Tumor Mutational Burden as a Predictive Biomarker for Immunotherapy Response in Acral Melanoma: A Comprehensive Molecular and Clinical Analysis
Main Article Content
Abstract
Acral melanoma, a rare yet aggressive subtype of cutaneous melanoma, exhibits distinct genomic and clinical characteristics compared to non-acral counterparts. Despite advancements in immune checkpoint inhibitor (ICI) therapy, predictive biomarkers for treatment response remain incompletely elucidated. Tumor mutational burden (TMB), a quantifiable measure of somatic mutations within the tumor genome, has emerged as a potential biomarker for immunotherapy efficacy across various malignancies. This review critically evaluates the role of TMB in predicting clinical outcomes to ICIs in acral melanoma, integrating evidence from molecular profiling studies and clinical trials. We discuss the interplay between TMB, tumor microenvironment (TME), and immune evasion mechanisms, while addressing limitations such as heterogeneity in TMB quantification and confounding factors like ultraviolet (UV) signature mutational patterns. Our analysis underscores the need for standardized TMB thresholds and multimodal biomarker approaches to optimize patient stratification in this challenging disease subset.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
References
I. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711–23 doi 10.1056/NEJMoa1003466.
II. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369(2):122–33 doi 10.1056/NEJMoa1302369.
III. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(17):1627–39 doi 10.1056/NEJMoa1507643.
IV. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1803–13
doi 10.1056/NEJMoa1510665.
V. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372(26):2509–20
doi 10.1056/NEJMoa1500596.
VI. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, 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(10031):1909–20
doi 10.1016/S0140-6736(16)00561-4.
VII. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277–90
doi 10.1056/NEJMoa1712126.
VIII. Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol 2018;36(8):773–9
doi 10.1200/JCO.2017.76.9901.
IX. Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 2015;350(6266):1387–90
doi 10.1126/science.aad1253.
X. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348(6230):124–8
doi 10.1126/science.aaa1348.
XI. .Desrichard A, Snyder A, Chan TA. Cancer Neoantigens and Applications for Immunotherapy. Clin Cancer Res 2016;22(4):807–12
doi 10.1158/1078-0432.CCR-14-3175.
XII. Efremova M, Finotello F, Rieder D, Trajanoski Z. Neoantigens Generated by Individual Mutations and Their Role in Cancer Immunity and Immunotherapy. Front Immunol 2017;8:1679
doi 10.3389/fimmu.2017.01679.
XIII. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science
;348(6230):69–74
doi 10.1126/science.aaa4971.
XIV. Yarchoan M, Johnson BA 3rd, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nature reviews Cancer 2017;17(4):209–22 doi 10.1038/nrc.2016.154.
XV. McGranahan N, Swanton C. Neoantigen quality, not quantity. Sci Transl Med 2019;11(506)
doi 10.1126/scitranslmed.aax7918.
XVI. Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med 2017;377(25):2500–1
doi 10.1056/NEJMc1713444