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Biomarkers: Is Tumor Mutational Burden the New Prognostic Grail?

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Lung Cancer

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

Immune checkpoint inhibitors (ICI) have improved outcomes for patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of patients experience benefit, and biomarkers of response are needed to improve patient selection. Tumor mutational burden (TMB), defined as the number of somatic mutations in a tumor, has been identified as a potential predictive biomarker. Studies assessing TMB and outcome in NSCLC have demonstrated improved response rates and progression-free survival to ICIs in patients with higher TMB compared to lower TMB, and patients with high TMB have a higher likelihood of benefit to ICI compared to chemotherapy. However, TMB imperfectly stratifies responders from non-responders, and these data are heterogenous with respect to treatment context, drug, TMB assay, and TMB threshold. Importantly, many of these analyses are retrospective, and few prospective clinical trials implementing TMB as a biomarker have been completed. Additional limitations to the implementation of TMB include the need for adequate tissue to perform sequencing, and heterogeneity in TMB assays. Efforts to develop blood-based TMB assays and standardization procedures may help address these limitations. Finally, further research to understand why TMB associates with response, and how TMB interacts with other biomarkers including PD-L1 and interferon-gamma expression, may help improve its predictive power.

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References

  1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957. https://doi.org/10.1056/NEJMoa0810699

    Article  CAS  PubMed  Google Scholar 

  2. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L, Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C, Associazione Italiana Oncologia T (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13(3):239–246. https://doi.org/10.1016/S1470-2045(11)70393-X

    Article  CAS  PubMed  Google Scholar 

  3. Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31(27):3327–3334. https://doi.org/10.1200/JCO.2012.44.2806

    Article  CAS  PubMed  Google Scholar 

  4. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS, Investigators F (2018) Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378(2):113–125. https://doi.org/10.1056/NEJMoa1713137

    Article  CAS  PubMed  Google Scholar 

  5. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F, Investigators P (2014) First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371(23):2167–2177. https://doi.org/10.1056/NEJMoa1408440

    Article  CAS  PubMed  Google Scholar 

  6. Soria JC, Tan DSW, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G Jr (2017) First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 389(10072):917–929. https://doi.org/10.1016/S0140-6736(17)30123-X

    Article  CAS  PubMed  Google Scholar 

  7. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371(21):1963–1971. https://doi.org/10.1056/NEJMoa1406766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, Barlesi F, Kim TM, Mazieres J, Novello S, Rigas JR, Upalawanna A, D’Amelio AM Jr, Zhang P, Mookerjee B, Johnson BE (2016) Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 17(7):984–993. https://doi.org/10.1016/S1470-2045(16)30146-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland A, Giannone V, D’Amelio AM Jr, Zhang P, Mookerjee B, Johnson BE (2017) Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 18(10):1307–1316. https://doi.org/10.1016/S1470-2045(17)30679-4

    Article  CAS  PubMed  Google Scholar 

  10. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135. https://doi.org/10.1056/NEJMoa1504627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7

    Article  CAS  PubMed  Google Scholar 

  13. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, Investigators K (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://doi.org/10.1056/NEJMoa1606774

    Article  CAS  PubMed  Google Scholar 

  14. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR, Group OAKS (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265. https://doi.org/10.1016/S0140-6736(16)32517-X

    Article  PubMed  Google Scholar 

  15. Nadal E, Massuti B, Domine M, Garcia-Campelo R, Cobo M, Felip E (2019) Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors. Cancer Immunol Immunother 68(3):341–352. https://doi.org/10.1007/s00262-019-02310-2

    Article  CAS  PubMed  Google Scholar 

  16. Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, Patnaik A, Gubens M, Ramalingam SS, Felip E, Goldman JW, Scalzo C, Jensen E, Kush DA, Hui R (2019) Five-year overall survival for patients with advanced nonsmall-cell lung cancer treated with Pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol:JCO1900934. https://doi.org/10.1200/JCO.19.00934

  17. Gettinger S, Horn L, Jackman D, Spigel D, Antonia S, Hellmann M, Powderly J, Heist R, Sequist LV, Smith DC, Leming P, Geese WJ, Yoon D, Li A, Brahmer J (2018) Five-year follow-up of Nivolumab in previously treated advanced non-small-cell lung Cancer: results from the CA209-003 study. J Clin Oncol 36(17):1675–1684. https://doi.org/10.1200/JCO.2017.77.0412

