title: Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials.
abstract: The National Comprehensive Cancer Network (NCCN) guidelines for patients with metastatic non-small cell lung cancer (NSCLC) recommend testing for EGFR, BRAF, ERBB2, and MET mutations; ALK, ROS1, and RET rearrangements; and MET amplification. We investigated the feasibility and utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) test, in clinical practice.
  
  
  
  CGP was performed to a mean coverage depth of 576× on 6,832 consecutive cases of NSCLC (2012-2015). Genomic alterations (GAs) (point mutations, small indels, copy number changes, and rearrangements) involving EGFR, ALK, BRAF, ERBB2, MET, ROS1, RET, and KRAS were recorded. We also evaluated lung adenocarcinoma (AD) cases without GAs, involving these eight genes.
  
  
  
  The median age of the patients was 64 years (range: 13-88 years) and 53% were female. Among the patients studied, 4,876 (71%) harbored at least one GA involving EGFR (20%), ALK (4.1%), BRAF (5.7%), ERBB2 (6.0%), MET (5.6%), ROS1 (1.5%), RET (2.4%), or KRAS (32%). In the remaining cohort of lung AD without these known drivers, 273 cancer-related genes were altered in at least 0.1% of cases, including STK11 (21%), NF1 (13%), MYC (9.8%), RICTOR (6.4%), PIK3CA (5.4%), CDK4 (4.3%), CCND1 (4.0%), BRCA2 (2.5%), NRAS (2.3%), BRCA1 (1.7%), MAP2K1 (1.2%), HRAS (0.7%), NTRK1 (0.7%), and NTRK3 (0.2%).
  
  
  
  CGP is practical and facilitates implementation of the NCCN guidelines for NSCLC by enabling simultaneous detection of GAs involving all seven driver oncogenes and KRAS. Furthermore, without additional tissue use or cost, CGP identifies patients with "pan-negative" lung AD who may benefit from enrollment in mechanism-driven clinical trials.
  
  
  
  National Comprehensive Cancer Network guidelines for patients with metastatic non-small cell lung cancer (NSCLC) recommend testing for several genomic alterations (GAs). The feasibility and utility of comprehensive genomic profiling were studied in NSCLC and in lung adenocarcinoma (AD) without GAs. Of patients with NSCLC, 71% harbored at least one GA to a gene listed in the guidelines or KRAS; 273 cancer-related genes were altered in at least 0.1% of the AD cases. Although logistical and administrative hurdles limit the widespread use of next-generation sequencing, the data confirm the feasibility and potential utility of comprehensive genomic profiling in clinical practice.
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA jsuh@foundationmedicine.com.
authors.forename: James H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Albacker
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA Zhejiang Cancer Hospital, Hangzhou, People's Republic of China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Garrett
authors.initials: G
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Gay
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Vergilio
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000235:genetics; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010358:Patient Participation; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors
keywords: Clinical trials; Comprehensive genomic profiling; National Comprehensive Cancer Network guidelines; Non-small cell lung cancer