PURPOSE: Heterogeneity in tumor mutational burden (TMB) quantification across sequencing platforms limits the application and further study of this potential biomarker of response to immune checkpoint inhibitors (ICI). We hypothesized that harmonization of TMB across platforms would enable integration of distinct clinical datasets to better characterize the association between TMB and ICI response. METHODS: Cohorts of NSCLC patients sequenced by one of three targeted panels or by whole exome sequencing (WES) were compared (total n=7297). TMB was calculated uniformly and compared across cohorts. TMB distributions were harmonized by applying a normal transformation followed by standardization to z-scores. In sub-cohorts of patients treated with ICIs (DFCI n=272; MSKCC n=227), the association between TMB and outcome was assessed. Durable clinical benefit (DCB) was defined as responsive/stable disease lasting ≥6 months. RESULTS: TMB values were higher in the panel cohorts than the WES cohort. Average mutation rates per gene were highly concordant across cohorts (Pearson coefficient 0.842-0.866). Subsetting the WES cohort by gene panels only partially reproduced the observed differences in TMB. Standardization of TMB into z-scores harmonized TMB distributions and enabled integration of the ICI-treated sub-cohorts. Simulations indicated that cohorts >900 are necessary for this approach. TMB did not associate with response in never smokers or patients harboring targetable driver alterations, although these analyses were under-powered. Increasing TMB thresholds increased DCB rate, but DCB rates within deciles varied. Receiver operator curves yielded an area under the curve of 0.614 with no natural inflection point. CONCLUSION: Z-score conversion harmonizes TMB values and enables integration of datasets derived from different sequencing panels. Clinical and biologic features may provide context to the clinical application of TMB, and warrant further study.
PURPOSE: Heterogeneity in tumor mutational burden (TMB) quantification across sequencing platforms limits the application and further study of this potential biomarker of response to immune checkpoint inhibitors (ICI). We hypothesized that harmonization of TMB across platforms would enable integration of distinct clinical datasets to better characterize the association between TMB and ICI response. METHODS: Cohorts of NSCLC patients sequenced by one of three targeted panels or by whole exome sequencing (WES) were compared (total n=7297). TMB was calculated uniformly and compared across cohorts. TMB distributions were harmonized by applying a normal transformation followed by standardization to z-scores. In sub-cohorts of patients treated with ICIs (DFCI n=272; MSKCC n=227), the association between TMB and outcome was assessed. Durable clinical benefit (DCB) was defined as responsive/stable disease lasting ≥6 months. RESULTS: TMB values were higher in the panel cohorts than the WES cohort. Average mutation rates per gene were highly concordant across cohorts (Pearson coefficient 0.842-0.866). Subsetting the WES cohort by gene panels only partially reproduced the observed differences in TMB. Standardization of TMB into z-scores harmonized TMB distributions and enabled integration of the ICI-treated sub-cohorts. Simulations indicated that cohorts >900 are necessary for this approach. TMB did not associate with response in never smokers or patients harboring targetable driver alterations, although these analyses were under-powered. Increasing TMB thresholds increased DCB rate, but DCB rates within deciles varied. Receiver operator curves yielded an area under the curve of 0.614 with no natural inflection point. CONCLUSION: Z-score conversion harmonizes TMB values and enables integration of datasets derived from different sequencing panels. Clinical and biologic features may provide context to the clinical application of TMB, and warrant further study.
