D J McGrail1, P G Pilié2, N U Rashid3, L Voorwerk4, M Slagter5, M Kok6, E Jonasch2, M Khasraw7, A B Heimberger8, B Lim9, N T Ueno9, J K Litton9, R Ferrarotto10, J T Chang11, S L Moulder9, S-Y Lin12. 1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: djmcgrail@mdanderson.org. 2. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. 3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, USA. 4. Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 5. Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands. 6. Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 7. The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, USA. 8. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, USA. 9. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. 10. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. 11. Department of Integrative Biology and Pharmacology, The University of Texas Health Sciences Center at Houston, Houston, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. 12. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: sylin@mdanderson.org.
Abstract
BACKGROUND: High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. PATIENTS AND METHODS: Data from over 10 000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936). RESULTS: In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10-16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. CONCLUSIONS: Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.
BACKGROUND:High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. PATIENTS AND METHODS: Data from over 10 000 patienttumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936). RESULTS: In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10-16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. CONCLUSIONS: Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.
Authors: Aaron M Goodman; Shumei Kato; Lyudmila Bazhenova; Sandip P Patel; Garrett M Frampton; Vincent Miller; Philip J Stephens; Gregory A Daniels; Razelle Kurzrock Journal: Mol Cancer Ther Date: 2017-08-23 Impact factor: 6.261
Authors: Sumit K Subudhi; Luis Vence; Hao Zhao; Jorge Blando; Shalini S Yadav; Qing Xiong; Alexandre Reuben; Ana Aparicio; Paul G Corn; Brian F Chapin; Louis L Pisters; Patricia Troncoso; Rebecca Slack Tidwell; Peter Thall; Chang-Jiun Wu; Jianhua Zhang; Christopher L Logothetis; Andrew Futreal; James P Allison; Padmanee Sharma Journal: Sci Transl Med Date: 2020-04-01 Impact factor: 17.956
Authors: Lorenzo F Fanchi; Krijn K Dijkstra; José G Van den Berg; Emile E Voest; John B Haanen; Myriam Chalabi; Arend G Aalbers; Karolina Sikorska; Marta Lopez-Yurda; Cecile Grootscholten; Geerard L Beets; Petur Snaebjornsson; Monique Maas; Marjolijn Mertz; Vivien Veninga; Gergana Bounova; Annegien Broeks; Regina G Beets-Tan; Thomas R de Wijkerslooth; Anja U van Lent; Hendrik A Marsman; Elvira Nuijten; Niels F Kok; Maria Kuiper; Wieke H Verbeek; Marleen Kok; Monique E Van Leerdam; Ton N Schumacher Journal: Nat Med Date: 2020-04-06 Impact factor: 53.440
Authors: Sanjeev Mariathasan; Shannon J Turley; Dorothee Nickles; Alessandra Castiglioni; Kobe Yuen; Yulei Wang; Edward E Kadel; Hartmut Koeppen; Jillian L Astarita; Rafael Cubas; Suchit Jhunjhunwala; Romain Banchereau; Yagai Yang; Yinghui Guan; Cecile Chalouni; James Ziai; Yasin Şenbabaoğlu; Stephen Santoro; Daniel Sheinson; Jeffrey Hung; Jennifer M Giltnane; Andrew A Pierce; Kathryn Mesh; Steve Lianoglou; Johannes Riegler; Richard A D Carano; Pontus Eriksson; Mattias Höglund; Loan Somarriba; Daniel L Halligan; Michiel S van der Heijden; Yohann Loriot; Jonathan E Rosenberg; Lawrence Fong; Ira Mellman; Daniel S Chen; Marjorie Green; Christina Derleth; Gregg D Fine; Priti S Hegde; Richard Bourgon; Thomas Powles Journal: Nature Date: 2018-02-14 Impact factor: 49.962
Authors: Matthias Gromeier; Michael C Brown; Gao Zhang; Xiang Lin; Yeqing Chen; Zhi Wei; Nike Beaubier; Hai Yan; Yiping He; Annick Desjardins; James E Herndon; Frederick S Varn; Roel G Verhaak; Junfei Zhao; Dani P Bolognesi; Allan H Friedman; Henry S Friedman; Frances McSherry; Andrea M Muscat; Eric S Lipp; Smita K Nair; Mustafa Khasraw; Katherine B Peters; Dina Randazzo; John H Sampson; Roger E McLendon; Darell D Bigner; David M Ashley Journal: Nat Commun Date: 2021-01-13 Impact factor: 14.919
Authors: Roman M Chabanon; Mathieu Rouanne; Christopher J Lord; Jean-Charles Soria; Philippe Pasero; Sophie Postel-Vinay Journal: Nat Rev Cancer Date: 2021-08-10 Impact factor: 60.716
Authors: Coren A Milbury; James Creeden; Wai-Ki Yip; David L Smith; Varun Pattani; Kristi Maxwell; Bethany Sawchyn; Ole Gjoerup; Wei Meng; Joel Skoletsky; Alvin D Concepcion; Yanhua Tang; Xiaobo Bai; Ninad Dewal; Pei Ma; Shannon T Bailey; James Thornton; Dean C Pavlick; Garrett M Frampton; Daniel Lieber; Jared White; Christine Burns; Christine Vietz Journal: PLoS One Date: 2022-03-16 Impact factor: 3.240
Authors: Farhad Kosari; Maria Disselhorst; Jun Yin; Tobias Peikert; Julia Udell; Sarah Johnson; James Smadbeck; Stephen Murphy; Alexa McCune; Giannoula Karagouga; Aakash Desai; Janet Schaefer-Klein; Mitesh J Borad; John Cheville; George Vasmatzis; Paul Baas; Aaron S Mansfield Journal: J Thorac Oncol Date: 2021-11-17 Impact factor: 15.609
Authors: Daniel J McGrail; Patrick G Pilié; Hui Dai; Truong Nguyen Anh Lam; Yulong Liang; Leonie Voorwerk; Marleen Kok; Xiang H-F Zhang; Jeffrey M Rosen; Amy B Heimberger; Christine B Peterson; Eric Jonasch; Shiaw-Yih Lin Journal: Sci Transl Med Date: 2021-10-27 Impact factor: 17.956