Rare Subtype Of Melanoma Research Articles

801P Neoadjuvant checkpoint inhibitor immunotherapy (IMT) for resectable mucosal melanoma (MM)

Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients (pts) with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in pts with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for pts with resectable MM. Under an institutionally approved research protocol, we identified adult MM pts with resectable disease who received neoadjuvant anti-PD1 +/- anti-CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade ≥3 toxicities were assessed. We identified 36 pts. Median age was 62; 58% were female. 78% of pts got anti-PD1 + anti-CTLA4. Node-positive disease or satellite lesions was present in 47% of pts. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of pts did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2mo with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for pts with objective response and for pts with pathologic response. OS was significantly higher for pts with pathologic response. Grade 3 toxicities were reported in 39% of pts. Neoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these pts.

Vulvovaginal melanoma or vulvar and vaginal melanoma: Can these tumors be considered the same? (009)

<b>Objectives:</b> Vulvovaginal melanoma (VVM) is a rare but aggressive subtype of melanoma. VVM is considered to be less immunogenic and less responsive to immune-oncology therapy (IO) than cutaneous melanomas (CM). Vulvar and vaginal melanomas are typically grouped together due to the rare nature of the disease, though limited data suggest worse outcomes with vaginal melanomas. There is a paucity of data regarding molecular differences between these two melanoma subtypes. Our goal was to explore molecular profiles and survival between vaginal and vulvar melanomas. <b>Methods:</b> Samples were analyzed using next-generation sequencing (NGS) (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%). Microsatellite instability (MSI) was tested by fragment analysis (FA), immunohistochemistry (IHC), and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cut-off ≥10 mutations/MB). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Real-world overall survival (OS) 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 were included in this analysis: 137 (74.9%) vulvar and 46 (25.1%) vaginal. Rates of gene mutations between these tumors were similar. Vaginal tumors trended toward increased frequency of <i>ATRX</i> (47.1 vs 23.2%) and <i>TP53</i> (29.0 vs 16.1%) mutations compared to vulvar tumors. Vulvar tumors trended toward higher rates of <i>SF3B1</i> mutations (33.8 vs 4%) as well as more <i>KIT</i> mutations (17.7 vs 8.8%) and amplification (16.7 vs 8.0%). PD-L1 expression was similar in vaginal and vulvar tumors (40 vs 32.7%). MMR deficiency and high TMB were absent in both groups. Vulvar melanoma trended towards increased immune checkpoint gene expression compared to vaginal melanoma, most notably a 2-fold increase in both <i>IFNG</i> and <i>IDO1</i> expression. No difference was seen in immune cell infiltrates. Treatment and survival data were available for 78 vulvar and 40 vaginal melanomas (OS: 34 vs 21 mo). In total, 15% of vulvar patients (<i>n</i>=12) and 18% of vaginal patients (<i>n</i>=7) received IO therapy. Median survival was similar between groups (vulvar 18 mo vs vaginal 19 mo, p=0.9). The survival of cutaneous melanoma (CM) patients receiving IO therapy (<i>n</i>=1047) was roughly twice as long (36.6 mo,p=0.038). <b>Conclusions:</b> This is one of the largest VVM cohorts to be studied to date. Overall, we found that these tumors were very similar in their molecular profiles and immunogenicity. Survival and response to IO therapy appeared similar between vulvar and vaginal melanomas. Our findings support continuing study of VVM as a single entity in light of the rarity of this disease.Fig. 1

665 Incidence and characteristics of acral lentiginous melanoma in Asian Americans and Pacific Islanders

Acral lentiginous melanoma (ALM) is a rare but aggressive subtype of cutaneous malignant melanoma (CMM). While uncommon in White individuals, ALM represents a higher proportion of CMM in skin of color (e.g. Asian Americans). Patients of color have worse CMM outcomes and ALM-specific survival compared to White patients, yet the reasons for these differences remain unclear. Given its rarity, there have been limited population-based studies of ALM incidence and tumor characteristics among Asian Americans and Pacific Islanders (AAPI).

Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma

BackgroundAcral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed...

Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study

Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P= 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P= 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Abstract 1514: Examining the impact of chromosomal instability on mucosal melanoma tumor infiltrate and responses to PD-1 based therapy

Abstract Mucosal melanoma (McM) is a rare subtype of melanoma arising from melanocytes of mucosal surfaces that comprises less than 2% of all melanomas in the US. Although PD-1 based checkpoint inhibition is standard initial therapy, McM has been shown to respond less often than cutaneous melanoma. We explored the hypothesis of this resistance being due to a lower tumor mutational burden (TMB) and high levels of chromosomal instability resulting in the formation of micronuclei, a greater than average fraction of genome altered (FGA) as defined by the MSK-IMPACT hybridization capture based NGS platform, and decreased immune infiltration. We utilized MSK-IMPACT data, to collect TMB and FGA data from 112 mucosal melanoma patients of which 56 had received frontline PD-1 based immunotherapy (28 a-PD-1 nivolumab/pembrolizumab, 28 nivolumab + ipilimumab). This population had a median follow-up time of 92 months, median progression free survival (PFS) of 13 months and median overall survival (OS) of 47 months. Dichotomized TMB was not associated with PFS or OS. However, higher than median FGA was associated with a significantly worse PFS (median 16 months vs. not reached [NR]) and OS (median 38months vs. NR). We then explored the association to traditional markers of chromosomal instability using multiplex immunofluorescence (IF) in tumor samples taken from 18 patients within the treatment cohort. We quantified cGMP-AMP synthase (cGAS) positive micronuclei present and found that FGA correlated directly with the number of micronuclei in the tumor, supporting that FGA is a reasonable indicator of chromosomal instability. As expected, there was no such association with micronuclei and TMB. Using multiplex IF we quantified CD8+ and CD8xPD1 co-positive cells at the tumor invading margin. Tumors with higher FGA had lower infiltration of CD8+ cells and CD8xPD1 co-positive cells. The same relationship was found when directly comparing number of micronuclei to CD8+ and CD8xPD1 co-positive cells. Our data suggests that patients with McM that harbor higher levels of chromosomal instability characterized by presence of micronuclei and resultant higher fraction of genome altered on MSK-IMPACT have fewer PD1+/CD8+ T cells in the tumor microenvironment and have inferior progression-free and overall survival with standard PD-1 blockade. This immunosuppressive mechanism may represent a uniquely poor prognosis group that may benefit from altering the downstream signaling resultant of chromosomal instability. Citation Format: Emma Armstrong, Lee Gottesdiener, Nikolaus Schultz, Samuel F. Bakhoum, Travis J. Hollmann, Alexander Shoushtari. Examining the impact of chromosomal instability on mucosal melanoma tumor infiltrate and responses to PD-1 based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1514.

Abstract 6130: Comprehensive genomic and transcriptomic profiling of acral lentiginous melanoma

Abstract Background: Acral lentiginous melanoma (ALM) is a rare melanoma subtype found on the palms, soles and nailbeds. Outcomes are poor for patients with advanced ALM, and novel treatment approaches are needed. Here, we seek to explore the global genomic and transcriptomic landscape of ALM. Methods: A total of 699 primary CM (non-ALM cutaneous melanoma) and 18 primary ALM samples underwent next generation sequencing of DNA (592 Gene Panel, NextSeq, or WES, NovaSeq), and whole transcriptome sequencing (NovaSeq, WTS). Wilcoxon, Fisher’s exact test were used to determine statistical significance (displayed as p value without and q value with multi comparison correction). xCell, HLA subtyping, neoantigen load (HBA: high binding affinity; IBA: intermediate binding affinity; LBA: low binding affinity), Interferon gamma score (IFNγ), MAPK pathway activity score (MPAS), and Innate anti-PD-1 Resistance score (IPRES) were calculated by mRNA expression. Global differentially regulated genes were assessed via limma R package (C: log fold change). Results: The most common alterations in ALM included NRAS (22.2%), NF1 (20.0%), BRAF (11.1%) and CDKN2A (11.1%) mutations, and EMSY (22.2%), ELL (11.1%), MAML2 (11.1%), MRE11(11.1%) and PIK3R2 (11.1%) amplifications. ALM had lower TMB (1.5 v 9 Mut/Mb, q&amp;lt;.0001), lower rates of TERT (0 v 66.7%, q&amp;lt;.01) and a trend towards lower BRAF (11.1 v 39.8%, p&amp;lt;.05) mutations, compared to CM. Neoantigen load was lower in ALM compared to CM, regardless of MHC binding affinity (HBA: 1 vs 4, q &amp;lt;.01; IBA: 2 vs 7, q &amp;lt;.001; LBA: 7 vs 18, q &amp;lt;.001). HLA-G RNA expression was upregulated in ALM with respect to CM (C = 1.14, q &amp;lt;.001). ALM showed less CD4+ T cell Th1 (C = -0.8, p &amp;lt;.05), B cell plasma (C = -1.8, p&amp;lt;.05), and γδ T cells (C = -5.9, p&amp;lt;.05), but more CD4+ T cell central memory cell (C = 9.7, p&amp;lt;.05), stroma score (C = 1.7, p&amp;lt;.05), and endothelial cells (C = 1.7, p&amp;lt;.05), versus CM. There was a trend towards lower IFNγ in ALM (-0.4 vs -0.3, p = .1), but no difference in IPRES, compared to CM (-0.09 vs 0.1, p=.9). MPAS scores were lower for ALM compared to CM (-1.6 vs -0.4, q&amp;lt;.001), even when stratifying by BRAF (q&amp;lt;.05) or NF1 (q&amp;lt;.05) status, but not NRAS (p = .22). Pathways related to keratinization (p &amp;lt;.0001) and amyloid fiber formation (p&amp;lt;.0001) were enriched in ALM, due to overexpression of KRT16 (C = 3.5, q &amp;lt;.01), KRT6B (C = 3.4, q &amp;lt;.01), and KRT17 (C = 3.2, q &amp;lt;.05), among others. Conclusion: ALM has distinct immunologic features, including upregulation of HLA-G, as well as lower MAPK activation in ALM, compared to CM, highlighting the need for novel therapeutic approaches in the treatment of this rare subtype. Citation Format: Gino K. In, Jun Yin, Phillip Walker, Justin Moser, Joanne Xiu, Kelsey Poorman, Geoffery T. Gibney, Matthew Oberley, Thuy Phung, Leonel F. Hernandez-Aya, Jose Lutzky, Wolfgang Michael Korn, Michael B. Atkins. Comprehensive genomic and transcriptomic profiling of acral lentiginous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6130.

Uveal melanoma: Real-world analysis of immune checkpoint inhibitors efficacy and lymphocyte-to-monocyte ratio as a biomarker of response.

e21590 Background: Uveal melanoma (UM) is a rare subtype of melanoma. Real-world data is needed to guide management since patients with advanced UM were excluded from immune checkpoint inhibition (ICI) phase III clinical trials. Lymphopenia and elevated monocyte count, which represents a surrogate marker of systemic inflammation and a source of pro-angiogenic tumor-associated macrophages (TAM), have been associated with poor treatment outcomes in various solid tumors. We sought to characterize ICI efficacy in patients with UM vs cutaneous melanoma (CM) and to investigate pre-treatment lymphocyte-to-monocyte ratio (LMR) as a biomarker of response. Methods: We conducted a multicentric cohort study across 3 academic centers in Canada. Best overall responses as per the investigators were recorded. Overall survival (OS) and progression-free survival (PFS) were compared using the log rank (Mantel-Cox) test, with univariate analyses performed using Cox proportional hazard regression model. Results: A total of 122 patients with metastatic melanoma were included, either UM (n = 60) or CM (n = 62). UM patients were treated either with anti-PD-1 monotherapy (69%) or combination with anti-CTLA-4 (31%). Median OS was 35.4 months for CM versus 8.0 months for UM (HR 0.38, 95%CI 0.24-0.60, p = 0.0001). Median PFS was 10.7 months for CM versus 3.5 months for UM (HR 0.38, 95%CI 0.22-0.65, p = 0.0001). Best overall response in the UM group was progressive disease (74%), stable disease (10%) or partial response (16%). In UM patients, higher baseline LMR (HR 0.48, 95%CI 0.24-0.97, p = 0.04) and presence of immune-related adverse events (HR 0.42, 95%CI 0.20-0.89, p = 0.02) were associated with improved OS in univariate analysis. In CM, such association with high LMR was not significant (HR 0.58, 95% 0.28-1.21, p = 0.10) unless excluding patients with corticosteroid-induced lymphopenia due to recently treated brain metastases (HR 0.42, 95%CI 0.19-0.92, p = 0.03). Conclusions: Advanced UM treated with ICI have inferior survival outcomes compared with cutaneous primaries. Higher pre-treatment LMR is associated with improved OS to ICI in UM patients and could represent a surrogate marker of immune activation. Our findings reinforce the need for new treatment strategies in UM.

