Advertisement

Hot or Not: Tumor Mutational Burden (TMB) as a Biomarker of Immunotherapy Response in Genitourinary Cancers

Published:October 30, 2020DOI:https://doi.org/10.1016/j.urology.2020.10.030
      Pembrolizumab was recently approved for treatment of cancers with high tumor mutational burden (TMB). We conduct a focused literature review of TMB as a predictive biomarker. TMB quantifies the sum of nonsynonymous coding mutations (typically single nucleotide substitutions and short insertion-deletions) per megabase of sequenced DNA. As a proxy for expression of immunogenic neoantigens, TMB may be an effective predictive biomarker for response to immune checkpoint inhibitors. However, like other biomarkers in this setting, TMB has many limitations; the effect of this FDA approval in the current management of genitourinary cancers is likely limited to select situations.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Urology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • US Food and Drug Administration
        Highlights of prescribing information: KEYTRUDA.
        2020 (Published)
        • Brahmer JR
        • Drake CG
        • Wollner I
        • et al.
        Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates.
        J Clin Oncol. 2010; 28: 3167-3175https://doi.org/10.1200/JCO.2009.26.7609
        • Topalian SL
        • Hodi FS
        • Brahmer JR
        • et al.
        Safety, activity, and immune correlates of anti–PD-1 antibody in cancer.
        N Engl J Med. 2012; 366: 2443-2454https://doi.org/10.1056/NEJMoa1200690
        • Vaddepally RK
        • Kharel P
        • Pandey R
        • Garje R
        • Chandra AB
        Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence.
        Cancers (Basel). 2020; 12: 1-19https://doi.org/10.3390/cancers12030738
        • Yi M
        • Jiao D
        • Xu H
        • et al.
        Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors.
        Mol Cancer. 2018; 17: 1-14https://doi.org/10.1186/s12943-018-0864-3
        • Lawrence MS
        • Stojanov P
        • Mermel CH
        • et al.
        Discovery and saturation analysis of cancer genes across 21 tumour types.
        Nature. 2014; 505: 495-501https://doi.org/10.1038/nature12912
        • Alexandrov LB
        • Nik-Zainal S
        • Wedge DC
        • et al.
        Signatures of mutational processes in human cancer.
        Nature. 2013; 500: 415-421https://doi.org/10.1038/nature12477
        • Berger MF
        • Hodis E
        • Heffernan TP
        • et al.
        Melanoma genome sequencing reveals frequent PREX2 mutations.
        Nature. 2012; 485: 502-506https://doi.org/10.1038/nature11071
        • Lee W
        • Jiang Z
        • Liu J
        • et al.
        The mutation spectrum revealed by paired genome sequences from a lung cancer patient.
        Nature. 2010; 465: 473-477https://doi.org/10.1038/nature09004
        • Snyder A
        • Makarov V
        • Merghoub T
        • et al.
        Genetic basis for clinical response to CTLA-4 blockade in melanoma.
        N Engl J Med. 2014; 371: 2189-2199https://doi.org/10.1056/NEJMoa1406498
        • Rizvi NA
        • Hellmann MD
        • Snyder A
        • et al.
        Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
        Science (80-). 2015; 348: 124-128https://doi.org/10.1126/science.aaa1348
        • Samstein RM
        • Lee CH
        • Shoushtari AN
        • et al.
        Tumor mutational load predicts survival after immunotherapy across multiple cancer types.
        Nat Genet. 2019; 51: 202-206https://doi.org/10.1038/s41588-018-0312-8
        • Choudhury NJ
        • Kiyotani K
        • Yap KL
        • et al.
        Low T-cell receptor diversity, high somatic mutation burden, and high neoantigen load as predictors of clinical outcome in muscle-invasive bladder cancer.
        Eur Urol Focus. 2016; 2: 445-452https://doi.org/10.1016/j.euf.2015.09.007
        • Le DT
        • Uram JN
        • Wang H
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520https://doi.org/10.1056/NEJMoa1500596
        • Büttner R
        • Longshore JW
        • López-Ríos F
        • et al.
        Implementing TMB measurement in clinical practice: considerations on assay requirements.
