Faculty Bibliography

Currently, there is no validated biomarker to identify patients (pts) with stage III melanoma at high-vs low-risk of early relapse. We studied if ctDNA can predict RFS in these pts. We measured BRAF V600E/K ctDNA at baseline (BL, n = 596), and in plasma samples (73, in n = 41 pts) collected for up to 1 year from COMBI-AD study, comparing dabrafenib + trametinib (D + T) vs placebo in pts with resected BRAF V600 mutant stage III melanoma. We used analytically validated mutation-specific droplet digital PCR assays; ctDNA results were categorized as positive/negative using detection threshold of 0.28 copies/mL (BRAF V600E) and 0.34 copies/mL (BRAF V600K). For visualization of longitudinal analysis, zero cut-off was used. At BL, BRAF ctDNA was detectable in 79/596 pts (13.2%), mostly among pts with higher substage. Pts with detectable BL ctDNA identified a high-risk group with decreased RFS, compared to pts with undetectable BL ctDNA (low-risk group). In placebo arm, median RFS for high-risk group was 3.71 months (mo) vs 24.41 mo for low-risk (HR = 3.1598 [2.1492-4.6456], p < 0.001). In D + T arm, median RFS for high-risk group was 16.59 mo vs 68.11 mo for low-risk (HR = 2.7779 [1.7844-4.3245], p < 0.001). Detectable BL ctDNA was an independent predictor of RFS in a model including age, sex, substage, and treatment (HR = 2.7425 [2.0303-3.7045], p < 0.001). Among subset of pts with longitudinally collected samples, ctDNA was not detectable in 10/11 pts with no relapse events, while ctDNA was detected in 52% of pts with relapse within 3 mo of last longitudinal ctDNA assessment. Further sensitivity and specificity analyses are in progress. The study clinically validates BL BRAF mutant ctDNA as an independent prognostic biomarker for relapse in stage III melanoma. Combined with BL ctDNA assessment, longitudinal ctDNA monitoring may be useful in patient management

Survival outcomes in melanoma, and their association with mutations in the telomerase reverse transcriptase (TERT) promoter, remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism, or vary based on melanoma histopathological subtype. We analyzed 408 primary tumors from a prospective melanoma cohort for somatic TERT^-124[C>T] and TERT^-146[C>T] mutations, the germline polymorphism rs2853669, and BRAF^V600 and NRAS^Q61 mutations. We tested the associations between these variants and clinicopathologic factors and survival outcomes. TERT^-124[C>T] was associated with thicker tumors, ulceration, mitoses (>0/mm²), nodular histotype and CNS involvement. In a multivariable model controlling for AJCC stage, TERT^-124[C>T] was an independent predictor of shorter recurrence-free survival (RFS) (HR=2.58, p=0.001), and overall survival (HR=2.47, p=0.029). Patients with the germline variant and TERT^-124[C>T] mutant melanomas had significantly shorter RFS than those patients lacking either or both sequence variants (p<0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading compared to nodular melanoma. No associations were found between survival and TERT^-146[C>T], BRAF or NRAS mutations. These findings strongly suggest that TERT^-124[C>T] mutation is a biomarker of aggressive primary melanomas, an effect that may be modulated by rs2853669.

In various diseases, particularly cancer, cell-free DNA (cfDNA) has been widely studied as a marker of disease prognosis or to facilitate the detection of therapeutic targets. In dermatology, most studies have focused on melanoma; other skin diseases such as vascular malformations and psoriasis have also been examined. Genetic alterations unique to the tissue of origin such as sequence variations, copy number alterations, chromosomal rearrangements, differential DNA methylation patterns, and fragmentation patterns can be identified in circulation providing information on patient disease status. These alterations can be detected either by PCR-based methods or next-generation sequencing depending on the target of interest. In this article, we discuss the origins of cfDNA, the most common methods of detection, current studies assessing cfDNA as a biomarker, and cfDNA's potential clinical applications in melanoma and other skin diseases. In addition, we provide important factors to consider during blood processing and DNA extraction as well as limitations for each assay.