Comparing overall survival of patients with metastatic uveal melanoma by sequence of Tebentafusp versus combination immune checkpoint inhibitors.

e21505 Background: Uveal melanoma is a rare melanoma subtype with poor outcome from immune checkpoint inhibition (ICI) compared to cutaneous melanoma. UM expresses high levels of Glycoprotein 100 (Gp-100) implicating potential sensitivity to tebentafusp (tebe), a novel immune-mobilizing monoclonal T cell receptor therapy. A recent phase 3 study compared tebe to investigator chosen standard of care (SOC) with crossover at progression. SOC regimens were single agent pembrolizumab, ipilimumab and Dacarbazine with 82% of SOC patients receiving pembrolizumab1. Other single arm studies suggest that survival with combination ICI is superior to single agent. We sought to compare overall survival (OS) of first or second line tebe in relation to combination ICI. Methods: Retrospective chart review at a single institution was conducted on patients with metastatic UM (mUM) treated with tebe on clinical trial between June 2018 and December 2021, either in first [NCT03070392] or second line [NCT02570308] setting. Patients were included if they received ipilimumab plus nivolumab either before or after tebe. Data including patient demographics and factors demonstrated in the phase 2 and 3 trials to correlate with survival including lactate dehydrogenase (LDH), size of largest liver lesion and early onset of rash with tebe were extracted. OS was the main outcome measure and was calculated as the time interval between the date of diagnosis of metastatic disease and date of death. Results: Six patients were identified in our data set as having received both ICI and Tebe, three in each sequence order. Mean characteristics were included in table. OS trended towards improvement in the cohort of patients who received tebe first in sequence both in OS in time from UM diagnosis (42.1 vs 63.5 months) (p = 0.21) and in OS in time from detection of mUM (29.8 vs 42.0 months) (p = 0.28), although neither difference was statistically significant given the small sample size. Conclusions: Our limited data demonstrate longer OS with tebe followed by combination ICI on progression compared to the reverse sequence. This comparison of patients at a single institution is underpowered to show a statistically significant OS difference but does demonstrate a trend in favor of first line tebe similar to the conclusive comparison of tebe and single agent ICI in the randomized trial. Reference: 1. Orloff, Marlana et al. Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in phase 3 randomized trial of first-line metastatic uveal melanoma. (2021): 9526-9526.[Table: see text]

