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To the Editor Several positive predictive biomarkers of immune checkpoint inhibitor treatments were recently identified, including high microsatellite instability and elevated tumor mutation burden (TMB).1POLE and POLD1 genes encode DNA polymerases epsilon and delta, respectively, which contain a polymerase domain for DNA replication and an exonuclease domain with proofreading activity that corrects replication errors.2 Because POLE and POLD1 proofreading-inactivating variants have been associated with an ultramutated phenotype, Wang et al3 evaluated POLE/POLD1 nonsynonymous variants as biomarkers for immune checkpoint inhibitor treatment outcome and concluded they were an independent factor of longer overall survival after adjustment for microsatellite instability status and cancer types. This evaluation has 2 major methodological issues.
First, Wang et al3 considered for the POLE/POLD1 variant group “[a]ll nonsynonymous mutations including missense, frame-shift, nonsense, nonstop, splice site, and translation start site changes.” This variant selection has no biological relevance because only POLE/POLD1 missense variants and in-frame deletions located in the proofreading exonuclease domain have been demonstrated as pathogenic.2 Indeed, POLE/POLD1 variants should be considered as pathogenic only when they couple functional polymerase activity with nonfunctional proofreading in the same molecule.4 Hence, most variant types and locations selected by Wang et al3 are unlikely to result in an ultramutated phenotype.
Second, TMB has not been included in the multivariable analysis, though it is a known biomarker for immune checkpoint inhibitor treatment outcome. Wang et al3 indicated in the Methods section that “[t]o compare the tumor mutation burden (TMB) between different groups, a subset generated from MSK-IMPACT was selected to ensure the TMB could be comparable,” but they reported in the Results section that “[t]he TMB of patients with these [POLE/POLD1] mutations was substantially higher than in those without the mutations in most of the cancer types.” From this result, TMB should have been included in the multivariable analysis to evaluate if POLE/POLD1 variant status remained an independent factor of longer overall survival after adjustment with TMB.
Corresponding Author: Lisa Golmard, PharmD, PhD, Department of Genetics, Institut Curie, PSL Research University, 26 rue d’Ulm, F-75005 Paris, France (email@example.com).
Published Online: March 5, 2020. doi:10.1001/jamaoncol.2020.0056
Conflict of Interest Disclosures: None reported.
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Golmard L, Golmard J, Stoppa-Lyonnet D. Evaluation of POLE/POLD1 Variants as Potential Biomarkers for Immune Checkpoint Inhibitor Treatment Outcomes. JAMA Oncol. Published online March 05, 2020. doi:10.1001/jamaoncol.2020.0056
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