    Article  CAS  PubMed  Google Scholar 

  18. Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, Chapman PB, Schwartz GK, Allison JP, Wolchok JD (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116(7):1767–1775. https://doi.org/10.1002/cncr.24951

    Article  CAS  PubMed  Google Scholar 

  19. Gajewski TF, Louahed J, Brichard VG (2010) Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J 16(4):399–403. https://doi.org/10.1097/PPO.0b013e3181eacbd8

    Article  CAS  PubMed  Google Scholar 

  20. Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, Alaparthy S, Berman D, Jure-Kunkel M, Siemers NO, Jackson JR, Shahabi V (2012) An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother 61(7):1019–1031. https://doi.org/10.1007/s00262-011-1172-6

    Article  CAS  PubMed  Google Scholar 

  21. Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, Park YM, Oh S, Shin JG, Yao S, Chen L, Choi IH (2006) Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274). FEBS Lett 580(3):755–762. https://doi.org/10.1016/j.febslet.2005.12.093

    Article  CAS  PubMed  Google Scholar 

  22. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, Investigators K (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028. https://doi.org/10.1056/NEJMoa1501824

    Article  PubMed  Google Scholar 

  23. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499(7457):214–218. https://doi.org/10.1038/nature12213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, van Buuren MM, van ’t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Australian Pancreatic Cancer Genome I, Consortium IBC, Consortium IM-S, PedBrain I, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR (2013) Signatures of mutational processes in human cancer. Nature 500(7463):415–421. https://doi.org/10.1038/nature12477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, Allison JP (2008) Epitope landscape in breast and colorectal cancer. Cancer Res 68(3):889–892. https://doi.org/10.1158/0008-5472.CAN-07-3095

    Article  CAS  PubMed  Google Scholar 

  26. Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482(7385):400–404. https://doi.org/10.1038/nature10755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, van Dijk LJ, Behjati S, Hilkmann H, El Atmioui D, Nieuwland M, Stratton MR, Kerkhoven RM, Kesmir C, Haanen JB, Kvistborg P, Schumacher TN (2013) Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 31(32):e439–e442. https://doi.org/10.1200/JCO.2012.47.7521

    Article  PubMed  Google Scholar 

  28. Johnson DB, Frampton GM, Rioth MJ, Yusko E, Xu Y, Guo X, Ennis RC, Fabrizio D, Chalmers ZR, Greenbowe J, Ali SM, Balasubramanian S, Sun JX, He Y, Frederick DT, Puzanov I, Balko JM, Cates JM, Ross JS, Sanders C, Robins H, Shyr Y, Miller VA, Stephens PJ, Sullivan RJ, Sosman JA, Lovly CM (2016) Targeted next generation sequencing identifies markers of response to PD-1 blockade. Cancer Immunol Res 4(11):959–967. https://doi.org/10.1158/2326-6066.CIR-16-0143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, Plodkowski A, Long N, Sauter JL, Rekhtman N, Hollmann T, Schalper KA, Gainor JF, Shen R, Ni A, Arbour KC, Merghoub T, Wolchok J, Snyder A, Chaft JE, Kris MG, Rudin CM, Socci ND, Berger MF, Taylor BS, Zehir A, Solit DB, Arcila ME, Ladanyi M, Riely GJ, Schultz N, Hellmann MD (2018) Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 36(7):633–641. https://doi.org/10.1200/JCO.2017.75.3384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Garofalo A, Sholl L, Reardon B, Taylor-Weiner A, Amin-Mansour A, Miao D, Liu D, Oliver N, MacConaill L, Ducar M, Rojas-Rudilla V, Giannakis M, Ghazani A, Gray S, Janne P, Garber J, Joffe S, Lindeman N, Wagle N, Garraway LA, Van Allen EM (2016) The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. Genome Med 8(1):79. https://doi.org/10.1186/s13073-016-0333-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J, Huang F, He Y, Sun J, Tabori U, Kennedy M, Lieber DS, Roels S, White J, Otto GA, Ross JS, Garraway L, Miller VA, Stephens PJ, Frampton GM (2017) Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9(1):34. https://doi.org/10.1186/s13073-017-0424-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Campesato LF, Barroso-Sousa R, Jimenez L, Correa BR, Sabbaga J, Hoff PM, Reis LF, Galante PA, Camargo AA (2015) Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget 6(33):34221–34227. https://doi.org/10.18632/oncotarget.5950