Selected Articles from This Issue

Interleukin-15 (IL-15) regulates the generation, persistence, and differentiation of natural killer (NK) and CD8 T cells. To expand its role in cancer immunotherapy, Chen and colleagues designed a multitumor model treated with the combination of intratumoral anti-CD40, parenteral IL-15 and anti-PD-1. Anti-CD40 given intratumorally not only reduced dosing requirements and toxicity, but it also stimulated the antitumor activity of the distal tumors, suggestive of an abscopal effect. IL-15 with intratumoral anti-CD40 was additive/synergistic, and the inclusion of the anti-PD-1 was additive to the combination. Thus, this treatment shows promise for patients with solid tumors or resistance to anti-PD-1 therapy.Cancer-associated fibroblasts (CAF) are a heterogenous cell population with a complex immunoregulatory role, which has not been well defined in head and neck squamous cell carcinoma (HNSCC). Leveraging protein activity inference tools to analyze scRNA-sequencing of HNSCC patients, pre- and post-nivolumab, Obradovic and colleagues identified distinct subpopulations of head and neck CAF (HNCAF). Enrichment of a T-cell stimulating population (tsCAF) was found to associate with treatment response and ex vivo assays confirmed this CAF subset reduces CD8 T-cell exhaustion. Analysis of an independent HNSCC cohort treated with pembrolizumab validated this tsCAF subset as a potential biomarker of response.Approximately 30% of MSI-H/dMMR tumors do not respond to immune checkpoint inhibitors (ICI), highlighting the importance of identifying predictive biomarkers or molecular profiling correlated with resistance to these agents. Here, Chida and colleagues performed transcriptomic profiling of MSI-H/dMMR gastrointestinal tumors treated with PD-1 blockade. The study revealed that nonresponders had the enrichment of epithelial mesenchymal transition, angiogenesis, hypoxia, mTORC1, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways, which have been associated with an immunosuppressive tumor microenvironment. Meanwhile, the IFN-γ pathway was upregulated in responders. High expression of VEGF-A might predict a negative response to ICI in this population.Acral melanoma is a rare subtype of melanoma that arises on non-sun exposed skin of the hands, feet, and nailbeds. Patients with acral melanoma have lower response rates to immunotherapy than those with nonacral cutaneous melanoma, suggesting unique microenvironmental features. In their study, Li and colleagues performed comprehensive single cell analysis of a cohort of acral melanoma specimens and found them to harbor fewer effector CD8 T cells and NK cells and a complete absence of γδ T cells compared to non-acral cutaneous melanoma. VISTA, TIGIT, and adenosine signaling were identified as targetable immune checkpoints in acral melanoma.

Single-cell Characterization of the Cellular Landscape of Acral Melanoma Identifies Novel Targets for Immunotherapy.

Acral melanoma is a rare subtype of melanoma that arises on the non-hair-bearing skin of the palms, soles, and nail beds. In this study, we used single-cell RNA sequencing (scRNA-seq) to map the transcriptional landscape of acral melanoma and identify novel immunotherapeutic targets. We performed scRNA-seq on nine clinical specimens (five primary, four metastases) of acral melanoma. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by analysis of The Cancer Genome Atlas (TCGA) and single-cell datasets. Cell-cell interactions were inferred and compared with those in nonacral cutaneous melanoma. Multiple phenotypic subsets of T cells, natural killer (NK) cells, B cells, macrophages, and dendritic cells with varying levels of activation/exhaustion were identified. A comparison between primary and metastatic acral melanoma identified gene signatures associated with changes in immune responses and metabolism. Acral melanoma was characterized by a lower overall immune infiltrate, fewer effector CD8 T cells and NK cells, and a near-complete absence of γδ T cells compared with nonacral cutaneous melanomas. Immune cells associated with acral melanoma exhibited expression of multiple checkpoints including PD-1, LAG-3, CTLA-4, V-domain immunoglobin suppressor of T cell activation (VISTA), TIGIT, and the Adenosine A2A receptor (ADORA2). VISTA was expressed in 58.3% of myeloid cells and TIGIT was expressed in 22.3% of T/NK cells. Acral melanoma has a suppressed immune environment compared with that of cutaneous melanoma from nonacral skin. Expression of multiple, therapeutically tractable immune checkpoints were observed, offering new options for clinical translation.

A Case of Amelanotic Melanoma in the Setting of Cemiplimab Therapy for Invasive Squamous Cell Carcinoma

Cemiplimab is the first PD-1 inhibitor approved in the United States for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), but not melanoma. We describe a case of amelanotic melanoma (AM) developing in a patient on cemiplimab therapy for invasive SCC. Cutaneous AM is a rare subtype of cutaneous melanoma that shows little or no melanin pigmentation on clinical and histological examination thus often leading to a high misdiagnosis rate. Physicians should consider atypical presentations of melanoma, including amelanotic melanoma, during surveillance of patients managed with immune checkpoint inhibitor therapy.

Review of bi-specific therapies in uveal melanoma.

Uveal melanoma is a rare subtype of melanoma that once metastatic portends a poor prognosis. Likely due to the distinct differences in biology, metastatic potential, and immunologic profile as compared to cutaneous melanoma, uveal melanoma's response to immune checkpoint inhibition has been disappointing. Bi-specific fusion protein therapies (T cell engagers) are a novel strategy to forcibly bridge the immune system with a target on a cancer cell. This approach has been explored in a number of cancer types and has recently demonstrated success in uveal melanoma. Tebentafusp, a first in class ImmTAC (Immune-mobilizing monoclonal TCRs against cancer), has now shown an overall survival benefit when compared to investigator's choice. This review aims to summarize the experience with this first in class bi-specific T cell engager as well as highlight bi-specifics as a novel treatment strategy in uveal melanoma.

