Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed t...

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Bibliographic Details
Published in:	Nature genetics Vol. 51; no. 2; pp. 202 - 206
Main Authors:	Samstein, Robert M., Lee, Chung-Han, Shoushtari, Alexander N., Hellmann, Matthew D., Shen, Ronglai, Janjigian, Yelena Y., Barron, David A., Zehir, Ahmet, Jordan, Emmet J., Omuro, Antonio, Kaley, Thomas J., Kendall, Sviatoslav M., Motzer, Robert J., Hakimi, A. Ari, Voss, Martin H., Russo, Paul, Rosenberg, Jonathan, Iyer, Gopa, Bochner, Bernard H., Bajorin, Dean F., Al-Ahmadie, Hikmat A., Chaft, Jamie E., Rudin, Charles M., Riely, Gregory J., Baxi, Shrujal, Ho, Alan L., Wong, Richard J., Pfister, David G., Wolchok, Jedd D., Barker, Christopher A., Gutin, Philip H., Brennan, Cameron W., Tabar, Viviane, Mellinghoff, Ingo K., DeAngelis, Lisa M., Ariyan, Charlotte E., Lee, Nancy, Tap, William D., Gounder, Mrinal M., D’Angelo, Sandra P., Saltz, Leonard, Stadler, Zsofia K., Scher, Howard I., Baselga, Jose, Razavi, Pedram, Klebanoff, Christopher A., Yaeger, Rona, Segal, Neil H., Ku, Geoffrey Y., DeMatteo, Ronald P., Ladanyi, Marc, Rizvi, Naiyer A., Berger, Michael F., Riaz, Nadeem, Solit, David B., Chan, Timothy A., Morris, Luc G. T.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.02.2019 Nature Publishing Group
Subjects:	45/23 631/208/248 631/250/251 631/67/580 Agriculture Animal Genetics and Genomics Antineoplastic Agents - immunology Biological markers Biomarkers Biomedical and Life Sciences Biomedicine Cancer Cancer metastasis Cancer patients Cancer Research Cancer therapies Cancer treatment Gene expression Gene Function Gene mutation High-Throughput Nucleotide Sequencing - methods Histology Human Genetics Humans Immune checkpoint inhibitors Immunotherapy Immunotherapy - methods Laboratories Letter Lung cancer Melanoma Metastases Metastasis Mutation Mutation - genetics Neoplasms - genetics Neoplasms - immunology Neoplasms - therapy Next-generation sequencing Patients Survival Tumor Burden - genetics Tumor Burden - immunology Tumors
ISSN:	1061-4036, 1546-1718, 1546-1718
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Summary:	Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB. Analysis of advanced cancer patients treated with immune-checkpoint inhibitors shows that tumor mutational burden, as assessed by targeted next-generation sequencing, predicts survival after immunotherapy across multiple cancer types.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Co-senior authors: LGTM, NR, DBS, TAC RMS, RS, LGTM performed the analyses. CHL, ANS, MDH, YYJ, DAB, SMK, EJJ provided clinical annotations. AZ, MFB, DBS, ML, JB established the assays and coordinated data collection. CHL, ANS, MDH, YYJ, RJM, GJR, CAB, SB, PR, HAA, JR, DFB,AAH,BHB, MHV, CMR, HIS, ALH, DGP, NL, RJW, VT ,PHG, CB, LMD,IKM, JEC, RY, NHS, RPD, LS, JDW, CEA, ZKS, WDT, MMT,NAR, SD, JB, PR, GYK, DBS contributed to sample acquisition and patient recruitment. LGTM, DS, NR and TAC supervised the study. LGTM, TAC, CHL, ANS, MDH,and RMS wrote the manuscript with contributions from all authors. Author Contributions
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-018-0312-8