170O - Prognostic and predictive values of KRAS in EGFR-based subgroups and combined with p53 in completely resected non-small cell lung cancer (NSCLC): a...

Date 29 September 2012
Event ESMO Congress 2012
Session Biomarkers in lung cancer
Topics Biomarkers
Non-Small-Cell Lung Cancer, Early Stage
Presenter Pasi Janne
Authors P.A. Janne1, F.A. Shepherd2, C. Domerg3, G. Le Teuff3, R. Kratzke4, P. Hainaut5, J. Pignon3, R. Rosell6, J. Soria7, M. Tsao8
  • 1Lowe Center For Thoracic Oncology, Dana Farber Cancer Institute, Boston/US
  • 2Department Of Medicine, Princess Margaret Hospital, Toronto/CA
  • 3Oncology, Institut de Cancerologie Gustave-Roussy, Villejuif/FR
  • 4Oncology, University of Minnesota, Minneapolis/US
  • 5International Prevention Research Institute, 69006 - Lyon/FR
  • 6Medical Oncology Service, Catalan Institute of Oncology ICO Badalona Hospital Germans Trias i Pujol, Medical Oncology, 08916 - Badalona/ES
  • 7Dept. Of Medicine, Institut de Cancérologie Gustave Roussy, 94805 - Villejuif CEDEX/FR
  • 8Pathology Department, Princess Margaret Hospital, University Health Network, Toronto/CA

 

Abstract

Background

We reported previously that KRAS is neither significantly prognostic nor predictive of benefit from adjuvant chemotherapy (ACT) in NSCLC (Shepherd et al. Proc ASCO 2012). P53 and EGFR mutations are also detected in NSCLC and P53 mutations can occur concurrently with KRAS mutations. We undertook to evaluate the prognostic and predictive effect of (i) KRAS in EGFR Wild-Type (WT) Adenocarcinoma (ADC) patients (pts) and (ii) KRAS combined with P53.

Methods

Analysis included IALT, JBR10, CALGB-9633 and ANITA trials. KRAS, P53 and EGFR mutations (exons 19 and 21) were determined in blinded fashion in 3 laboratories by direct sequencing. KRAS (WT/Mut) and P53 (WT/Mut) were combined in 4 groups with WT/WT as reference group. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the multivariable Cox model stratified by trial and adjusted on covariates, for Overall (OS) and Disease-Free Survival (DFS).

Results

Among 1543 pts (605 ADC, 938 non-ADC) with documented KRAS genotype, EGFR was available in 485/605 ADC (12% of mutations) and P53 in 1181/1543 (36% of mutations). In EGFR-WT ADC pts (n = 426), KRAS mutation, detected in 40%, was neither predictive (p = 0.96) nor prognostic in the observation group (OBS) (p = 0.65). In pts with KRAS and P53 status, 16% had only KRAS Mut, 32% P53 Mut only and 4% had both. Among pts with KRAS/P53 mutations, OS was worse in the ACT group (HR ACT vs. OBS 2.49; 95%CI 1.10-5.66, p = 0.03) but not in pts with either mutation alone: KRASMut/P53WT HR = 0.73 (0.47-1.13) KRASWT/P53Mut HR = 0.97 (0.73-1.29) and WT/WT HR = 0.82 (0.64-1.06). No significant heterogeneity among these 4 HRs (p = 0.06) was observed but there was a significant difference when comparing only WT/WT and Mut/Mut groups (p = 0.01). The prognostic value of this combination was not significant in the OBS group (p = 0.57). Results were similar for DFS.

Conclusions

Patients with both KRAS and P53 mutations have significantly worse outcome with ACT compared to those with WT/WT tumors. Further studies are needed to understand the biologic basis for this. Supported by unrestricted grants from Sanofi Aventis and LNCC.

Disclosure

J. Pignon: unrestricted research grant from Roche for a meta-analysis on bevacizumab in advanced NSCLC.

All other authors have declared no conflicts of interest.