        ESMO Open. 2019; 4: 1-12https://doi.org/10.1136/esmoopen-2018-000442
        • Turajlic S
        • Litchfield K
        • Xu H
        • et al.
        Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.
        Lancet Oncol. 2017; 18: 1009-1021https://doi.org/10.1016/S1470-2045(17)30516-8
        • Panda A
        • de Cubas AA
        • Stein M
        • et al.
        Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma.
        JCI insight. 2018; 3https://doi.org/10.1172/jci.insight.121522
        • Wu YM
        • Cieślik M
        • Lonigro RJ
        • et al.
        Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer.
        Cell. 2018; 173 (e14): 1770-1782https://doi.org/10.1016/j.cell.2018.04.034
        • Chalmers ZR
        • Connelly CF
        • Fabrizio D
        • et al.
        Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
        Genome Med. 2017; 9: 1-14https://doi.org/10.1186/s13073-017-0424-2
        • Goodman AM
        • Kato S
        • Bazhenova L
        • et al.
        Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers.
        Mol Cancer Ther. 2017; 16: 2598-2608https://doi.org/10.1158/1535-7163.MCT-17-0386
        • Vokes NI.
        • Liu D
        • Ricciuti B
        • et al.
        Harmonization of tumor mutational burden quantification and association with response to immune checkpoint blockade in non–small-cell lung cancer.
        JCO Precis Oncol. 2019; 47: 1-12https://doi.org/10.1200/PO.19.00171
        • Yarchoan M
        • Hopkins A
        • Jaffee EM
        Tumor mutational burden and response rate to PD-1 inhibition.
        N Engl J Med. 2017; 377: 2500-2501https://doi.org/10.1056/NEJMc1713444
        • Peters S
        • Creelan B
        • Hellmann MD
        • et al.
        Abstract CT082: Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026.
        AACR Annual Meeting. American Association for Cancer Research, 2017https://doi.org/10.1158/1538-7445.AM2017-CT082 (CT082-CT082)
        • Ready N
        • Hellmann MD
        • Awad MM
        • et al.
        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. 2019; 37: 992-1000https://doi.org/10.1200/JCO.18.01042
        • Hellmann MD
        • Ciuleanu TE
        • Pluzanski A
        • et al.
        Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.
        N Engl J Med. 2018; 378: 2093-2104https://doi.org/10.1056/NEJMoa1801946
        • Marabelle A
        • Fakih M
        • Lopez J
        • et al.
        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. 2020; 21: 1353-1365https://doi.org/10.1016/S1470-2045(20)30445-9
        • Kuderer NM
        • Burton KA
        • Blau S
        • et al.
        Comparison of 2 commercially available next-generation sequencing platforms in oncology.
        JAMA Oncol. 2017; 3: 996-998https://doi.org/10.1001/jamaoncol.2016.4983
        • Torga G
        • Pienta KJ
        Patient-paired sample congruence between 2 commercial liquid biopsy tests.
        JAMA Oncol. 2018; 4: 868-870https://doi.org/10.1001/jamaoncol.2017.4027
        • Chae YK
        • Davis AA
        • Agte S
        • et al.
        Clinical implications of circulating tumor DNA Tumor Mutational Burden (ctDNA TMB) in non-small cell lung cancer.
        Oncologist. 2019; 24: 820-828https://doi.org/10.1634/theoncologist.2018-0433
        • Qiu P
        • Poehlein CH
        • Marton MJ
        • Laterza OF
        • Levitan D
        Measuring Tumor Mutational Burden (TMB) in plasma from mCRPC Patients using two commercial NGS assays.
        Sci Rep. 2019; 9: 114https://doi.org/10.1038/s41598-018-37128-y
        • Jansen CS
        • Prokhnevska N
        • Master VA
        • et al.
        An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.
        Nature. 2019; 576: 465-470https://doi.org/10.1038/s41586-019-1836-5
        • Siddiqui I
        • Schaeuble K
        • Chennupati V
        • et al.
        Intratumoral Tcf1+PD-1+CD8+ T Cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy.
