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To the Editor A recent study published by Wang et al1 evaluated POLE/POLD1 variants as potential biomarkers for immune checkpoint inhibitor (ICI) treatment outcomes in multiple cancer types using the cBioPortal database (https://www.cbioportal.org). The authors conclude that “mutations in all exons of these 2 genes should be integrated into predictive biomarker panels for ICI therapy.”1 However, this interpretation may be incorrect considering that not all POLE/POLD1 variants are oncogenic and therefore would not result in a high tumor mutation burden (TMB).
In fact, only a few hotspot variants in or close to the exonuclease domain of POLE/POLD1 have been shown to be oncogenic and lead to DNA repair defects that result in a high TMB.2 These specific defects result in the accumulation of thousands of somatic variants per genome with a TMB of greater than 50 variants per megabase.3 It is this extremely high TMB that is believed to generate immunogenic neoantigens that render these tumors highly sensitive to immune checkpoint blockade.
Nonhotspot POLE/POLD1 variants are common across tumor types, and most are not oncogenic.3,4 These passenger variants are random events near driver variants undergoing clonal selection. Some of the observed variants in POLE/POLD1 may affect the proofreading function of these genes, but to prove that any of these nonhotspot variants are oncogenic, a subgroup analysis interrogating the clinical consequences of each variant should be performed.
In addition, the data set used in this study appears to be mainly composed of hypermutated tumors (eg, melanoma, lung, bladder, those with microsatellite instability) in which the higher the TMB, the higher the likelihood of passenger POLE/POLD1 variants. Therefore, the higher overall survival observed in these patients is more likely associated with TMB and the type of cancer than with the consequences of the POLE/POLD1 variant itself. To circumvent this problem, the authors should conduct a sensitivity analysis based on TMB thresholds in POLE/POLD1 wild-type tumors vs POLE/POLD1 variant tumors. If better overall survival is observed regardless of the TMB, POLE/POLD1 variants could be considered as a potential biomarker; if not, increased survival in the group with POLE/POLD1 variants would likely be the result of higher TMB.
In our point of view, the authors’ assertions1 could lead to inappropriate use of any POLE/POLD1 variant to guide the selection of patients for ICI therapy. Clinicians caring for patients with POLE/POLD1 variants should be thoughtful prior to selecting therapy based on these findings by Wang et al.1
Corresponding Author: Benoît Rousseau, MD, PhD, Department of Medicine, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, 417 E 68th St, New York, NY 10065 (email@example.com).
Published Online: March 5, 2020. doi:10.1001/jamaoncol.2020.0065
Conflict of Interest Disclosures: Dr Rousseau reported receiving nonfinancial support from Roche/FoundationOne Medicine; receiving personal fees from Bayer and Gilead; receiving nonfinancial support from Astellas and Servier; and serving as the principal investigator of an academic clinical trial assessing nivolumab in POLE-mutated tumors within the exonuclease domain. Dr Vidal reported receiving grants from Sociedad Española de Oncología Médica and Grupo de Tratamiento de los Tumores Digestivos and personal fees from Amgen, Merck Serono, Merck Sharp & Dohme, Roche, and Sanofi. Dr Diaz reported serving on the board of directors of Jounce Therapeutics and Personal Genome Diagnostics; receiving research support from Merck & Co; receiving consultant fees from 4Paws, NeoPhore, and Personal Genome Diagnostics; serving as an uncompensated consultant for Merck & Co; holding multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University; and holding equity in Jounce Therapeutics, NeoPhore, Personal Genome Diagnostics, and Thrive Earlier Detection; and his spouse holds equity in Amgen.
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Rousseau B, Vidal J, Diaz LA. 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.2020.0065
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