Medial Plantar Fasciocutaneous Flap Reconstruction for Load-Bearing Foot Defects in Patients With Acral Melanoma

Acral lentiginous melanoma (ALM) is a rare subtype of malignant melanoma that usually involves the weight-bearing plantar area. Plantar defect reconstruction has traditionally been performed with skin grafts or free flaps. This study examined the efficacy and safety of a medial plantar artery perforator flap (MPAPF) for plantar defect reconstruction after wide excision of an ALM. Twenty-five patients who underwent reconstruction with a MPAPF between 2011 and 2021 were enrolled in this study. The defects were classified into 6 plantar zones. Demographic and clinical data were retrospectively analyzed. Reconstruction with medial plantar fasciocutaneous island flaps was performed in all cases, except for 4 patients who had lesions in forefoot, which required free medial plantar flaps. Defects in lateral and posterior heel were more likely to present with venous congestion and require longer healing times and revision surgery (P < 0.05). The average follow-up period was 49 months. Four and 5 patients developed local recurrence and distant metastasis, respectively. Four cases of hyperkeratosis and paresthesia were documented, but there were no cases of ulceration or wound dehiscence. None of the cases required secondary debulking procedures. The MPAPF is safe and effective for plantar defect reconstruction among patients with ALM. Meticulous dissection and adequate tunneling are needed, particularly for defects in the lateral and posterior heel, to minimize flap congestion and revision operations.

Clinicopathological profile and outcomes of anorectal melanoma from a tertiary care center in India.

Background:Anorectal melanoma (AM) is a rare subtype of melanoma.Aim:To study the clinic–pathologic features and outcomes in patients with AM.Materials & methods:Clinical, pathologic findings and outcomes of patients with AM were recorded.Results:Twenty-seven patients with AM were identified with median age of 57 years. Most patients presented in stage III (44.4%). Lymph node involvement was seen in 70.4%. The response to chemotherapy and immunotherapy was 16.6 and 25.0%, respectively. At a median follow up of 11 months, median overall survival was 30 months. Ballantine stage 3 and weight loss at presentation were predictors of poor survival.Conclusion:AM presents at an advanced stage with lymph node and distant metastasis.

Investigation of unknown causes of uveal melanoma uncovers seven recurrent genetic mutations

Uveal melanoma (UM) is a rare subtype of melanoma but the most frequent primary cancer of the eye in adults. The goal of this study was to research the genetic causes of UM through a comprehensive frequency analysis of base-pair mismatches in patient genomes. It was hypothesized that chromosomes 15 and 16, due to their role in the expression of eye color, would exhibit UM-associated mutations. The U.S. National Institute of Health (NIH) provided genomic data from surgically resected eye enucleations and liver metastases from 32 UM patients, which we individually analyzed to identify nucleotide base-base mismatches by comparing DNA sequences from cancerous cells to reference DNA sequences. After identifying mismatches we performed a Pareto analysis of cross-patient data to identify chromosomes with recurrent and nonrecurrent genetic mutations across all samples. We then studied the mutated gene functions to evaluate causal links to cancer, such as for genes that encoded known tumor suppressor proteins. We discovered a total of 130 genetic mutations, including seven recurrent mutations, with most mutations occurring in chromosomes 3 and X. Recurrent mutations varied from 8.7% to 17.39% occurrence in the UM patient sample, with all mutations identified as missense. These findings suggest that UM is a recessive heterogeneous disease with selective homozygous mutations. Notably, this study has potential wider significance because the seven genes targeted by recurrent mutations are also involved in other cancers. As a result, immunotherapy is a highly promising treatment for uveal melanoma due to the disease’s heterogeneous nature.