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, Srinivasan P, Gao J, Chakravarty D, Devlin SM, Hellmann MD, Barron DA, Schram AM, Hameed M, Dogan S, Ross DS, Hechtman JF, DeLair DF, Yao J, Mandelker DL, Cheng DT, Chandramohan R, Mohanty AS, Ptashkin RN, Jayakumaran G, Prasad M, Syed MH, Rema AB, Liu ZY, Nafa K, Borsu L, Sadowska J, Casanova J, Bacares R, Kiecka IJ, Razumova A, Son JB, Stewart L, Baldi T, Mullaney KA, Al-Ahmadie H, Vakiani E, Abeshouse AA, Penson AV, Jonsson P, Camacho N, Chang MT, Won HH, Gross BE, Kundra R, Heins ZJ, Chen HW, Phillips S, Zhang H, Wang J, Ochoa A, Wills J, Eubank M, Thomas SB, Gardos SM, Reales DN, Galle J, Durany R, Cambria R, Abida W, Cercek A, Feldman DR, Gounder MM, Hakimi AA, Harding JJ, Iyer G, Janjigian YY, Jordan EJ, Kelly CM, Lowery MA, Morris LGT, Omuro AM, Raj N, Razavi P, Shoushtari AN, Shukla N, Soumerai TE, Varghese AM, Yaeger R, Coleman J, Bochner B, Riely GJ, Saltz LB, Scher HI, Sabbatini PJ, Robson ME, Klimstra DS, Taylor BS, Baselga J, Schultz N, Hyman DM, Arcila ME, Solit DB, Ladanyi M, Berger MF (2017) Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23(6):703–713. https://doi.org/10.1038/nm.4333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG, Parsons HA, Gydush G, Reed SC, Rotem D, Rhoades J, Loginov D, Livitz D, Rosebrock D, Leshchiner I, Kim J, Stewart C, Rosenberg M, Francis JM, Zhang CZ, Cohen O, Oh C, Ding H, Polak P, Lloyd M, Mahmud S, Helvie K, Merrill MS, Santiago RA, O’Connor EP, Jeong SH, Leeson R, Barry RM, Kramkowski JF, Zhang Z, Polacek L, Lohr JG, Schleicher M, Lipscomb E, Saltzman A, Oliver NM, Marini L, Waks AG, Harshman LC, Tolaney SM, Van Allen EM, Winer EP, Lin NU, Nakabayashi M, Taplin ME, Johannessen CM, Garraway LA, Golub TR, Boehm JS, Wagle N, Getz G, Love JC, Meyerson M (2017) Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun 8(1):1324. https://doi.org/10.1038/s41467-017-00965-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koeppel F, Blanchard S, Jovelet C, Genin B, Marcaillou C, Martin E, Rouleau E, Solary E, Soria JC, Andre F, Lacroix L (2017) Whole exome sequencing for determination of tumor mutation load in liquid biopsy from advanced cancer patients. PLoS One 12(11):e0188174. https://doi.org/10.1371/journal.pone.0188174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, Rittmeyer A, Fehrenbacher L, Otto G, Malboeuf C, Lieber DS, Lipson D, Silterra J, Amler L, Riehl T, Cummings CA, Hegde PS, Sandler A, Ballinger M, Fabrizio D, Mok T, Shames DS (2018) Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 24(9):1441–1448. https://doi.org/10.1038/s41591-018-0134-3

