{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T00:10:24Z","timestamp":1792887024304,"version":"4.5.0"},"reference-count":37,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Tumor mutational burden (TMB) is a putative biomarker of efficacy for immune checkpoint inhibitor (ICI) therapies of solid tumors, but not specifically for penile squamous cell carcinoma (PSCC).<\/jats:p><\/jats:sec>Objective<\/jats:title>To characterize biomarker features and ICI therapy outcomes associated with high TMB in PSCC in the routine clinical practice setting.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>In this cohort study, 397 PSCC cases were analyzed to identify genomic alterations in more than 300 cancer-associated genes and genomic signatures, including TMB, using a hybrid capture\u2013based comprehensive genomic profiling assay. Tumor mutational burden was categorized as low (&amp;lt;10 mutations per megabase [mut\/Mb]), high (10-19 mut\/Mb), or very high (\u226520 mut\/Mb). Germline status of genetic alterations was predicted using a validated somatic-germline computational method. Clinical outcomes of patients with metastatic PSCC receiving first-line ICI were abstracted using the deidentified nationwide Clinico-Genomic Database (CGDB) from January 1, 2011, through December 31, 2022.<\/jats:p><\/jats:sec>Exposure<\/jats:title>Comprehensive genomic profiling was performed using FoundationOne and FoundationOne CDx assays from Foundation Medicine Inc.<\/jats:p><\/jats:sec>Main outcomes and measures<\/jats:title>The spectrum of genetic alterations by TMB level in PSCC, the percentage of germline genetic alterations, and the outcome (overall survival with routine clinical treatment) by TMB of chemotherapy-naive patients with PSCC who received ICI treatment up front were assessed in this descriptive study.<\/jats:p><\/jats:sec>Results<\/jats:title>Among 397 patients (median [IQR] age, 65 [54-73] years; 266 [67.0%] of European, 83 [20.9%] of admixed American, and 34 [8.5%] of African or other genomic ancestry), the median (IQR) age (eg, 65 [53-73] years for low TMB vs 68 [61-78] years for TMB \u226510 mut\/Mb) and genomic ancestry distribution (eg, European 228 of 339 [67.3%] for low TMB vs 38 of 58 [65.5%] for TMB \u226510 mut\/Mb) were similar between TMB subgroups. There were 339 PSCC cases (85.4%) with low TMB, 40 cases (10.1%) with high TMB, and 18 cases (4.5%) with very high TMB. Comparisons of TMB of 10 mut\/Mb or higher vs low TMB showed an enrichment of genetic alterations in PIK3CA<\/jats:italic> (48.3% vs 18.3%; P<\/jats:italic>\u2009&amp;lt;\u2009.001) and KMT2D<\/jats:italic> (29.3% vs 7.7%; P<\/jats:italic>\u2009&amp;lt;\u2009.001) and less frequent genetic alterations in CDKN2A<\/jats:italic> (25.9% vs 45.7%; P<\/jats:italic>\u2009=\u2009.05). Most genetic alterations did not co-occur. Human papillomavirus identification was more frequent as TMB increased: 28.3% for low TMB, 50.0% for high, and 72.2% for very high. In total, 95 of 1377 genetic alterations (6.9%) were germline. Of 10 patients identified from the CGDB receiving frontline ICIs, median (IQR) follow-up was 9.9 months. Four patients had overall survival with clinical treatment of more than 12 months, including 2 of 3 patients with TMB of 10 mut\/Mb or higher.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this cohort study of advanced metastatic PSCC based on TMB levels, significant differences were observed for biomarkers in nearly 15% of patients with a TMB of 10 mut\/Mb or higher. Germline testing and ICI-based therapy should be integrated into the management of selected PSCC cases.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.48002","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T16:32:38Z","timestamp":1703694758000},"page":"e2348002","source":"Crossref","is-referenced-by-count":42,"title":["Genomic Profiles and Clinical Outcomes of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden"],"prefix":"10.1001","volume":"6","author":[{"given":"Andrea","family":"Necchi","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy"},{"name":"Vita-Salute San Raffaele University, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe E.","family":"Spiess","sequence":"additional","affiliation":[{"name":"Department of GU Oncology, H. 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P.","family":"Huang","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas I.","family":"Lin","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Danziger","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S.","family":"Ross","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc, Cambridge, Massachusetts"},{"name":"SUNY Upstate Medical University, Syracuse, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Jacob","sequence":"additional","affiliation":[{"name":"SUNY Upstate Medical University, Syracuse, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Sager","sequence":"additional","affiliation":[{"name":"SUNY Upstate Medical University, Syracuse, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Basnet","sequence":"additional","affiliation":[{"name":"SUNY Upstate Medical University, Syracuse, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Li","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryon P.","family":"Graf","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean C.","family":"Pavlick","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc, Cambridge, 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