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Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.

ABSTRACT: A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/?-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.

SUBMITTER: Blakely CM

PROVIDER: S-EPMC5709185 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.

Blakely Collin M CM Watkins Thomas B K TBK Wu Wei W Gini Beatrice B Chabon Jacob J JJ McCoach Caroline E CE McGranahan Nicholas N Wilson Gareth A GA Birkbak Nicolai J NJ Olivas Victor R VR Rotow Julia J Maynard Ashley A Wang Victoria V Gubens Matthew A MA Banks Kimberly C KC Lanman Richard B RB Caulin Aleah F AF St John John J Cordero Anibal R AR Giannikopoulos Petros P Simmons Andrew D AD Mack Philip C PC Gandara David R DR Husain Hatim H Doebele Robert C RC Riess Jonathan W JW Diehn Maximilian M Swanton Charles C Bivona Trever G TG

Nature genetics 20171106 12

A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified crit ...[more]

PMID: 29106415

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Project description:IntroductionPreferred first-line treatment for patients with metastatic EGFR-mutant lung cancer is osimertinib, yet it is not known whether patient outcomes may be improved by identifying and intervening on molecular markers associated with therapeutic resistance.MethodsAll patients with metastatic EGFR-mutant lung cancer treated with first-line osimertinib at the Memorial Sloan Kettering Cancer Center (n = 327) were identified. Available pretreatment and postprogression tumor samples underwent targeted gene panel sequencing and mutational signature analysis using SigMA algorithm. Progression-free survival (PFS) and overall survival were estimated using the Kaplan-Meier method.ResultsUsing multivariate analysis, baseline atypical EGFR (median PFS = 5.8 mo, p < 0.001) and concurrent TP53/RB1 alterations (median PFS = 10.5 mo, p = 0.015) were associated with shorter PFS on first-line osimertinib. Of 95 patients with postprogression biopsies, acquired resistance mechanisms were identified in 52% (off-target, n = 24; histologic transformation, n = 14; on-target, n = 12), with MET amplification (n = 9), small cell lung transformation (n = 7), and acquired EGFR amplification (n = 7), the most frequently identified mechanisms. Although there was no difference in postprogression survival on the basis of identified resistance (p = 0.07), patients with subsequent second-line therapy tailored to postprogression biopsy results had improved postprogression survival (hazard ratio = 0.09, p = 0.006). The paired postprogression tumors had higher tumor mutational burden (p = 0.008) and further dominant APOBEC mutational signatures (p = 0.07) compared with the pretreatment samples.ConclusionsPatients with EGFR-mutant lung cancer treated with first-line osimertinib have improved survival with treatment adaptation on the basis of identified mechanisms of resistance at time of progression using tissue-based genomic analysis. Further survival gains may be achieved using risk-based treatment adaptation of pretreatment genomic alterations.

Dataset Information

Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.

Publications

Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.

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