Introduction: Nevisense is a non-invasive device that measures electrical impedance spectroscopy (EIS) of individual skin lesions to aid in the diagnosis of melanoma. While EIS has demonstrated high sensitivity in diagnosing melanoma, its impact on a clinician"™s diagnostic confi dence remains unknown. Objective: To conduct a pilot study to evaluate whether clinician diagnostic confidence, sensitivity, specificity and accuracy can be increased by adding EIS measurement scores to clinical and dermoscopic images of lesions clinically suspicious for melanoma. Methods: Three pigmented lesions specialists and three 4^th year medical students completed an online survey to evaluate 34 melanocytic lesions suspicious for melanoma. For each lesion, participants provided their diagnosis, biopsy recommendation, and confidence in diagnosing a lesion as benign or malignant based on history and clinical and dermoscopic images, and again after receiving an EIS score. Results: Addition of EIS scores increased mean biopsy sensitivity for melanoma/severely dysplastic nevi from 70% to 84% (p =.014) and mean diagnostic accuracy from 74% to 86% (p =.005). Mean diagnostic confidence increased for all histopathologic categories for both students and dermatologists (all p <.05). Conclusions: In this pilot study, EIS increased novice and expert diagnosticians"™ confidence regarding dermoscopically equivocal melanocytic lesions. Further studies are needed to explore how EIS can help clinicians reassure patients regarding the management of clinically dysplastic melanocytic nevi.

BACKGROUND:MoleMap NZ is a novel New Zealand based store-and-forward telemedicine service to detect melanoma. It utilizes expert review of total body photography and close-up and dermoscopic images of skin lesions suspicious for malignancy. OBJECTIVE:The purpose of this study was to assess the effectiveness of MoleMap NZ as a melanoma early detection program. METHODS:We conducted a review of 2,108 melanocytic lesions recommended for biopsy/excision by MoleMap NZ dermoscopists from January 2015-December 2016. RESULTS:Pathologic diagnoses were available for 1,571 lesions. Of these, 1,303 (83%) lesions were benign and 260 (17%) lesions were diagnosed as melanoma, for a melanoma-specific benign-to-malignant ratio of 5.0 to 1. The number-needed-to-biopsy one melanoma was 6. Among melanomas with available tumor thickness data (n=137), 92% were <0.8mm (range: in situ - 3.1mm), with in-situ melanomas comprising 74%. LIMITATIONS/CONCLUSIONS:Only lesions recommended for excision were analyzed. Pathology results were available for 75% of these cases. Tumor thickness data was available for 53% of melanomas diagnosed. CONCLUSION/CONCLUSIONS:This real-world study of MoleMap NZ, a community-based teledermoscopy program, suggests that it has the potential to increase patients' access to specialist expertise via telemedicine. Additional studies are needed to more accurately define its efficacy.

A diagnosis of late stage melanoma is associated with significant mortality. From a public health perspective, knowledge of geographic disparities in late-stage diagnoses can inform efforts to facilitate the diagnosis of earlier stage, highly curable melanomas. We conducted a county-level analysis of melanoma in New York State to identify communities that may benefit from pilot health interventions to reduce the burden of late stage melanoma. From 1995 to 2016, late-stage melanoma incidence increased from 1.5 to 2.8 cases/100,000 in NY State. We found statistically significant associations between decreased county-level health system access (including physician density and resident educational status), and increased county incidence and proportion of late-stage disease among diagnosed cases (p<0.001 for both). Increased county-level socioeconomic status (SES), (including measures of resident wealth and medical insurance status), was positively associated with greater late-stage incidence (p<0.001). However, decreased county-level SES was positively associated with a greater proportion of late-stage disease among cases at diagnosis (p=0.009). Counties with reduced access to physician services and lower SES may be suitable for pilot interventions promoting recognition and diagnosis of early stage melanomas to reduce late stage diagnoses and associated mortality.