Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.

In summary, high PD-L1 expression in patients with neuroblastoma may represent an unfavorable prognostic factor associated with a higher risk of cancer relapse. This work proposes PD-L1 immunohistochemical assessment as a novel parameter for identifying patients with an increased likelihood of cancer recurrence.

Dermoscopy and RCM may be useful tools for the identification of DM. Certain RCM features may help distinguish DM from MIS and other invasive melanomas. Larger studies are warranted.

The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are < 15%. Hence, melanoma detection in earlier stages (stages I-III) maximises the chances of patient survival. We measured the expression of a panel of 17 microRNAs (miRNAs) (MELmiR-17) in melanoma tissues (stage III; n = 76 and IV; n = 10) and serum samples (collected from controls with no melanoma, n = 130; and patients with melanoma (stages I/II, n = 86; III, n = 50; and IV, n = 119)) obtained from biobanks in Australia and Germany. In melanoma tissues, members of the 'MELmiR-17' panel were found to be predictors of stage, recurrence, and survival. Additionally, in a minimally-invasive blood test, a seven-miRNA panel (MELmiR-7) detected the presence of melanoma (relative to controls) with high sensitivity (93%) and specificity (≥ 82%) when ≥ 4 miRNAs were expressed. Moreover, the 'MELmiR-7' panel characterised overall survival of melanoma patients better than both serum LDH and S100B (delta log likelihood = 11, p < 0.001). This panel was found to be superior to currently used serological markers for melanoma progression, recurrence, and survival; and would be ideally suited to monitor tumour progression in patients diagnosed with early metastatic disease (stages IIIa-c/IV M1a-b) to detect relapse following surgical or adjuvant treatment.

Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAF^V600E melanoma. In AJCC stage III melanoma patients, CD73 expression (the enzyme that generates adenosine) correlated significantly with patients presenting nodal metastatic melanoma, suggesting that targeting this pathway may be effective in advanced stage disease. In addition, dabrafenib and trametinib treatment of CD73⁺ BRAF^V600E-mutant melanomas caused profound CD73 downregulation in tumor cells. Inhibition of BRAF and MEK in combination with the A2A adenosine receptor provided significant protection against tumor initiation and metastasis formation in mice. Our results suggest that targeting adenosine may enhance therapeutic responses for melanoma patients receiving targeted or immune-based therapies. <i>Cancer Res; 77(17); 4684-96. ©2017 AACR</i>.

Here we have carried out a multiparameter analysis using a panel of 28 immunohistochemical markers to identify markers of transformation from benign and dysplastic naevus to primary melanoma in three separate cohorts totalling 279 lesions. We have identified a set of eight markers that distinguish naevi from melanoma. None of markers or parameters assessed differentiated benign from dysplastic naevi. Indeed, the naevi clustered tightly in terms of their immunostaining patterns whereas primary melanomas showed more diverse staining patterns. A small subset of histopathologically benign lesions had elevated levels of multiple markers associated with melanoma, suggesting that these represent naevi with an increased potential for transformation to melanoma.

9011 Background: Higher overall burden of somatic mutations in tumors may be associated with better response rates to immunotherapy. Desmoplastic melanoma (DM) is a rare subtype of melanoma comprising approximately 1% of cases. Since DM has been reported to have a higher mutational load than other sub-types of melanoma, we hypothesized that patients with metastatic DM may respond more frequently to anti-PD1 or anti-PDL1 immunotherapies. Methods: A retrospective analysis of over 1000 melanoma patients treated with anti-PD1/PDL1 therapies among seven institutions (UCLA, MD Anderson, UCSF, Memorial Sloan Kettering, Vanderbilt, Melanoma Institute Australia, and Westmead) was conducted to identify patients with DM. We assessed objective response rates (ORR), overall survival (OS), and progression-free survival (PFS). Results: We identified 23 patients with stage IV DM (either pure or mixed subtype), 2 with stage M1a, 11 with M1b, and 10 with M1c disease. Eighteen patients had received prior systemic therapy, including 12 whose disease progressed following ipilimumab. Three patients were treated with nivolumab (anti-PD1 antibody, doses 0.1 or 3 mg/kg), 1 with nivolumab (3mg/kg) plus ipilimumab (1 mg/kg), 3 with BMS-936559 (anti-PDL1, 0.1 or 0.3 mg/kg), and 16 with pembrolizumab (anti-PD1, 2 or 10 mg/kg). Patients received a median of 9 cycles of therapy. A RECIST ORR of 70% was observed, including 9 complete responses and 7 partial responses (3 with > 75% decrease in tumor size per RECIST criteria). Median length of follow-up was 13.4 months. Three patients with eventual isolated progression underwent surgical excision without further disease progression, and only 2 of 23 patients received subsequent systemic therapy. Eighteen patients were alive at last follow-up; Kaplan-Meier median OS (range 2.8 months to 3.5+ years) and median PFS (range 1.4 months to 2.7+ years) were not reached. Conclusions: Patients with metastatic DM appear to have higher response rates and favorable clinical outcomes to anti-PD/PDL1 therapy compared to other patients with advanced melanoma. Additional mechanistic studies are ongoing.

