L V Sequist1, R S Heist2, A T Shaw2, P Fidias2, R Rosovsky3, J S Temel2, I T Lennes2, S Digumarthy4, B A Waltman5, E Bast6, S Tammireddy6, L Morrissey6, A Muzikansky7, S B Goldberg2, J Gainor8, C L Channick9, J C Wain10, H Gaissert10, D M Donahue10, A Muniappan10, C Wright10, H Willers11, D J Mathisen10, N C Choi11, J Baselga2, T J Lynch12, L W Ellisen2, M Mino-Kenudson13, M Lanuti10, D R Borger2, A J Iafrate13, J A Engelman2, D Dias-Santagata13. 1. Massachusetts General Hospital Cancer Center, Boston; Harvard Medical School, Boston. Electronic address: lvsequist@partners.org. 2. Massachusetts General Hospital Cancer Center, Boston; Harvard Medical School, Boston. 3. Massachusetts General Hospital Cancer Center, Boston; Harvard Medical School, Boston; The Mass General/North Shore Cancer Center, Danvers. 4. Harvard Medical School, Boston; Department of Radiology. 5. Harvard Medical School, Boston. 6. Massachusetts General Hospital Cancer Center, Boston. 7. Harvard Medical School, Boston; Department of Biostatistics. 8. Harvard Medical School, Boston; Department of Medicine. 9. Harvard Medical School, Boston; Division of Pulmonary and Critical Care Medicine. 10. Harvard Medical School, Boston; Division of Thoracic Surgery. 11. Harvard Medical School, Boston; Department of Radiation Oncology, Massachusetts General Hospital, Boston. 12. Yale University School of Medicine and Yale Cancer Center, New Haven. 13. Harvard Medical School, Boston; Department of Pathology, Massachusetts General Hospital, Boston, USA.
Abstract
BACKGROUND: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.
BACKGROUND: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.
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