Authors: David P Carbone; Martin Reck; Luis Paz-Ares; Benjamin Creelan; Leora Horn; Martin Steins; Enriqueta Felip; Michel M van den Heuvel; Tudor-Eliade Ciuleanu; Firas Badin; Neal Ready; T Jeroen N Hiltermann; Suresh Nair; Rosalyn Juergens; Solange Peters; Elisa Minenza; John M Wrangle; Delvys Rodriguez-Abreu; Hossein Borghaei; George R Blumenschein; Liza C Villaruz; Libor Havel; Jana Krejci; Jesus Corral Jaime; Han Chang; William J Geese; Prabhu Bhagavatheeswaran; Allen C Chen; Mark A Socinski Journal: N Engl J Med Date: 2017-06-22 Impact factor: 91.245
Authors: Martin Reck; Delvys Rodríguez-Abreu; Andrew G Robinson; Rina Hui; Tibor Csőszi; Andrea Fülöp; Maya Gottfried; Nir Peled; Ali Tafreshi; Sinead Cuffe; Mary O'Brien; Suman Rao; Katsuyuki Hotta; Melanie A Leiby; Gregory M Lubiniecki; Yue Shentu; Reshma Rangwala; Julie R Brahmer Journal: N Engl J Med Date: 2016-10-08 Impact factor: 91.245
Authors: Robert M Samstein; Chung-Han Lee; Alexander N Shoushtari; Matthew D Hellmann; Ronglai Shen; Yelena Y Janjigian; David A Barron; Ahmet Zehir; Emmet J Jordan; Antonio Omuro; Thomas J Kaley; Sviatoslav M Kendall; Robert J Motzer; A Ari Hakimi; Martin H Voss; Paul Russo; Jonathan Rosenberg; Gopa Iyer; Bernard H Bochner; Dean F Bajorin; Hikmat A Al-Ahmadie; Jamie E Chaft; Charles M Rudin; Gregory J Riely; Shrujal Baxi; Alan L Ho; Richard J Wong; David G Pfister; Jedd D Wolchok; Christopher A Barker; Philip H Gutin; Cameron W Brennan; Viviane Tabar; Ingo K Mellinghoff; Lisa M DeAngelis; Charlotte E Ariyan; Nancy Lee; William D Tap; Mrinal M Gounder; Sandra P D'Angelo; Leonard Saltz; Zsofia K Stadler; Howard I Scher; Jose Baselga; Pedram Razavi; Christopher A Klebanoff; Rona Yaeger; Neil H Segal; Geoffrey Y Ku; Ronald P DeMatteo; Marc Ladanyi; Naiyer A Rizvi; Michael F Berger; Nadeem Riaz; David B Solit; Timothy A Chan; Luc G T Morris Journal: Nat Genet Date: 2019-01-14 Impact factor: 38.330
Authors: Douglas B Johnson; Garrett M Frampton; Matthew J Rioth; Erik Yusko; Yaomin Xu; Xingyi Guo; Riley C Ennis; David Fabrizio; Zachary R Chalmers; Joel Greenbowe; Siraj M Ali; Sohail Balasubramanian; James X Sun; Yuting He; Dennie T Frederick; Igor Puzanov; Justin M Balko; Justin M Cates; Jeffrey S Ross; Catherine Sanders; Harlan Robins; Yu Shyr; Vincent A Miller; Philip J Stephens; Ryan J Sullivan; Jeffrey A Sosman; Christine M Lovly Journal: Cancer Immunol Res Date: 2016-09-26 Impact factor: 11.151
Authors: Scott J Antonia; Augusto Villegas; Davey Daniel; David Vicente; Shuji Murakami; Rina Hui; Takashi Yokoi; Alberto Chiappori; Ki H Lee; Maike de Wit; Byoung C Cho; Maryam Bourhaba; Xavier Quantin; Takaaki Tokito; Tarek Mekhail; David Planchard; Young-Chul Kim; Christos S Karapetis; Sandrine Hiret; Gyula Ostoros; Kaoru Kubota; Jhanelle E Gray; Luis Paz-Ares; Javier de Castro Carpeño; Catherine Wadsworth; Giovanni Melillo; Haiyi Jiang; Yifan Huang; Phillip A Dennis; Mustafa Özgüroğlu Journal: N Engl J Med Date: 2017-09-08 Impact factor: 91.245