Skin Cancer Back to Basics

ABSTRACT Amelanotic melanoma is a rare subtype of cutaneous melanoma. Sun exposure is a known primary risk factor; however, the mechanism for amelanosis is poorly understood. Amelanotic melanoma is challenging to recognize clinically because of absence of pigment and its resemblance to a variety of benign and malignant neoplasms. Detection often occurs at late or metastatic stages, leading to poorer outcomes. Surgical excision is the current standard of care, with adjuvant therapies under investigation. This article discusses the clinical assessment and management of AM to improve early recognition and patient outcomes.

Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review.

Mucosal melanoma is a rare and aggressive subtype of melanoma. Unlike its cutaneous counterpart, mucosal melanoma has only gained limited benefit from novel treatment approaches due to the lack of actionable driver mutations and poor response to immunotherapy. Over the last years, whole-genome and exome sequencing techniques have led to increased knowledge on the molecular landscape of mucosal melanoma. Molecular studies have underlined noteworthy findings with potential therapeutic implications, including the presence of KIT mutations, which are potential targets of tyrosine kinase inhibitors currently in use in the clinic (imatinib), but also SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are presently under investigation in clinical trials. Recent results from a pooled analysis of patients with mucosal melanoma treated with immunotherapy have suggested that the combination of immune checkpoint inhibitors might improve survival outcomes in this subset of patients, as compared with single-agent immunotherapy. However, these results are not confirmed across different studies, and combo-immunotherapy correlates with a higher rate of adverse events. In this review, we describe the clinical, biological, and genetic features of mucosal melanoma. We also provide an update on the results of approved systemic treatment in this setting and overview the therapeutic strategies currently under investigation in clinical trials.

Sentinel Lymph Node Biopsy Positivity in Patients With Acral Lentiginous and Other Subtypes of Cutaneous Melanoma

Acral lentiginous melanoma (ALM) is a rare subtype of malignant melanoma typically occurring on the palmar and plantar surfaces. Although it has distinctive genetic, prognostic, and behavioral characteristics relative to cutaneous melanomas overall, owing to its rarity, treatment is largely guided by data extrapolated from more common subtypes. Although sentinel lymph node (SLN) status has been shown to be a significant prognostic factor for ALM, the independent effect of ALM-subtype disease on the likelihood of SLN positivity and the stage-specific positivity rates for ALM are not well characterized. To evaluate the association of ALM with SLN status as well as to characterize the clinical stage-specific rates of SLN positivity for ALM based on the AJCC Cancer Staging Manual, 8th edition (AJCC-8). The National Cancer Database (NCDB) includes all reportable cases from Commission on Cancer accredited facilities and represents approximately 50% of all newly diagnosed melanoma cases in the US. This retrospective cohort study included cases of AJCC-8 clinical stage I to II melanomas from the NCDB diagnosed from 2012 to 2015. The analysis took place between April 2021 and September 2021. Melanoma histopathologic subtype. Sentinel lymph node status. We identified 60 148 patients with malignant melanomas, 959 of whom had ALM-subtype disease. Among patients in the cohort, 25 550 (42.5%) were women and the mean (SD) age was 64 (16) years. Multivariable logistic regression controlling for demographic and histopathologic characteristics revealed that ALM was independently associated with the highest risk for SLN positivity among included subtypes (vs superficial spreading melanoma: odds ratio, 1.91; 95% CI, 1.59-2.28). Subgroup analysis by AJCC clinical stage demonstrated that ALM was independently associated with the highest risk for SLN positivity for both stage IB and II disease. The rate of SLN positivity for patients with stage IB and II ALM was 18.39% (95% CI, 13.82%-24.03%) and 39.53% (34.98%-44.26%), respectively. In this cohort study ALM was independently associated with SLN positivity and had relatively high positivity rates at clinical stage IB and II. This suggests that SLNB should be encouraged for all patients with clinical stage IB and II ALM, and such patients should receive appropriate counseling about the higher regional metastatic risk of their cancers. Future work with a larger cohort is required to elucidate the risk of SLN positivity for stage IA ALM.

1047P Efficacy of checkpoint inhibitors (CPIs) in acral melanoma (AM)

AM is a rare melanoma subtype with poor prognosis. While retrospective data suggests low activity of PD1 alone, no data are available on the efficacy of combination PD1/CTLA4 in AM. AM primary site is associated with differences in tumour mutation burden, which may impact CPI activity. We examined the efficacy of CPIs in AM, and in primary site subgroups.