Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice
L. V. Sequist1,2,*, R. S. Heist1,2, A. T. Shaw1,2, P. Fidias1,2, R. Rosovsky1,2,3, J. S. Temel1,2, I. T. Lennes1,2, S. Digumarthy2,4, B. A. Waltman2, E. Bast1, S. Tammireddy1, L. Morrissey1, A. Muzikansky2,5, S. B. Goldberg1,2, J. Gainor2,6, C. L. Channick2,7, J. C. Wain2,8, H. Gaissert2,8, D. M. Donahue2,8, A. Muniappan2,8, C. Wright2,8, H. Willers2,9, D. J. Mathisen2,8, N. C. Choi2,9, J. Baselga1,2, T. J. Lynch10, L. W. Ellisen1,2, M. Mino-Kenudson2,11, M. Lanuti2,8, D. R. Borger1,2, A. J. Iafrate2,11, J. A. Engelman1,2 and D. Dias-Santagata2,11
+ Author Affiliations
1Massachusetts General Hospital Cancer Center, Boston
2Harvard Medical School, Boston
3The Mass General/North Shore Cancer Center, Danvers
4Department of Radiology
5Department of Biostatistics
6Department of Medicine
7Division of Pulmonary and Critical Care Medicine
8Division of Thoracic Surgery
9Department of Radiation Oncology, Massachusetts General Hospital, Boston
10Yale University School of Medicine and Yale Cancer Center, New Haven
11Department of Pathology, Massachusetts General Hospital, Boston, USA
↵*Correspondence to: Dr L. V. Sequist, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Professional Office Building room 212, Boston, MA 02114, USA. Tel: +1-617-726-7812; Fax: +1-617-724-3166; E-mail: lvsequist@partners.org and Dr Dora Dias-Santagata, Translational Research Laboratory, Massachusetts General Hospital, 55 Fruit Street, Jackson 1028, Boston, MA 02114, USA. Tel: +1-617-724-1261; Fax: +1-617-726-6974; E-mail: ddiassantagata@partners.org
Received August 14, 2011.
Revision received September 17, 2011.
Accepted September 26, 2011.
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.
Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice