The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations-The Lung Cancer Mutation Consortium (LCMC2)

Abstract

Purpose: Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas.Experimental Design: Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC.Results: The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1, or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR/ALK/ROS1, when compared with 75 never smokers with the same alterations. In addition, coexisting TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations.Conclusion: Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. Clin Cancer Res; 24(5); 1038-47. ©2017 AACR.

Figure 1.. Mutations and co-mutation plot in LCMC II.

A. Distribution of Oncogenic Drivers in Full Genotyping Cohort. The relative proportion of the various driver mutations are shown for the 423 subjects with complete testing for 12 genes. No AKT1 orMAP2K1 mutations were detected in this set. sEGFR = sensitizing EGFR mutation; oEGFR = other EGFR mutations; ALKr, RETr, and ROS1r denote rearrangements in the respective genes; METamp denotes amplification of MET; oBRAF denotes a mutation other than V600E; and doubletons denotes samples with two or more of the oncogenic drivers shown here. B. Co-mutation plot.Genetic and expression alterations in the 14 core genes plus key tumor suppressor genes in 154 lung adenocarcinomas with complete analysis. No AKT1 or MAP2K1 mutations were detected in this set. EGFR_S = sensitizing EGFR mutations; EGFR_O = other EGFR mutations; TP53_D = disruptive alterations; TP53_N = nondisruptive alterations. Prepared using http://www.cbioportal.org/oncoprinter.jsp#.

Figure 1.. Mutations and co-mutation plot in LCMC II.

A. Distribution of Oncogenic Drivers in Full Genotyping Cohort. The relative proportion of the various driver mutations are shown for the 423 subjects with complete testing for 12 genes. No AKT1 orMAP2K1 mutations were detected in this set. sEGFR = sensitizing EGFR mutation; oEGFR = other EGFR mutations; ALKr, RETr, and ROS1r denote rearrangements in the respective genes; METamp denotes amplification of MET; oBRAF denotes a mutation other than V600E; and doubletons denotes samples with two or more of the oncogenic drivers shown here. B. Co-mutation plot.Genetic and expression alterations in the 14 core genes plus key tumor suppressor genes in 154 lung adenocarcinomas with complete analysis. No AKT1 or MAP2K1 mutations were detected in this set. EGFR_S = sensitizing EGFR mutations; EGFR_O = other EGFR mutations; TP53_D = disruptive alterations; TP53_N = nondisruptive alterations. Prepared using http://www.cbioportal.org/oncoprinter.jsp#.

Figure 2.. Survival comparisons according to targeted therapy.

Survival curves for subjects with any of sEGFR, ERBB2, BRAF p.V600E (veBRAF), ALKr, ROS1r, RETr, or METamp alterations who received targeted therapy (Ttx), versus those with similar alterations who did not receive targeted therapy (No Ttx), versus those with no mutations in any of these genes.

Figure 3.. Survival comparisons according to presence or absence of TP53 mutation.

A. Comparison of survival among 60 subjects with sEGFR mutations with and without TP53 mutation. B. Comparison of survival among 49 subjects with sEGFR mutations with a disruptive TP53 versus those without any TP53 mutation. C. Comparison of survival among 83 subjects with sEGFR, ALKr, or ROS1r mutations with and without TP53 mutation. D. Comparison of survival among 71 subjects with sEGFR, ALKr, or ROS1r mutations with a disruptive TP53 versus those without any TP53 mutation.

Figure 4.. Survival comparisons among subjects with sEGFR, ALKr, or ROS1r mutations according to smoking status.

A. Survival of never smokers without sEGFR-ALKr-ROS1r mutation, or with sEGFR-ALKr-ROS1r mutation who received targeted therapy. B. Survival of former and current smokers without sEGFR-ALKr-ROS1r mutation, or with sEGFR-ALKr-ROS1r mutation who received targeted therapy.