    Article  CAS  PubMed  Google Scholar 

  37. Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, Khodadoust MS, Esfahani MS, Liu CL, Zhou L, Scherer F, Kurtz DM, Say C, Carter JN, Merriott DJ, Dudley JC, Binkley MS, Modlin L, Padda SK, Gensheimer MF, West RB, Shrager JB, Neal JW, Wakelee HA, Loo BW Jr, Alizadeh AA, Diehn M (2017) Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov 7(12):1394–1403. https://doi.org/10.1158/2159-8290.CD-17-0716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Muller JN, Falk M, Talwar J, Neemann N, Mariotti E, Bertrand M, Zacherle T, Lakis S, Menon R, Gloeckner C, Tiemann M, Heukamp LC, Thomas RK, Griesinger F, Heuckmann JM (2017) Concordance between comprehensive cancer genome profiling in plasma and tumor specimens. J Thorac Oncol 12(10):1503–1511. https://doi.org/10.1016/j.jtho.2017.07.014

    Article  PubMed  Google Scholar 

  39. Davis AA, Chae YK, Agte S, Pan A, Simon NI, Taxter TJ, Behdad A, Carneiro BA, Cristofanilli M, Giles FJ (2017) Comparison of tumor mutational burden (TMB) across tumor tissue and circulating tumor DNA (ctDNA). J Clin Oncol 35(15_suppl):e23028–e23028. https://doi.org/10.1200/JCO.2017.35.15_suppl.e23028

    Article  Google Scholar 

  40. Peters S (2019) Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab±tremelimumab vs chemotherapy. In: American Association for Cancer Research Annual Meeting

    Google Scholar 

  41. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128. https://doi.org/10.1126/science.aaa1348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC, Investigators K (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092. https://doi.org/10.1056/NEJMoa1801005

    Article  CAS  PubMed  Google Scholar 

  43. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH Jr, Italiano A, Kao S, Piha-Paul SA, Delord JP, McWilliams RR, Fabrizio DA, Aurora-Garg D, Xu L, ** F, Norwood K, Bang YJ, (2020) Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. Oct;21(10):1353–1365. https://doi.org/10.1016/S1470-2045(20)30445-9. Epub 2020 Sep 10. PMID: 32919526. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors

  44. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA, CheckMate I (2017) First-line Nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376(25):2415–2426. https://doi.org/10.1056/NEJMoa1613493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O’Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L (2018) Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378(22):2093–2104. https://doi.org/10.1056/NEJMoa1801946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kowanetz M, Zou W, Shames D, Cummings C, Rizvi N, Spira A, Frampton G, Leveque V, Flynn S, Mocci S, Shankar G, Funke R, Ballinger M, Waterkamp D, Chen D, Sandler A, Hampton G, Amler L, Hegde P, Hellmann M (2017) OA20.01 tumor mutation burden (TMB) is associated with improved efficacy of Atezolizumab in 1L and 2L+ NSCLC patients. J Thorac Oncol 12(1, Supplement):S321–S322. https://doi.org/10.1016/j.jtho.2016.11.343

    Article  Google Scholar 

  47. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A, Group PS (2016) Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387(10030):1837–1846. https://doi.org/10.1016/S0140-6736(16)00587-0

    Article  CAS  PubMed  Google Scholar 

  48. Peters S, Gettinger S, Johnson ML, Janne PA, Garassino MC, Christoph D, Toh CK, Rizvi NA, Chaft JE, Carcereny Costa E, Patel JD, Chow LQM, Koczywas M, Ho C, Fruh M, van den Heuvel M, Rothenstein J, Reck M, Paz-Ares L, Shepherd FA, Kurata T, Li Z, Qiu J, Kowanetz M, Mocci S, Shankar G, Sandler A, Felip E (2017) Phase II trial of Atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J Clin Oncol 35(24):2781–2789. https://doi.org/10.1200/JCO.2016.71.9476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Spigel DR, Chaft JE, Gettinger S, Chao BH, Dirix L, Schmid P, Chow LQM, Hicks RJ, Leon L, Fredrickson J, Kowanetz M, Sandler A, Funke R, Rizvi NA (2018) FIR: efficacy, safety, and biomarker analysis of a phase II open-label study of Atezolizumab in PD-L1-selected patients with NSCLC. J Thorac Oncol 13(11):1733–1742. https://doi.org/10.1016/j.jtho.2018.05.004

    Article  PubMed  PubMed Central  Google Scholar 

  50. Rizvi NA, Chul Cho B, Reinmuth N, Lee KH, Ahn M-J, Luft A, van den Heuvel M, Cobo M, Smolin A, Vicente D, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Nakagawa K, Zhao L, Stockman PK, Chand V, Peters S (2018) LBA6Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC. Ann Oncol 29(suppl_10). https://doi.org/10.1093/annonc/mdy511.005

