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Objective: Our goal was to compare molecular and immune profiles of vulvovaginal melanoma (VVM) with cutaneous melanoma (CM) and explore the significance of immune checkpoint inhibitor (ICI) agents on survival., Methods: Samples from VVM and CM tumors underwent comprehensive molecular and immune profiling. Treatment and survival data were extracted from insurance claims data and OS was calculated from time of ICI treatment to last contact. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons., Results: Molecular analysis was performed on 142 VVM and 3823 CM tumors. VVM demonstrated significantly (q < 0·01) less frequent BRAF and more frequent KIT, ATRX, and SF3B1 mutations. Alterations in pathways involving DNA damage and mRNA splicing were more common in VVM, while alterations in cell cycle and chromatin remodeling were less common. Immunogenicity of VVM was lower than CM, with an absence of high TMB (0% vs 46.9%) and lower PD-L1 positivity (18·0% vs 29·5%). Median immune checkpoint gene expression was lower in VVM, as were cell fractions for type I macrophages and CD8+ T-cells(q < 0·01). Myeloid dendritic cells were increased in VVM(q < 0·01). Median OS was shorter for VVM than for CM patients treated with ICIs (17·6 versus 37·9 months, HR:1·65 (95% CI 1·02-2·67) p = 0·04)., Conclusions: VVM has a distinct molecular and immune profile compared to CM, which may contribute to the worse survival in VVM compared to CM patients treated with ICI therapy. Though ICIs have been a mainstay of treatment in recent years, our findings suggest that new therapeutic strategies are needed., Competing Interests: Declaration of competing interest SW and JX are employees of Caris Life Sciences. GTG reports grants from Exelixis and Luceno Dynamics; fees for consulting for Bristol Myers Squibb, Merck, Novartis, Regeneron, Immunocore, Iovance, Lyell Immunopharma, Eisai, Incyte, Pfizer, Sapience Therapeutics, Exicure, and Genentech; fees for payment/honoraria from Immunocore; fees for participation on a Data Safety Monitoring Board/Advisory Board for Huyabio. GKI reports fees for consulting for Sanofi and Pfizer; fees for payment/honoraria from Merck, Sanofi, and Regeneron; fees for support for attending meetings from BMS and Sanofi; fees for participation on a Data Safety Monitoring Board/Advisory Board from Replimune, Castle, and Regeneron; institutional research support from BMS, Regeneron, Replimune, Pfizer, InstilBio, Checkmate Pharmaceuticals, and Xencor. TJH reports consulting fees from J & J, Clovis, AstraZeneca, GSK, Roche Genentech, Caris, Genelux, Aravive, Merck, Eisai, and Seagen. BKE reports fees for participation on a Data Safety Monitoring Board/Advisory Board for Merck and GSK. JB reports fees for consulting for Caris, AstraZeneca, Genentech, GSK Tesaro, and Verastem; fees for participation on a Data Safety Monitoring Board/Advisory Board from Caris, AstraZeneca, GSK Tesaro, and Verastem; fees for a leadership/fiduciary role from American Association of Gynecologic Laparoscopy, and Society of Gynecologic Oncology. The remaining authors have nothing to disclose. All of these disclosures mentioned above are unrelated to this study. No author declares a conflict of interest related to the study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with limited success of immune‐checkpoint inhibitors (ICIs). Approximately half of pSCC cases are associated with human papillomavirus (HPV) infection. Methods: Evaluation was done retrospectively of the landscape of somatic alterations and ICI‐related biomarkers in pSCC by using the Caris Life Sciences data set with the aim to establish signatures for HPV‐dependent oncogenesis. The pSCC tumors were analyzed by using next‐generation sequencing (NGS) of DNA and RNA. Programmed death ligand 1 (PD‐L1) expression was evaluated by immunohistochemistry (IHC). Microsatellite instability (MSI) was tested by fragment analysis, IHC (SP142; ≥1%), and NGS. Tumor mutational burden (TMB)–high was defined as ≥10 mutations/Mb. HPV16/18 status was determined by using whole‐exome sequencing (WES) when available. Significance was adjusted for multiple comparisons (q value <.05). Results: NGS of the overall cohort (N = 108) revealed TP53 (46%), CDKN2A (26%), and PIK3CA (25%) to be the most common mutations. Overall, 51% of tumors were PD‐L1+, 10.7% had high TMB, and 1.1% had mismatch repair–deficient (dMMR)/MSI‐high status. Twenty‐nine patients had their HPV status made available by WES (HPV16/18+, n = 13; HPV16/18−, n = 16). KMT2C mutations (33% vs. 0%) and FGF3 amplifications (30.8% vs. 0%) were specific to HPV16/18+ tumors, whereas CDKN2A mutations (0% vs. 37.5%) were exclusive to HPV16/18− tumors. TMB‐high was exclusively found in the HPV16/18+ group (30.8%). The two groups had comparable PD‐L1 and dMMR/MSI‐H status. Conclusions: In a large and comprehensive NGS‐based evaluation of somatic alterations in pSCC, HPV16/18+ versus HPV16/18− pSCCs were molecularly distinct tumors. Our finding that TMB‐high is exclusive to HPV16/18+ tumors requires confirmation in larger data sets. Plain Language Summary: Penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy in the advanced setting, with poor prognosis and little success with immune‐checkpoint inhibitors (ICIs) in an unselected patient approach. Human papillomavirus (HPV) infection is a known risk factor for pSCC; its impact on genomic tumor profiling is less defined.Using next‐generation sequencing, we explored the genetic landscape and ICI‐related biomarkers of pSCC and HPV‐driven oncogenic molecular signatures.Our results indicate that HPV‐positive and HPV‐negative pSCCs are molecularly distinct tumors. Increased tumor mutational burden is associated with HPV‐positive tumors, and could serve as a biomarker for predicting therapeutic response to ICI‐based therapies.Our results support the growing literature indicating that HPV status in pSCC can be used to guide patient stratification in ICI‐based clinical trials. This study reports on the genetic landscape of immune‐checkpoint inhibitor (ICI) biomarkers in penile squamous cell carcinoma (pSCC) and shows that HPV‐positive and HPV‐negative tumors are molecularly distinct, which is consistent with prior studies. Tumor mutational burden–high status was associated with HPV‐positive tumors. These results support that HPV status in pSCC can be used to guide patient stratification in ICI‐based clinical trials. [ABSTRACT FROM AUTHOR]

To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes. 1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves. The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1 , FGFR2 , CCND1 , and PTEN mutations, as well as increased ER and PR positivity. Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors. • MLH1 hypermethylated patients display discrepant survival and immunotherapy outcomes compared to MLH1 mutated patients. • MLH1 hypermethylated tumors have an altered mutational profile compared to MLH1 mutated tumors. • MLH1 hypermethylated tumors display a more immune cold phenotype than MLH1 mutated tumors. • MLH1 tumors have greater estrogen receptor and progesterone receptor positivity than MLH1 mutated tumors. • The MLH1 hypermethylated cohort may benefit from multiple targeted agents rather than sole checkpoint inhibition. [ABSTRACT FROM AUTHOR]