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Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies
Open accessPublished version of a preprint
Abstract
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 nominated STK11 and KEAP1 as 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. 555. This article is highlighted in the In This Issue feature, p. 539
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In the citing paper
“Inactivating mutations or loss of STK11/LKB1, which define one of the major genomic sub-groups of KRAS-mutant lung cancers1,19,62, are of particular interest because they are associated with decreased responsiveness to immune checkpoint blockade9,63 and poor overall prognosis64.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [62]
Experimental — accuracy not yet measuredIn the citing paper
“KRAS mutations predominate in NSCLCs, accounting for ~78% of all RAS mutations found in such tumours17. The activating missense KRAS mutations that occur in ~25% of NSCLCs19–23 are typically mutually exclusive with other clinically actionable driver mutations, such as those in EGFR, BRAF and ALK24.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [21]
In the citing paper
“Importantly, large-scale profiling studies utilizing either whole exome sequencing or broad targeted sequencing panels in NSCLC tumors have revealed multiple non-random patterns of co-occurring or mutually exclusive mutations, which typically vary depending on the particular oncogenic driver mutation15, 34, 58–62.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [59]
In the citing paper
“Somatic mutations in LKB1 and KEAP1 significantly co-occur with mutant KRAS and with each other in NSCLC15, 59, 63, 91.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [59]
In the citing paper
“Landmark large scale sequencing studies have established a census of major KRAS co-mutations in both early-stage and advanced LUAD15, 34, 59, 62.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [59]
In the citing paper
“Activating mutations in KRAS are the most prevalent oncogenic driver event in both early-stage and metastatic LUAD, occurring in 25–32% of tumors34, 59, 60, 62, 67.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [59]
In the citing paper
“Although EGFR –mutant tumors represent the prototypical oncogene-addicted LUAD subgroup that spearheaded adoption of the single-driver model, the overwhelming majority of EGFR-mutant lung tumors harbor one or more co-mutations, even when the analysis is limited to pre-defined sets of cancer-relevant genes within established panels (FoundationOne, Guardant360, MSK-IMPACT)15, 59, 72, 73.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [59]
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Metadata
- Authors
- Jordan, E. J., Kim, H. R., Arcila, M. E., Barron, D., Chakravarty, D., Gao, J., Chang, M. T., Ni, A., Kundra, R., Jonsson, P., Jayakumaran, G., Gao, S. P., Johnsen, H. C., Hanrahan, A. J., Zehir, A., Rekhtman, N., Ginsberg, M. S., Li, B. T., Yu, H. A., Paik, P. K., Drilon, A., Hellmann, M. D., Reales, D. N., Benayed, R., Rusch, V. W., Kris, M. G., Chaft, J. E., Baselga, J., Taylor, B. S., Schultz, N., Rudin, C. M., Hyman, D. M., Berger, M. F., Solit, D. B., Ladanyi, M., & Riely, G. J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- 6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
- 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
- Corresponding author
- Riely, Gregory J.
- ORCID
- Jordan, Emmet J.
- Kim, Hyunjae R.
- Arcila, Maria E.
- Chakravarty, Debyani
- Gao, JianJiong
- Kundra, Ritika
- Jonsson, Philip
- Jayakumaran, Gowtham
- Zehir, Ahmet
- Rekhtman, Natasha
- Ginsberg, Michelle S.
- Li, Bob T.
- Yu, Helena A.
- Paik, Paul K.
- Drilon, Alexander
- Hellmann, Matthew D.
- Reales, Dalicia N.
- Benayed, Ryma
- Rusch, Valerie W.
- Kris, Mark G.
- Chaft, Jamie E.
- Taylor, Barry S.
- Schultz, Nikolaus
- Rudin, Charles M.
- Hyman, David M.
- Berger, Michael F.
- Solit, David B.
- Ladanyi, Marc
- Riely, Gregory J.
- Venue
- Cancer Discovery
- Published
- 2017-06-01
- Volume
- 7
- Issue
- 6
- Pages
- 596-609
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5482929
- OpenAlex
- W2603411876
- Cited by
- 643
- References
- 49
- Citations by year
- 2026: 30 · 2025: 40 · 2024: 65 · 2023: 99 · 2022: 94 · 2021: 101 · 2020: 79 · 2019: 65 · 2018: 55 · 2017: 12
- FWCI
- 47.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR002384)
- National Cancer Institute (P30CA008748)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- lung adenocarcinoma, metastatic lung cancer, actionable mutations, targeted therapy, predictive biomarkers, drug response, STK11, Keap1, clinical benefit, molecular profiling
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Adolescent, Adult, Aged, Female, Genetic Testing, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Biomarkers, Tumor, Young Adult, Molecular Targeted Therapy
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