Pooled Analysis of the Prognostic and Predictive Effects of TP53 Comutation Status Combined With KRAS or EGFR Mutation in Early-Stage Resected Non-Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy

Abstract

Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non-small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.

Fig 1

Overall survival. Unadjusted Kaplan-Meier curves of the prognostic effect in the observation arm. (A) TP53/KRAS combination. (B) TP53/EGFR combination. MUT, mutant; WT, wild type.

Fig 2

Overall survival. Unadjusted Kaplan-Meier curves of treatment effect according to TP53 and KRAS mutation status. (A) Double wild type. (B) TP53 wild-type, KRAS mutant. (C) TP53 mutant, KRAS wild type. (D) Double mutant. ACT, adjuvant chemotherapy; OBS, observation.

Fig 3

Overall survival. Unadjusted Kaplan-Meier curves of treatment effect according to EGFR and TP53 mutation status, in adenocarcinoma. (A) Double wild type. (B) TP53 wild-type, EGFR mutant. (C) TP53 mutant, EGFR wild type. (D) Double mutant. ACT, adjuvant chemotherapy; OBS, observation.

Fig A1

Flowchart of patients entered in the four trials and included in the (TP53, KRAS) and (TP53, EGFR) analyses. NSCLC, non–small-cell lung cancer.

Fig A2

Disease-free survival. Unadjusted Kaplan-Meier curves of the prognostic effect in the observation arm. (A) TP53/KRAS combination. (B) TP53/EGFR combination. MUT, mutant; WT, wild type.

Fig A3

Disease-free survival - Unadjusted Kaplan-Meier curves of treatment effect according to TP53 and KRAS mutation status. (A) Double wild type. (B) TP53 wild-type, KRAS mutant. (C) TP53 mutant, KRAS wild type. (D) Double mutant. ACT, adjuvant chemotherapy; OBS, observation.

Fig A4

Disease-free survival - Unadjusted Kaplan-Meier curves of treatment effect according to TP53 and EGFR mutation status. (A) Double wild type. (B) TP53 wild-type, EGFR mutant. (C) TP53 mutant, EGFR wild type. (D) Double mutant. ACT, adjuvant chemotherapy; OBS, observation.

Fig A5

Subgroup analyses. Flowchart of patients with adenocarcinoma entered in three trials and with KRAS and EGFR available mutation status.