS mutations have been reported in approximately 30% of lung adenocarcinomas. They occur most frequently in codons 12 and 13 in non–small cell lung cancer (NSCLC), and are most common in cancer in smokers and in nonsquamous NSCLC. Some data suggest that KRAS mutation is associated with poorer outcome in NSCLC. In an analysis of pooled data from NSCLC adjuvant therapy trials reported in Journal of Clinical Oncology, Frances A. Shepherd, MD, FRCPC, Professor of Medicine at the University of Toronto and Princess Margaret Cancer Centre, Toronto, Ontario, and colleagues found that, overall, KRAS mutation status was not significantly associated with overall prognosis or predictive of differential effects of adjuvant chemotherapy versus observation.1
Nevertheless, their findings did suggest a detrimental effect of chemotherapy in patients with codon 13 mutations and increased risk of secondary tumors in patients with KRAS mutations not receiving adjuvant therapy.
The analysis included patients from four randomized trials of adjuvant therapy vs observation in NSCLC patients: three Lung Adjuvant Cisplatin Evaluation (LACE) trials—consisting of IALT (stage IB-II disease), ANITA (stage IB-IIIA), and JBR.10 (stage IB-II)—evaluating cisplatin-based therapy and the Cancer and Leukemia Group B (CALGB) 9633 trial (stage IB) evaluating carboplatin-based therapy. In total, the analysis included 1,543 patients, of whom 780 received adjuvant chemotherapy and 763 received observation.
KRAS mutations were found in 300 patients (19%). On univariate analysis, mutations were significantly more common in female patients, in younger patients, and in those with adenocarcinomas (34% vs 6% for squamous carcinomas and 23% for other nonadenocarcinomas). On multivariate analysis, only younger age and histology continued to be significantly associated with mutation.
Mutations were found at codon 12 in 275 patients (92%), codon 13 in 24, and codon 14 in 1. The most frequent alteration was a G>T transversion, found in 223 patients. Mutations were found in 11 of 68 lifetime nonsmokers (codon 12 mutations in 10). The G>T transversion, considered to be the characteristic mutation from tobacco smoke exposure, accounted for 78% of codon 12 mutations in smokers (75/134) and 50% in nonsmokers (5/10).
Effect of Mutation Status
After a median of 5.5 years of follow-up and accounting for effects of baseline characteristics in multivariate analyses, the presence of KRAS mutation vs wild-type KRAS was not associated with a significant effect on overall survival among all patients (hazard ratio [HR] = 1.17, P = .12; no significant heterogeneity among trials, P = .47), the observation group (HR = 1.04, P = .79), or patients with adenocarcinoma (HR = 1.00, P = .97). Outcomes were similar for disease-free survival on these analyses.
Trends toward worse overall survival in patients with KRAS mutations were observed in the subgroup with squamous carcinomas (HR = 1.41, 95% confidence interval [CI] = 0.89–2.23) and the subgroup with other nonadenocarcinomas (HR = 1.86, 95% CI = 1.22–2.82). Analyses by KRAS mutation subtypes vs wild-type KRAS showed no differences for codon 12 mutations, codon 13 mutations, or codon 12 mutation subgroups.
Mutation Status and Therapy
There was no significant difference in risk for death in patients receiving adjuvant chemotherapy vs patients receiving observation among those with wild-type KRAS (HR = 0.89, P = .15) or mutant KRAS (HR = 1.05, P = .77; P = .37 for interaction; P = .52 for heterogeneity among trials). There was also no difference in risk when the analysis was restricted to patients with adenocarcinoma (HR = 0.88, P = .37, for wild type; HR = 0.92, P = .67, for mutant; P = .86 for interaction). Results were similar for disease-free survival.
There was no significant difference in overall survival between chemotherapy and observation subgroups with codon 12 KRAS mutations (HR = 0.95, P = .77). However, adjuvant therapy was associated with significantly increased risk of death compared with observation in the subgroup of patients with codon 13 mutations (HR = 5.78, P < .001; P = .002 for interaction). Although differences were not significant, hazard ratios for chemotherapy vs observation varied according to G12A or G12R (HR = 0.66, P = .48), G12C or G12V (HR = 0.94, P = .77), and G12D or G12S (HR 1.39, P = .49) subtypes of codon 12 mutation.
Risk of Second Cancers
Second primary cancers were identified in 86 of 1,433 patients (data were not available from the ANITA trial). KRAS mutation was associated with a significantly increased risk of a second primary cancer among observation patients (HR = 2.76, P = .005), whereas chemotherapy patients with KRAS mutations had a nonsignificantly reduced risk (HR = 0.66, P = .40; P = .02 for interaction).
The investigators noted that the finding of significantly increased risk of death in patients with codon 13 mutations who received adjuvant therapy needs to be interpreted with caution and validated in other studies, given the small number of patients (24) with codon 13 mutations in the current analysis. They also noted that the finding of reduced risk for second cancers in chemotherapy patients with KRAS mutations was unexpected. The investigators theorized that chemotherapy may have had a therapeutic effect on subclinical deposits of KRAS mutant cells in lung or other organs.
The investigators concluded:
KRAS is not a significant prognostic marker in patients with resected NSCLC. Overall, it is not significantly predictive of a differential benefit from adjuvant chemotherapy, particularly in patients with adenocarcinoma, and at this time, it cannot be recommended as a tool to select patients for adjuvant chemotherapy. Although our results suggest a potentially detrimental effect from chemotherapy in patients with codon 13 mutations, validation studies will be critical. ■
Disclosure: Dr. Shepherd reported no potential conflicts of interest.
1. Shepherd FA, Domerg C, Hainaut P, et al: Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol. April 29, 2013 (early release online).