1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study

Abstract Background There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma &gt; 1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma &gt; 1 mm in BT. Methods This phase III, multicentre trial [NCT02385214] administered by the Australia &amp; New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma &gt; 1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients’ QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation. Results Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6%; p &lt; 0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6%; p = 0.036). After 12 months’ follow-up, no differences were noted in QoL between groups. Discussion This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma. </jats:sec

Is skipped nodal metastasis a phenomenon of cutaneous melanoma?

From PubMed via Jisc Publications RouterHistory: received 2021-09-20, revised 2021-10-31, accepted 2021-11-04Publication status: aheadofprintSkipped nodal metastasis (SNM) is a recognized phenomenon of visceral cancers when metastases bypass the regional basin and skip to a distant nodal basin without evidence of distant metastases. Its occurrence is undocumented in cutaneous melanoma patients but of potential prognostic significance. We therefore assessed the frequency of SNM in a large series of patients with limb melanomas. We studied melanoma patients attending a tertiary oncology hospital in northwest England using two approaches. First, we systematically searched medical records of an unselected patient sample treated 2002-2015, and second, we studied lymphoscintigrams of all patients with limb melanoma who underwent sentinel node biopsy 2008-2019. Of 672 melanoma patients whose clinical records were examined, 16 had regional nodal metastases without apparent visceral spread and one appeared to have SNM but further scans were uncovered that showed concurrent pulmonary metastases. Of 667 limb melanoma patients with lymphoscintigrams, 7 showed dual lymphatic drainage patterns to distal as well as regional nodal basins, but none had micro-metastases solely in the distant basin. Occurrence of SNM in cutaneous melanoma is highly unlikely. [Abstract copyright: Copyright © 2021. Published by Elsevier Ltd.

Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan–Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20–34) compared with 34 years (95% CI: 30–40) for wild-type individuals (hazard ratio (HR)=1.64, 95% CI: 1.04–2.58, P=0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28–37) compared with 41 years (95% CI: 32–48, HR=1.44, 95% CI: 1.08–1.93, P=0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28–34) compared with 44 years of age (95% CI: 38–53) in wild-type individuals (HR=2.48, 95% CI: 1.47–4.17, P=0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome

Female immunity protects from cutaneous squamous cell carcinoma

PURPOSE: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation. METHODS: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed primary cSCC patients (N=738, N=160), advanced stage cSCC (N=63, N=20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole exome, bulk and single cell RNA sequencing. RESULTS: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations, a response that is absent in prednisolone treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women’s skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. CONCLUSIONS: This work shows the immune response is sex biased in cSCC, and highlights female immunity offers greater protection than male immunity

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma

Unlabelled Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma.Significance Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments