Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies.
Tumor genetic testing is standard of care for patients with advanced lung adenocarcinoma, but the fraction of patients who derive clinical benefit remains undefined. Here, we report the experience of 860 patients with metastatic lung adenocarcinoma analyzed prospectively for mutations in >300 cancer-associated genes. Potentially actionable genetic events were stratified into one of four levels based upon published clinical or laboratory evidence that the mutation in question confers increased sensitivity to standard or investigational therapies. Overall, 37.1% (319/860) of patients received a matched therapy guided by their tumor molecular profile. Excluding alterations associated with standard-of-care therapy, 14.4% (69/478) received matched therapy, with a clinical benefit of 52%. Use of matched therapy was strongly influenced by the level of preexistent clinical evidence that the mutation identified predicts for drug response. Analysis of genes mutated significantly more often in tumors without known actionable mutations nominatedSTK11andKEAP1as possible targetable mitogenic drivers.Significance:An increasing number of therapies that target molecular alterations required for tumor maintenance and progression have demonstrated clinical activity in patients with lung adenocarcinoma. The data reported here suggest that broader, early testing for molecular alterations that have not yet been recognized as standard-of-care predictive biomarkers of drug response could accelerate the development of targeted agents for rare mutational events and could result in improved clinical outcomes.Cancer Discov; 7(6); 596-609. ©2017 AACR.See related commentary by Liu et al., p. 555This article is highlighted in the In This Issue feature, p. 539.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Emmet J
EJ
Jordan
Department of Pathology, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Hyunjae R
HR
Kim
Department of Pathology, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Maria E
ME
Arcila
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
David
D
Barron
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Debyani
D
Chakravarty
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
JianJiong
J
Gao
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Matthew T
MT
Chang
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Andy
A
Ni
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Ritika
R
Kundra
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Philip
P
Jonsson
Department of Pathology, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Gowtham
G
Jayakumaran
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Sizhi Paul
SP
Gao
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Hannah C
HC
Johnsen
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Aphrothiti J
AJ
Hanrahan
Department of Pathology, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Ahmet
A
Zehir
Department of Pathology, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Natasha
N
Rekhtman
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Michelle S
MS
Ginsberg
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York.
Bob T
BT
Li
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York.
Helena A
HA
Yu
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York.
Paul K
PK
Paik
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York.
Alexander
A
Drilon
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York.
Matthew D
MD
Hellmann
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Dalicia N
DN
Reales
Department of Pathology, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Ryma
R
Benayed
Department of Surgery, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Valerie W
VW
Rusch
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York.
Mark G
MG
Kris
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York.
Jamie E
JE
Chaft
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
José
J
Baselga
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Barry S
BS
Taylor
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Nikolaus
N
Schultz
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York.
Charles M
CM
Rudin
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
David M
DM
Hyman
Department of Pathology, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Michael F
MF
Berger
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
David B
DB
Solit
Department of Pathology, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Marc
M
Ladanyi
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, New York, New York. rielyg@mskcc.org.
Gregory J
GJ
Riely
D000230:Adenocarcinoma / Q000235:genetics* / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D055815:Young Adult
D014408:Biomarkers, Tumor