Faculty Bibliography

Background/UNASSIGNED:Two primary histologic subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM), comprise the majority of all cutaneous melanomas. NM is associated with worse outcomes, which have been attributed to increased thickness at presentation, and it is widely expected that NM and SSM would exhibit similar behavior once metastasized. Herein, we tested the hypothesis that primary histologic subtype is an independent predictor of survival and may impact response to treatment in the metastatic setting. Methods/UNASSIGNED:We examined the most recent Surveillance, Epidemiology, and End Results (SEER) cohort (n = 118 508) and the New York University (NYU) cohort (n = 1621) with available protocol-driven follow-up. Outcomes specified by primary histology were studied in both the primary and metastatic settings with respect to BRAF-targeted therapy and immunotherapy. We characterized known driver mutations and examined a 140-gene panel in a subset of NM and SSM cases using next-generation sequencing. All statistical tests were two-sided. Results/UNASSIGNED:NM was an independent risk factor for death in both the SEER (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.41 to 1.70, P < .001) and NYU (HR = 1.47, 95% CI = 1.05, 2.07, P = .03) cohorts, controlling for thickness, ulceration, stage, and other variables. In the metastatic setting, NM remained an independent risk factor for death upon treatment with BRAF-targeted therapy (HR = 3.33, 95% CI = 1.06 to 10.47, P = .04) but showed no statistically significant difference with immune checkpoint inhibition. NM was associated with a higher rate of NRAS mutation (P < .001), and high-throughput sequencing revealed NM-specific genomic alterations in NOTCH4, ANK3, and ZNF560, which were independently validated. Conclusions/UNASSIGNED:Our data reveal distinct clinical and biological differences between NM and SSM that support revisiting the prognostic and predictive impact of primary histology subtype in the management of cutaneous melanoma.

The extent of PTEN loss that confers clinical and biological impact in melanoma is unclear. We evaluated the clinical and biologic relevance of PTEN dosage in melanoma, and tested the postulate that partial PTEN loss is due to epigenetic mechanisms. PTEN expression was assessed by immunohistochemistry in a stage III melanoma cohort (n=190) with prospective follow up. 21/190 (11%) of tumors had strong PTEN expression, 51/190 (27%) had intermediate PTEN, 44/190 (23%) had weak PTEN, and 74/190 (39%) had absent PTEN. Both weak and absent PTEN expression predicted shorter survival in multivariate analyses (HR 2.13, p<0.01). We demonstrate a continuous negative correlation between PTEN and activated Akt in melanoma cells with titrated PTEN expression and in two additional independent tumor datasets. PTEN genomic alterations (deletion, mutation), promoter methylation, and protein destabilization did not fully explain PTEN loss in melanoma, whereas PTEN levels increased with treatment of melanoma cells with the histone deacetylase inhibitor LBH589. Our data indicate that partial PTEN loss is due to modifiable epigenetic mechanisms and drives Akt activation and worse prognosis, suggesting a potential approach to improve the clinical outcome for a subset of advanced melanoma patients.