Whole-genome sequencing of matched germline and tumour pairs in a well-characterized cohort of melanoma patients allowed investigation of associations between melanoma body site, age at melanoma onset and MC1R variant status with overall mutation burden and specific base pair changes observed in the corresponding melanoma. We observed statistically significant associations between mutation burden in melanoma and body site, age at onset and MC1R genotype, for both ultraviolet radiation (UVR) signature changes (C>T and CC>TT) and non-UVR base pair substitutions, as well as with overall variant load.

9541 Background: BRAF V600E and V600K/R mm have distinct clinicopathologic features suggesting different etiology. V600K/R mm appears less responsive to MAPK inhibitors (MAPKi) compared to V600E MM. We investigated potential mechanisms for this by comparing the gene expression and mutation profiles of these two melanoma subgroups. Methods: BRAF V600 mutant mm patients (pts) treated with MAPKi (BRAFi +/- MEKi) between July/2009 and July/2013 were selected. Demographics, clinicopathologic features and clinical outcomes were examined. Pre-treatment FFPE tumors underwent RNA expression profiling (795-gene nanostring panel) and DNA sequencing (239 gene NGS panel). Molecular results were validated using an independent cohort from the The Cancer Genome Atlas (TCGA). Results: 95 mm pts were included (78 V600E, 17 V600K/R), with median (med) follow-up of 18.4 months (mo). 74 (78%) had BRAFi, 21 (22%) had BRAF/MEKi. At MAPKi start, there were no differences between subgroups regarding age, gender, ECOG, AJCC stage or LDH level. V600K/R pts had a trend to less tumour regression by RECIST (med 30% vs 51%, p = 0.08) and shorter PFS (med 5.1 vs 7.1mo, p = 0.08) than V600E, with no difference in OS (20.8mo vs 17.9mo, p = 0.64). V600K/R had lower expression of the MAPK-pathway feedback regulator DUSP6 and glycosyltransferase GCNT1, compared to V600E (p &lt; 0.05). Analysis of TCGA data (122 V600E, 21 V600K/R) confirmed these findings. There was a trend toward higher mutational load in V600K/R than V600E, confirmed with TCGA data (p &lt; 0.05). V600K/R had a higher proportion of mutations in PIK3CA and several tumour suppressor genes (FBXW7, NF2, RB1 and SMAD4), with only FBXW7 confirmed using TCGA data. Conclusions: V600K/R mm has inferior response and shorter survival with MAPKi than V600E, potentially due to less reliance on MAPK pathway activation (lower DUSP6 expression) and greater use of alternative drivers of oncogenesis (higher mutational load, particularly in tumor suppressor genes). Further analyses will be performed, including comparison of MAPK and additional pathway signalling in cell models. Response to immunotherapy will also be examined.

Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-κB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorage-independent cell growth in an NF-κB-dependent manner. We identified DNA copy-number gain and constitutive ubiquitination by a TNFα autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-κB-dependent activation mechanism as a novel approach to treat this disease.

Cancer research continues to highlight the extensive genetic diversity that exists both between and within tumors. This intrinsic heterogeneity poses one of the central challenges to predicting patient clinical outcome and the personalization of treatments. Despite progress in some individual tumor types, it is not yet possible to prospectively, accurately classify patients by expected survival. One hypothesis proposed to explain this is that the prognostic classifiers developed to date are insufficiently sensitive and specific; however it is also possible that patients are not equally easy to classify by any given biomarker. We demonstrate in a cohort of 45 AJCC stage III melanoma patients that clinico-pathologic biomarkers can identify those patients that are most likely to be misclassified by a molecular biomarker. The process of modelling the classifiability of patients was then replicated in a cohort of 49 stage II breast cancer patients and 53 stage III colon cancer patients. A multi-step procedure incorporating this information not only improved classification accuracy but also indicated the specific clinical attributes that had made classification problematic in each cohort. These findings show that, even when cohorts are of moderate size, including features that explain the patient-specific performance of a prognostic biomarker in a classification framework can improve the modelling and estimation of survival.

Editorial piece on a novel and innovative approach to estimating the prevalence of different types of melanocytic lesions in all adults undergoing skin biopsies in a population described by Lott et al.

Answer questions and earn CME/CNE To update the melanoma staging system of the American Joint Committee on Cancer (AJCC) a large database was assembled comprising >46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. Based on analyses of this new database, the existing seventh edition AJCC stage IV database, and contemporary clinical trial data, the AJCC Melanoma Expert Panel introduced several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. Key changes in the eighth edition AJCC Cancer Staging Manual include: 1) tumor thickness measurements to be recorded to the nearest 0.1 mm, not 0.01 mm; 2) definitions of T1a and T1b are revised (T1a, <0.8 mm without ulceration; T1b, 0.8-1.0 mm with or without ulceration or <0.8 mm with ulceration), with mitotic rate no longer a T category criterion; 3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB); 4) the N category descriptors "microscopic" and "macroscopic" for regional node metastasis are redefined as "clinically occult" and "clinically apparent"; 5) prognostic stage III groupings are based on N category criteria and T category criteria (ie, primary tumor thickness and ulceration) and increased from 3 to 4 subgroups (stages IIIA-IIID); 6) definitions of N subcategories are revised, with the presence of microsatellites, satellites, or in-transit metastases now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any; 7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and 8) a new M1d designation is added for central nervous system metastases. This evidence-based revision of the AJCC melanoma staging system will guide patient treatment, provide better prognostic estimates, and refine stratification of patients entering clinical trials. CA Cancer J Clin 2017;67:472-492. © 2017 American Cancer Society.