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.

BACKGROUND 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. METHODS 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. RESULTS 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%). CONCLUSION 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. IMPLICATIONS FOR PRACTICE 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.

[1]  R. Wu,et al.  Broad, hybrid capture-based next generation sequencing identified actionable genomic alterations in HER2-negative breast cancer. , 2016 .

[2]  P. Stephens,et al.  Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing , 2016, Clinical Cancer Research.

[3]  Manish B. Patel,et al.  Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[4]  Sanjay Goel,et al.  RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors. , 2015, Cancer discovery.

[5]  Kai Wang,et al.  The distribution of BRAF gene fusions in solid tumors and response to targeted therapy , 2015, International journal of cancer.

[6]  P. Stephens,et al.  Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI. , 2015, Lung cancer.

[7]  Mikin V Patel,et al.  Core Lung Biopsy for Biomarker Analysis: Is There Increased Risk Compared With Conventional Biopsy? , 2015, Journal of thoracic imaging.

[8]  Mark Rosenzweig,et al.  Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. , 2015, Cancer discovery.

[9]  N. Schultz,et al.  Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. , 2015, Cancer discovery.

[10]  Donavan T. Cheng,et al.  Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. , 2015, The Journal of molecular diagnostics : JMD.

[11]  M. Ladanyi,et al.  Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[12]  J. Spicer,et al.  LBA2_PREGFR MUTATION TESTING AND ONCOLOGIST TREATMENT CHOICE IN ADVANCED NSCLC: GLOBAL TRENDS AND DIFFERENCES , 2015 .

[13]  S. Fox,et al.  Molecular methods for somatic mutation testing in lung adenocarcinoma: EGFR and beyond. , 2015, Translational lung cancer research.

[14]  K. Arnaoutakis.  Crizotinib in ROS1-rearranged non-small-cell lung cancer. , 2015, The New England journal of medicine.

[15]  M. Ladanyi,et al.  Broad, Hybrid Capture–Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches , 2015, Clinical Cancer Research.

[16]  P. Stephens,et al.  Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib. , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[17]  Jeffrey W. Clark,et al.  Crizotinib in ROS1-rearranged non-small-cell lung cancer. , 2014, The New England journal of medicine.

[18]  Mari Mino-Kenudson,et al.  Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cance , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  A. Iafrate,et al.  Two Novel ALK Mutations Mediate Acquired Resistance to the Next-Generation ALK Inhibitor Alectinib , 2014, Clinical Cancer Research.

[20]  Steven J. M. Jones,et al.  Comprehensive molecular profiling of lung adenocarcinoma , 2014, Nature.

[21]  R. Maxfield,et al.  Molecular testing guidelines for lung adenocarcinoma: Utility of cell blocks and concordance between fine-needle aspiration cytology and histology samples , 2014, CytoJournal.

[22]  A. Iafrate,et al.  Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). , 2014 .

[23]  R. Yelensky,et al.  Identifying ALK rearrangements that are not detected by FISH with targeted next-generation sequencing of lung carcinoma. , 2014 .

[24]  Makoto Nishio,et al.  The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. , 2014, Cancer discovery.

[25]  I. Petersen,et al.  CD74-NRG1 fusions in lung adenocarcinoma. , 2014, Cancer discovery.

[26]  L. Yarmus,et al.  Optimizing endobronchial ultrasound for molecular analysis. How many passes are needed? , 2013, Annals of the American Thoracic Society.

[27]  P. Stephens,et al.  Clinical next‐generation sequencing successfully applied to fine‐needle aspirations of pulmonary and pancreatic neoplasms , 2013, Cancer cytopathology.

[28]  Alex M. Fichtenholtz,et al.  Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing , 2013, Nature Biotechnology.

[29]  L. Garraway,et al.  Oncogenic and drug sensitive NTRK1 rearrangements in lung cancer , 2013, Nature Medicine.

[30]  Robert Brian Jenkins,et al.  Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[31]  S. Peters,et al.  Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Lu Wang,et al.  Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. , 2013, Cancer discovery.

[33]  G. Giaccone,et al.  Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. , 2013, Archives of pathology & laboratory medicine.

[34]  C. Rudin,et al.  Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients. , 2013 .

[35]  S. Aebi,et al.  A patient with BRAF V600E lung adenocarcinoma responding to vemurafenib. , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[36]  Ronglai Shen,et al.  Molecular Epidemiology of EGFR and KRAS Mutations in 3,026 Lung Adenocarcinomas: Higher Susceptibility of Women to Smoking-Related KRAS-Mutant Cancers , 2012, Clinical Cancer Research.

[37]  Dara L Aisner,et al.  Molecular pathology of non-small cell lung cancer: a practical guide. , 2012, American journal of clinical pathology.

[38]  M. Ladanyi,et al.  Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine Kinase Mutations in Lung Adenocarcinomas , 2012, Clinical Cancer Research.

[39]  William Pao,et al.  Lung Adenocarcinomas with HER2-Activating Mutations Are Associated with Distinct Clinical Features and HER2/EGFR Copy Number Gains , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[40]  Jeffrey W. Clark,et al.  Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[41]  W. Travis,et al.  Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing. , 2011, Seminars in respiratory and critical care medicine.

[42]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[43]  Young Lim Choi,et al.  EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. , 2010, The New England journal of medicine.

[44]  Sreenath V. Sharma,et al.  ErbBs in lung cancer. , 2009, Experimental cell research.

[45]  F. Cappuzzo,et al.  HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. , 2006, The New England journal of medicine.

[46]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[47]  R. Pazdur,et al.  Next-Generation Sequencing in Oncology in the Era of Precision Medicine. , 2016, JAMA oncology.

[48]  Jeffrey W. Clark,et al.  Crizotinib in ROS 1-Rearranged Non – Small-Cell Lung Cancer , 2014 .