In response
We appreciate the comments made by Dr. Egber Smit and collaborators to our article on KRAS codon variants as prognostic markers in resected lung adenocarcinoma.1 In our manuscript, we performed a multivariate analysis comparing KRAS-G12C and nonG12C versus KRAS wild-type, as shown in the Supplementary Table S4, but we agree with Dr. Smit that we did not present the multivariate analysis comparing KRAS-G12C with the other KRAS codon variants. Here, we show the results from the multivariate Cox analysis for overall survival according to KRAS amino acid substitution using each subtype of KRAS-nonG12C as a reference: G12D vs. G12C, HR = 2.81 (1.07 – 7.36, p = 0.035); G12A vs. G12C, HR = 5.99 (1.39 – 25.7, p = 0.016); G12V vs. G12C, HR = 1.62 (0.70 – 3.76, p = 0.259). These data indicate that the patients harboring KRAS-G12C mutations have significantly worse overall survival as compared with KRAS-G12D and KRAS-G12A, but not with KRAS-G12V mutations. In keeping with this, Ihle et al. reported that patients whose tumors had KRAS-G12C or KRAS-G12V mutations also had significantly worse progression-free survival as compared with patients whose tumors had other KRAS codon variants or wild-type KRAS, albeit in metastatic NSCLC.2
We did not systematically assess the EGFR mutation status in early-stage lung adenocarcinoma patients, but these data were available in a subset of patients included in this study. Among the patients whose tumors had wild-type KRAS (n = 94), 9 patients (10%) harbored an EGFR mutation, 48 were EGFR wild-type and in 37 patients the EGFR status was unknown. When the 9 patients harboring an EGFR mutation were excluded from survival analysis, KRAS mutation and KRAS-G12C remained an independent predictor of poor outcome.
We indicated in the discussion of our manuscript that the prognostic value of KRAS mutation status in NSCLC remains controversial. Although effective therapies targeting KRAS represent an unmet crucial need, we consider that it is relevant to distinguish among the distinct KRAS codon variants that may in the future, have important biological and therapeutic implications for patients with surgically-resected lung adenocarcinoma.
Sincerely,
Ernest Nadal, MD
David G. Beer, PhD
Nithya Ramnath, MD
References
- 1.Nadal E, Chen G, Prensner JR, et al. KRAS-G12C Mutation Is Associated with Poor Outcome in Surgically Resected Lung Adenocarcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2014 doi: 10.1097/JTO.0000000000000305. [DOI] [PubMed] [Google Scholar]
- 2.Ihle NT, Byers LA, Kim ES, et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst. 2012;104:228–239. doi: 10.1093/jnci/djr523. [DOI] [PMC free article] [PubMed] [Google Scholar]