  51. Hellmann MD, Nathanson T, Rizvi H, Creelan BC, Sanchez-Vega F, Ahuja A, Ni A, Novik JB, Mangarin LMB, Abu-Akeel M, Liu C, Sauter JL, Rekhtman N, Chang E, Callahan MK, Chaft JE, Voss MH, Tenet M, Li XM, Covello K, Renninger A, Vitazka P, Geese WJ, Borghaei H, Rudin CM, Antonia SJ, Swanton C, Hammerbacher J, Merghoub T, McGranahan N, Snyder A, Wolchok JD (2018) Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33(5):843–852. e844. https://doi.org/10.1016/j.ccell.2018.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ready N, Hellmann MD, Awad MM, Otterson GA, Gutierrez M, Gainor JF, Borghaei H, Jolivet J, Horn L, Mates M, Brahmer J, Rabinowitz I, Reddy PS, Chesney J, Orcutt J, Spigel DR, Reck M, O’Byrne KJ, Paz-Ares L, Hu W, Zerba K, Li X, Lestini B, Geese WJ, Szustakowski JD, Green G, Chang H, Ramalingam SS (2019) First-line Nivolumab plus Ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J Clin Oncol:JCO1801042. https://doi.org/10.1200/JCO.18.01042

  53. Squibb B-M (2018, Oct 19) Bristol-Myers Squibb provides update on the ongoing regulatory review of Opdivo Plus low-dose Yervoy in first-line lung cancer patients with tumor mutational burden ≥10 mut/Mb. https://bit.ly/2ySdgOC. Accessed 20 May 2019

  54. Singal G, Miller PG, Agarwala V, Li G, Kaushik G, Backenroth D, Gossai A, Frampton GM, Torres AZ, Lehnert EM, Bourque D, O’Connell C, Bowser B, Caron T, Baydur E, Seidl-Rathkopf K, Ivanov I, Alpha-Cobb G, Guria A, He J, Frank S, Nunnally AC, Bailey M, Jaskiw A, Feuchtbaum D, Nussbaum N, Abernethy AP, Miller VA (2019) Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic database. JAMA 321(14):1391–1399. https://doi.org/10.1001/jama.2019.3241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377(25):2500–2501. https://doi.org/10.1056/NEJMc1713444

    Article  PubMed  PubMed Central  Google Scholar 

  56. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, Barron DA, Zehir A, Jordan EJ, Omuro A, Kaley TJ, Kendall SM, Motzer RJ, Hakimi AA, Voss MH, Russo P, Rosenberg J, Iyer G, Bochner BH, Bajorin DF, Al-Ahmadie HA, Chaft JE, Rudin CM, Riely GJ, Baxi S, Ho AL, Wong RJ, Pfister DG, Wolchok JD, Barker CA, Gutin PH, Brennan CW, Tabar V, Mellinghoff IK, DeAngelis LM, Ariyan CE, Lee N, Tap WD, Gounder MM, D’Angelo SP, Saltz L, Stadler ZK, Scher HI, Baselga J, Razavi P, Klebanoff CA, Yaeger R, Segal NH, Ku GY, DeMatteo RP, Ladanyi M, Rizvi NA, Berger MF, Riaz N, Solit DB, Chan TA, Morris LGT (2019) Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 51(2):202–206. https://doi.org/10.1038/s41588-018-0312-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199. https://doi.org/10.1056/NEJMoa1406498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MHG, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207–211. https://doi.org/10.1126/science.aad0095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Miao D, Margolis CA, Vokes NI, Liu D, Taylor-Weiner A, Wankowicz SM, Adeegbe D, Keliher D, Schilling B, Tracy A, Manos M, Chau NG, Hanna GJ, Polak P, Rodig SJ, Signoretti S, Sholl LM, Engelman JA, Getz G, Janne PA, Haddad RI, Choueiri TK, Barbie DA, Haq R, Awad MM, Schadendorf D, Hodi FS, Bellmunt J, Wong KK, Hammerman P, Van Allen EM (2018) Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat Genet 50(9):1271–1281. https://doi.org/10.1038/s41588-018-0200-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387(10031):1909–1920. https://doi.org/10.1016/S0140-6736(16)00561-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, Sher X, Liu XQ, Lu H, Nebozhyn M, Zhang C, Lunceford JK, Joe A, Cheng J, Webber AL, Ibrahim N, Plimack ER, Ott PA, Seiwert TY, Ribas A, McClanahan TK, Tomassini JE, Loboda A, Kaufman D (2018) Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362(6411). https://doi.org/10.1126/science.aar3593

