Investigating molecular profiles of subtypes of mucosal melanomas: Is vulvovaginal melanoma a distinct entity? (263)

Abstract

<b>Objectives:</b> Vulvovaginal melanomas (VVM) are considered to be a subtype of mucosal melanoma (MM) that are less immunogenic and less responsive to immuno-oncology therapy (IO) than cutaneous melanoma (CM). Due to the rarity of MM, there is a paucity of data regarding the molecular and immune profile differences between MM subtypes. Herein we compared VVM with other subtypes of mucosal melanoma and explored the significance of IO agents on survival. <b>Methods:</b> Tumor samples were analyzed using next-generation sequencing (TruSeq, 45 genes; NextSeq, 592 genes and NovaSeq, WES), IHC, and WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was tested by IHC using 28-8 (Agilent) and SP-142 (Spring Biosciences) (positive cut-off ≥1%). MSI was tested by FA, IHC, and NGS. TMB was measured by totaling somatic mutations per tumor (TMB-high cut-off ≥ 10 mutations per MB). Immune cell fraction was calculated by Q uantiSeq. (Finotello 2019, Genome Medicine). Survival was extracted from insurance claims data and calculated from the time of IO treatment to the last contact using Kaplan-Meier survival curves for molecularly defined cohorts. Statistical significance was determined using Chi-square and Wilcoxon rank-sum test and adjusted for multiple comparisons (q<0.05). <b>Results:</b> A total of 183 VVM, 84 anorectal melanomas (ARM), and 95 head and neck mucosal melanomas (HNM) tumors were evaluated. The median ages of each cohort were 66, 67, and 71, respectively. The <i>SF3B1</i> RNA splicing gene was more frequently mutated among VVM and ARM compared with HNM (26.7%, 36.2%, and 1.8%, respectively, q<0.01). There was also a trend toward higher rates of <i>TP53</i> and <i>KIT</i> mutations in VVM and ARM compared with HNM. <i>BRCA1</i> and <i>APC</i> mutations were found exclusively in ARM tumors. <i>KIT</i> was the most common biomarker amplification (14.5% VVM, 10.5% ARM, and HNM). Otherwise, rates of biomarker amplification were low overall. When evaluating IO therapy-related biomarkers, VVM had the highest rate of PD-L1 positivity (34.6%) compared to ARM (18.5%) and HNM (33.3%). High TMB was present in 4.2% of ARM, 4.8% of HNM, and 0% of VVM tumors. MSI-H/dMMR tumors were absent in all three cohorts. Immune cell infiltrates were similar among all MM tumors, except for an increase in regulatory T cell infiltration in VVM tumors (q<0.01). Treatment and survival data were available for 119 VVM, 61 ARM, 42 HNM, and 4839 CM patients. Of these, 17% VVM (<i>n</i>=20), 31% ARM (<i>n</i>=19), 14% HNM (<i>n</i>=6) and 22% CM (<i>n</i>=1056) received IO therapy. Median survival was 17.5 months (mo) for VVM, 16.8 mo for ARM, and 33 mo for HNM, none of which were significantly different. There was a trend toward better survival for CM patients on IO therapy compared to MM patients (36.6 mo vs 18.8 mo, HR: 0.67, 95% CI: 0.45-1.06, p=0.087). <b>Conclusions:</b> MM represents a unique subset of melanoma, with worse survival and response to IO therapy than CM. VVM and ARM appear to be more similar on a molecular level than HNM.