        Immunity. 2019; 50 (e10): 195-211https://doi.org/10.1016/j.immuni.2018.12.021
        • Mariathasan S
        • Turley SJ
        • Nickles D
        • et al.
        TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
        Nature. 2018; 554: 544-548https://doi.org/10.1038/nature25501
        • Einstein DJ
        • McDermott DF.
        Combined blockade of vascular endothelial growth factor and programmed death 1 pathways in advanced kidney cancer.
        Clin Adv Hematol Oncol. 2017; 15: 478-488
        • Luke JJ
        • Bao R
        • Sweis RF
        • Spranger S
        • Gajewski TF
        WNT/β-catenin pathway activation correlates with immune exclusion across human cancers.
        Clin Cancer Res. 2019; 25: 3074-3083https://doi.org/10.1158/1078-0432.CCR-18-1942
        • Binnewies M
        • Roberts EW
        • Kersten K
        • et al.
        Understanding the tumor immune microenvironment (TIME) for effective therapy.
        Nat Med. 2018; 24: 541-550https://doi.org/10.1038/s41591-018-0014-x
        • Kantoff PW
        • Higano CS
        • Shore ND
        • et al.
        Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
        N Engl J Med. 2010; 363: 411-422https://doi.org/10.1056/NEJMoa1001294
        • Kwon ED
        • Drake CG
        • Scher HI
        • et al.
        Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial.
        Lancet Oncol. 2014; 15: 700-712https://doi.org/10.1016/S1470-2045(14)70189-5
        • Armenia J
        • Wankowicz SAM
        • Liu D
        • et al.
        The long tail of oncogenic drivers in prostate cancer.
        Nat Genet. 2018; 50: 645-651https://doi.org/10.1038/s41588-018-0078-z
        • Abida W
        • Cheng ML
        • Armenia J
        • et al.
        Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade.
        JAMA Oncol. 2019; 5: 471-478https://doi.org/10.1001/jamaoncol.2018.5801
        • Briggs S
        • Tomlinson I.
        Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers.
        J Pathol. 2013; 230: 148-153https://doi.org/10.1002/path.4185
        • Lee L
        • Ali S
        • Genega E
        • Reed D
        • Sokol E
        • Mathew P
        Aggressive-variant microsatellite-stable POLE mutant prostate cancer with high mutation burden and durable response to immune checkpoint inhibitor therapy.
        JCO Precis Oncol. 2018; : 1-8https://doi.org/10.1200/PO.17.00097
        • Chung JH
        • Dewal N
        • Sokol E
        • et al.
        Prospective comprehensive genomic profiling of primary and metastatic prostate tumors.
        JCO Precis Oncol. 2019; 3: 1-23https://doi.org/10.1200/PO.18.00283
        • Hsiehchen D
        • Watters MK
        • Lu R
        • Xie Y
        • Gerber DE
        Variation in the assessment of immune-related adverse event occurrence, grade, and timing in patients receiving immune checkpoint inhibitors.
        JAMA Netw Open. 2019; 2e1911519https://doi.org/10.1001/jamanetworkopen.2019.11519
        • Robinson D
        • Van Allen EM
        • Wu YM
        • et al.
        Integrative clinical genomics of advanced prostate cancer.
        Cell. 2015; 161: 1215-1228https://doi.org/10.1016/j.cell.2015.05.001
        • Pantelidou C
        • Sonzogni O
        • De Oliveria Taveira M
        • et al.
        PARP inhibitor efficacy depends on CD8+ T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer.
        Cancer Discov. 2019; 9: 722-737https://doi.org/10.1158/2159-8290.CD-18-1218
        • Rosenberg JE
        • Hoffman-Censits J
        • Powles T
        • et al.
        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. 2016; 387: 1909-1920https://doi.org/10.1016/S0140-6736(16)00561-4
        • Balar A V.
        Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
        Lancet. 2017; 389: 67-76https://doi.org/10.1016/S0140-6736(16)32455-2
        • Powles T
        • Durán I
        • van der Heijden MS
        • et al.
        Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.
        Lancet. 2018; 391: 748-757https://doi.org/10.1016/S0140-6736(17)33297-X
        • Bellmunt J
        • De Wit R
        • Vaughn DJ
        • et al.
        Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
        N Engl J Med. 2017; 376: 1015-1026https://doi.org/10.1056/NEJMoa1613683
        • Powles T
        • Park SH
        • Voog E
        • et al.
        Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma.
        N Engl J Med. 2020; 383: 1218-1230https://doi.org/10.1056/NEJMoa2002788
      1. Sridhar SS. Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): Association between clinical outcomes and exploratory biomarkers. In: ESMO 2020; 2020:699O.

        • Necchi A
        • Anichini A
        • Raggi D
        • et al.
        Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): An open-label, single-arm, phase II study.
        J Clin Oncol. 2018; 36: 3353-3360https://doi.org/10.1200/JCO.18.01148
        • Powles T
        • Kockx M
        • Rodriguez-Vida A
        • et al.
        Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.
        Nat Med. 2019; 25: 1706-1714https://doi.org/10.1038/s41591-019-0628-7
        • Gao J
        • Navai N
        • Alhalabi O
        • et al.
        Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.
        Nat Med. 2020; (Published online October)https://doi.org/10.1038/s41591-020-1086-y
        • Teo MY
        • Seier K
        • Ostrovnaya I
        • et al.
        Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers.
        J Clin Oncol. 2018; 36: 1685-1694https://doi.org/10.1200/JCO.2017.75.7740
        • McDermott DF
        • Huseni MA
        • Atkins MB
        • et al.
        Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.
        Nat Med. 2018; 24: 749-757https://doi.org/10.1038/s41591-018-0053-3
        • Necchi A
        • Bratslavsky G
        • Corona RJ
        • et al.
        Genomic characterization of testicular germ cell tumors relapsing after chemotherapy.
        Eur Urol Focus. 2020; 6: 122-130https://doi.org/10.1016/j.euf.2018.07.013
        • Fankhauser CD
        • Curioni-Fontecedro A
        • Allmann V
        • et al.
        Frequent PD-L1 expression in testicular germ cell tumors.
        Br J Cancer. 2015; 113: 411-413https://doi.org/10.1038/bjc.2015.244
        • Adra N
        • Althouse SK
        • Ammakkanavar NR
        • et al.
        Phase II trial of pembrolizumab in patients (pts) with incurable platinum refractory germ cell tumors (GCT).
        J Clin Oncol. 2017; 35 (4520-4520)https://doi.org/10.1200/JCO.2017.35.15_suppl.4520
        • Necchi A
        • Giannatempo P
        • Raggi D
        • et al.
        An open-label randomized phase 2 study of Durvalumab Alone or in Combination with Tremelimumab in Patients with Advanced Germ Cell Tumors (APACHE): results from the first planned interim analysis.
        Eur Urol. 2019; 75: 201-203https://doi.org/10.1016/j.eururo.2018.09.010
        • Raj N
        • Zheng Y
        • Kelly V
        • et al.
        PD-1 blockade in advanced adrenocortical carcinoma.
        J Clin Oncol. 2020; 38: 71-80https://doi.org/10.1200/JCO.19.01586
        • Le Tourneau C
        • Hoimes C
        • Zarwan C
        • et al.
        Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial.
        J Immunother cancer. 2018; 6: 111https://doi.org/10.1186/s40425-018-0424-9
        • Udager AM
        • Liu TY
        • Skala SL
        • et al.
        Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: Potential opportunities for immunotherapeutic approaches.
        Ann Oncol. 2016; 27: 1706-1712https://doi.org/10.1093/annonc/mdw216
        • Hui G
        • Ghafouri SN
        • Shen J
        • Liu S
        • Drakaki A
        Treating penile cancer in the immunotherapy and targeted therapy era.
        Case Rep Oncol Med. 2019; 2019: 1-4https://doi.org/10.1155/2019/8349793
        • Teng MWL
        • Ngiow SF
        • Ribas A
        • Smyth MJ
        Classifying cancers based on T-cell infiltration and PD-L1.
        Cancer Res. 2015; 75: 2139-2145https://doi.org/10.1158/0008-5472.CAN-15-0255