  62. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, Stephens PJ, Daniels GA, Kurzrock R (2017) Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 16(11):2598–2608. https://doi.org/10.1158/1535-7163.MCT-17-0386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Vokes NI, Liu D, Ricciuti B, Jimenez-Aguilar E, Rizvi H, Dietlein F, He MX, Margolis CA, Elmarakeby HA, Girshman J, Adeni A, Sanchez-Vega F, Schultz N, Dahlberg S, Zehir A, Jänne PA, Nishino M, Umeton R, Sholl LM, Van Allen EM, Hellmann MD, Awad MM. (2019) Harmonization of Tumor Mutational Burden Quantification and Association With Response to Immune Checkpoint Blockade in Non-Small-Cell Lung Cancer. JCO Precis Oncol.; 3:PO.19.00171. https://doi.org/10.1200/PO.19.00171. Epub 2019 Nov 12. PMID: 31832578

  64. Lim C, Tsao MS, Le LW, Shepherd FA, Feld R, Burkes RL, Liu G, Kamel-Reid S, Hwang D, Tanguay J, da Cunha SG, Leighl NB (2015) Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. Ann Oncol 26(7):1415–1421. https://doi.org/10.1093/annonc/mdv208

    Article  CAS  PubMed  Google Scholar 

  65. Sacher AG, Paweletz C, Dahlberg SE, Alden RS, O’Connell A, Feeney N, Mach SL, Janne PA, Oxnard GR (2016) Prospective validation of rapid plasma genoty** for the detection of EGFR and KRAS mutations in advanced lung Cancer. JAMA Oncol 2(8):1014–1022. https://doi.org/10.1001/jamaoncol.2016.0173

    Article  PubMed  PubMed Central  Google Scholar 

  66. Sacher AG, Komatsubara KM, Oxnard GR (2017) Application of plasma genoty** technologies in non-small cell lung cancer: a practical review. J Thorac Oncol 12(9):1344–1356. https://doi.org/10.1016/j.jtho.2017.05.022

    Article  PubMed  Google Scholar 

  67. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351(6280):1463–1469. https://doi.org/10.1126/science.aaf1490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mok TSK, Gadgeel S, Kim ES, Velcheti V, Hu S, Riehl T, Schleifman E, Paul SM, Mocci S, Shames DS, Phan S, Yun C, Mathisen M, Kowanetz M, Sweere U, Socinski MA (2017) 1383TiPBlood first line ready screening trial (B-F1RST) and blood first assay screening trial (BFAST) enable clinical development of novel blood-based biomarker assays for tumor mutational burden (TMB) and somatic mutations in 1L advanced or metastatic NSCLC. Ann Oncol 28(suppl_5). https://doi.org/10.1093/annonc/mdx380.084

  69. Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348(6230):69–74. https://doi.org/10.1126/science.aaa4971