Authors: Ahmet Zehir; Ryma Benayed; Ronak H Shah; Aijazuddin Syed; Sumit Middha; Hyunjae R Kim; Preethi Srinivasan; Jianjiong Gao; Debyani Chakravarty; Sean M Devlin; Matthew D Hellmann; David A Barron; Alison M Schram; Meera Hameed; Snjezana Dogan; Dara S Ross; Jaclyn F Hechtman; Deborah F DeLair; JinJuan Yao; Diana L Mandelker; Donavan T Cheng; Raghu Chandramohan; Abhinita S Mohanty; Ryan N Ptashkin; Gowtham Jayakumaran; Meera Prasad; Mustafa H Syed; Anoop Balakrishnan Rema; Zhen Y Liu; Khedoudja Nafa; Laetitia Borsu; Justyna Sadowska; Jacklyn Casanova; Ruben Bacares; Iwona J Kiecka; Anna Razumova; Julie B Son; Lisa Stewart; Tessara Baldi; Kerry A Mullaney; Hikmat Al-Ahmadie; Efsevia Vakiani; Adam A Abeshouse; Alexander V Penson; Philip Jonsson; Niedzica Camacho; Matthew T Chang; Helen H Won; Benjamin E Gross; Ritika Kundra; Zachary J Heins; Hsiao-Wei Chen; Sarah Phillips; Hongxin Zhang; Jiaojiao Wang; Angelica Ochoa; Jonathan Wills; Michael Eubank; Stacy B Thomas; Stuart M Gardos; Dalicia N Reales; Jesse Galle; Robert Durany; Roy Cambria; Wassim Abida; Andrea Cercek; Darren R Feldman; Mrinal M Gounder; A Ari Hakimi; James J Harding; Gopa Iyer; Yelena Y Janjigian; Emmet J Jordan; Ciara M Kelly; Maeve A Lowery; Luc G T Morris; Antonio M Omuro; Nitya Raj; Pedram Razavi; Alexander N Shoushtari; Neerav Shukla; Tara E Soumerai; Anna M Varghese; Rona Yaeger; Jonathan Coleman; Bernard Bochner; Gregory J Riely; Leonard B Saltz; Howard I Scher; Paul J Sabbatini; Mark E Robson; David S Klimstra; Barry S Taylor; Jose Baselga; Nikolaus Schultz; David M Hyman; Maria E Arcila; David B Solit; Marc Ladanyi; Michael F Berger Journal: Nat Med Date: 2017-05-08 Impact factor: 53.440
Authors: Michael S Lawrence; Petar Stojanov; Paz Polak; Gregory V Kryukov; Kristian Cibulskis; Andrey Sivachenko; Scott L Carter; Chip Stewart; Craig H Mermel; Steven A Roberts; Adam Kiezun; Peter S Hammerman; Aaron McKenna; Yotam Drier; Lihua Zou; Alex H Ramos; Trevor J Pugh; Nicolas Stransky; Elena Helman; Jaegil Kim; Carrie Sougnez; Lauren Ambrogio; Elizabeth Nickerson; Erica Shefler; Maria L Cortés; Daniel Auclair; Gordon Saksena; Douglas Voet; Michael Noble; Daniel DiCara; Pei Lin; Lee Lichtenstein; David I Heiman; Timothy Fennell; Marcin Imielinski; Bryan Hernandez; Eran Hodis; Sylvan Baca; Austin M Dulak; Jens Lohr; Dan-Avi Landau; Catherine J Wu; Jorge Melendez-Zajgla; Alfredo Hidalgo-Miranda; Amnon Koren; Steven A McCarroll; Jaume Mora; Brian Crompton; Robert Onofrio; Melissa Parkin; Wendy Winckler; Kristin Ardlie; Stacey B Gabriel; Charles W M Roberts; Jaclyn A Biegel; Kimberly Stegmaier; Adam J Bass; Levi A Garraway; Matthew Meyerson; Todd R Golub; Dmitry A Gordenin; Shamil Sunyaev; Eric S Lander; Gad Getz Journal: Nature Date: 2013-06-16 Impact factor: 49.962
Authors: Andrea Garofalo; Lynette Sholl; Brendan Reardon; Amaro Taylor-Weiner; Ali Amin-Mansour; Diana Miao; David Liu; Nelly Oliver; Laura MacConaill; Matthew Ducar; Vanesa Rojas-Rudilla; Marios Giannakis; Arezou Ghazani; Stacy Gray; Pasi Janne; Judy Garber; Steve Joffe; Neal Lindeman; Nikhil Wagle; Levi A Garraway; Eliezer M Van Allen Journal: Genome Med Date: 2016-07-26 Impact factor: 11.117
Authors: Diana M Merino; Lisa M McShane; David Fabrizio; Vincent Funari; Shu-Jen Chen; James R White; Paul Wenz; Jonathan Baden; J Carl Barrett; Ruchi Chaudhary; Li Chen; Wangjuh Sting Chen; Jen-Hao Cheng; Dinesh Cyanam; Jennifer S Dickey; Vikas Gupta; Matthew Hellmann; Elena Helman; Yali Li; Joerg Maas; Arnaud Papin; Rajesh Patidar; Katie J Quinn; Naiyer Rizvi; Hongseok Tae; Christine Ward; Mingchao Xie; Ahmet Zehir; Chen Zhao; Manfred Dietel; Albrecht Stenzinger; Mark Stewart; Jeff Allen Journal: J Immunother Cancer Date: 2020-03 Impact factor: 13.751
Authors: D J McGrail; P G Pilié; N U Rashid; L Voorwerk; M Slagter; M Kok; E Jonasch; M Khasraw; A B Heimberger; B Lim; N T Ueno; J K Litton; R Ferrarotto; J T Chang; S L Moulder; S-Y Lin Journal: Ann Oncol Date: 2021-03-15 Impact factor: 32.976
Authors: Wenya Linda Bi; Lakshmi Nayak; David M Meredith; Joseph Driver; Ziming Du; Samantha Hoffman; Yvonne Li; Eudocia Quant Lee; Rameen Beroukhim; Mikael Rinne; Ricardo McFaline-Figueroa; Ugonma Chukwueke; Christine McCluskey; Sarah Gaffey; Andrew D Cherniack; Jennifer Stefanik; Lisa Doherty; Christina Taubert; Meghan Cifrino; Deborah LaFrankie; Thomas Graillon; Patrick Y Wen; Keith L Ligon; Ossama Al-Mefty; Raymond Y Huang; Alona Muzikansky; E Antonio Chiocca; Sandro Santagata; Ian F Dunn; David A Reardon Journal: Neuro Oncol Date: 2022-01-05 Impact factor: 12.300
Authors: Xinan Wang; Biagio Ricciuti; Tom Nguyen; Xihao Li; Michael S Rabin; Mark M Awad; Xihong Lin; Bruce E Johnson; David C Christiani Journal: Cancer Res Date: 2021-03-02 Impact factor: 13.312
Authors: Xinan Wang; Biagio Ricciuti; Joao V Alessi; Tom Nguyen; Mark M Awad; Xihong Lin; Bruce E Johnson; David C Christiani Journal: J Natl Cancer Inst Date: 2021-06-11 Impact factor: 11.816
Authors: Alexander Drilon; Michael Duruisseaux; Ji-Youn Han; Masaoki Ito; Christina Falcon; Soo-Ryum Yang; Yonina R Murciano-Goroff; Haiquan Chen; Morihito Okada; Miguel Angel Molina; Marie Wislez; Philippe Brun; Clarisse Dupont; Eva Branden; Giulio Rossi; Alexa Schrock; Siraj Ali; Valérie Gounant; Fanny Magne; Torsten Gerriet Blum; Alison M Schram; Isabelle Monnet; Jin-Yuan Shih; Joshua Sabari; Maurice Pérol; Viola W Zhu; Misako Nagasaka; Robert Doebele; D Ross Camidge; Maria Arcila; Sai-Hong Ignatius Ou; Denis Moro-Sibilot; Rafael Rosell; Lucia Anna Muscarella; Stephen V Liu; Jacques Cadranel Journal: J Clin Oncol Date: 2021-06-02 Impact factor: 50.717