    Article  CAS  PubMed  Google Scholar 

  70. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160(1–2):48–61. https://doi.org/10.1016/j.cell.2014.12.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515(7528):577–581. https://doi.org/10.1038/nature13988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fehlings M, Simoni Y, Penny HL, Becht E, Loh CY, Gubin MM, Ward JP, Wong SC, Schreiber RD, Newell EW (2017) Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8(+) T cells. Nat Commun 8(1):562. https://doi.org/10.1038/s41467-017-00627-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, **ao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357(6349):409–413. https://doi.org/10.1126/science.aan6733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Luksza M, Riaz N, Makarov V, Balachandran VP, Hellmann MD, Solovyov A, Rizvi NA, Merghoub T, Levine AJ, Chan TA, Wolchok JD, Greenbaum BD (2017) A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551(7681):517–520. https://doi.org/10.1038/nature24473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Balachandran VP, Luksza M, Zhao JN, Makarov V, Moral JA, Remark R, Herbst B, Askan G, Bhanot U, Senbabaoglu Y, Wells DK, Cary CIO, Grbovic-Huezo O, Attiyeh M, Medina B, Zhang J, Loo J, Saglimbeni J, Abu-Akeel M, Zappasodi R, Riaz N, Smoragiewicz M, Kelley ZL, Basturk O, Australian Pancreatic Cancer Genome I, Garvan Institute of Medical R, Prince of Wales H, Royal North Shore H, University of G, St Vincent’s H, Institute QBMR, University of Melbourne CfCR, University of Queensland IfMB, Bankstown H, Liverpool H, Royal Prince Alfred Hospital COBL, Westmead H, Fremantle H, St John of God H, Royal Adelaide H, Flinders Medical C, Envoi P, Princess Alexandria H, Austin H, Johns Hopkins Medical I, Cancer AR-NCfARo, Gonen M, Levine AJ, Allen PJ, Fearon DT, Merad M, Gnjatic S, Iacobuzio-Donahue CA, Wolchok JD, DeMatteo RP, Chan TA, Greenbaum BD, Merghoub T, Leach SD (2017) Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551(7681):512–516. https://doi.org/10.1038/nature24462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ (2016) Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 17(7):956–965. https://doi.org/10.1016/S1470-2045(16)30066-3

    Article  CAS  PubMed  Google Scholar 

  77. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry S, Chartash EK, Daud A, Fling SP, Friedlander PA, Kluger HM, Kohrt HE, Lundgren L, Margolin K, Mitchell A, Olencki T, Pardoll DM, Reddy SA, Shantha EM, Sharfman WH, Sharon E, Shemanski LR, Shinohara MM, Sunshine JC, Taube JM, Thompson JA, Townson SM, Yearley JH, Topalian SL, Cheever MA (2016) PD-1 blockade with Pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 374(26):2542–2552. https://doi.org/10.1056/NEJMoa1603702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Panda A, de Cubas AA, Stein M, Riedlinger G, Kra J, Mayer T, Smith CC, Vincent BG, Serody JS, Beckermann KE, Ganesan S, Bhanot G, Rathmell WK (2018) Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma. JCI Insight 3(16). https://doi.org/10.1172/jci.insight.121522

  79. Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, Bumbaca S, Franci C, Cheung TK, Fritsche J, Weinschenk T, Modrusan Z, Mellman I, Lill JR, Delamarre L (2014) Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515(7528):572–576. https://doi.org/10.1038/nature14001

    Article  CAS  PubMed  Google Scholar 

  80. Abelin JG, Keskin DB, Sarkizova S, Hartigan CR, Zhang W, Sidney J, Stevens J, Lane W, Zhang GL, Eisenhaure TM, Clauser KR, Hacohen N, Rooney MS, Carr SA, Wu CJ (2017) Mass spectrometry profiling of HLA-associated Peptidomes in mono-allelic cells enables more accurate epitope prediction. Immunity 46(2):315–326. https://doi.org/10.1016/j.immuni.2017.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Graham DB, Luo C, O’Connell DJ, Lefkovith A, Brown EM, Yassour M, Varma M, Abelin JG, Conway KL, Jasso GJ, Matar CG, Carr SA, Xavier RJ (2018) Antigen discovery and specification of immunodominance hierarchies for MHCII-restricted epitopes. Nat Med 24(11):1762–1772. https://doi.org/10.1038/s41591-018-0203-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yarchoan M, Albacker LA, Hopkins AC, Montesion M, Murugesan K, Vithayathil TT, Zaidi N, Azad NS, Laheru DA, Frampton GM, Jaffee EM (2019) PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight 4(6). https://doi.org/10.1172/jci.insight.126908

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    Natalie I. Vokes & Mark M. Awad

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    Natalie I. Vokes

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Vokes, N.I., Awad, M.M. (2021). Biomarkers: Is Tumor Mutational Burden the New Prognostic Grail?. In: Chiang, A.C., Herbst, R.S. (eds) Lung Cancer. Current Cancer Research. Humana, Cham. https://doi.org/10.1007/978-3-030-74028-3_2

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