Faculty Bibliography

Background: Unlike other solid tumors, the impact of primary HS on melanoma survival and response to systemic therapy is not well studied. Nodular melanoma (NM) has a worse prognosis than superficial spreading melanoma (SSM), which is usually attributed to thicker primary tumors. Herein, we examine the hypothesis that HS might have an impact on MSS independent of thickness and that NM and SSM exhibit different mutational landscapes that associate with response to checkpoint inhibitor immunotherapy (IT) and BRAF targeted therapy (TT) in the metastatic setting. Methods: Primary NM and SSM patients prospectively enrolled at NYU (2002 - 2016) were compared to the most recent SEER cohort (1973 - 2012) and analyzed with respect to MSS. Next-Generation Sequencing (NGS) was performed on a subset of matched tumor-germline pairs, allowing a comparison of the mutational landscape between NM and SSM. In the metastatic setting, survival analyses were used to compare outcomes and responses to treatment across HS. Results: The NYU cohort of 1,621 patients with either NM (n = 510) or SSM (n = 1,111) was representative of the analogous SEER cohort (21,339 NM, 97,169 SSM), with NM presenting as thicker, more ulcerated, and later stage (all p < 0.001). Among the NYU cohort, NM was found to have lower rates of TIL (p = 0.047), higher mitotic index (p < 0.001), and higher rates of NRAS mutation (p < 0.001). In multivariate Cox models, NM was a significant predictor of worse MSS, independent of thickness and stage (p = 0.01). NM had a significantly lower mutational burden across the exome (p < 0.001). Some of the most under-mutated genes noted in NM were NOTCH4, BCL2L12 and RPS6KA6 (all p < 0.01). Among patients treated with TT (n = 56), NM remained a significant predictor of worse MSS (p = 0.004). However, there was no difference in response to IT. Conclusions: NM and SSM show divergent mutational patterns which may contribute to their different clinical behaviors and responses to BRAF targeted therapy. More studies are needed to better understand the key molecular and cellular processes driving such differences. Integration of HS data into prospective clinical trial reporting is needed to better assess its impact on response to treatment

Current staging guidelines are insufficient to predict which patients with thin primary melanoma are at high risk of recurrence. Computer-assisted image analysis may allow for more practical and objective histopathological analysis of primary tumors than traditional light microscopy. We studied a prospective cohort of stage IB melanoma patients treated at NYU Langone Medical Center from 2002 to 2014. Primary tumor width, manual area, digital area, and conformation were evaluated in a patient subset via computer-assisted image analysis. The associations between histologic variables and survival were evaluated using Cox proportional hazards model. Logistic regressions were used to build a classifier with clinicopathological characteristics to predict recurrence status. Of the 655 patients with stage IB melanoma studied, a subset of 149 patient tumors (63 recurred, 86 did not recur) underwent computer-assisted histopathological analysis. Increasing tumor width (hazard ratios (HR): 1.17, P=0.01) and digital area (HR: 1.08, P<0.01) were significantly associated with worse recurrence-free survival, whereas non-contiguous conformation (HR: 0.57, P=0.05) was significantly associated with better recurrence-free survival. The novel histopathological classifier composed of digital area, conformation, and baseline variables effectively distinguished recurrent cases from non-recurrent cases (AUC: 0.733, 95% confidence interval (CI): 0.647-0.818), compared to the baseline classifier alone (AUC: 0.635, 95% CI: 0.545-0.724). Primary tumor cross-sectional area, width, and conformation measured via computer-assisted analysis may help identify high-risk patients with stage IB melanoma.Modern Pathology advance online publication, 21 July 2017; doi:10.1038/modpathol.2017.64.

OBJECTIVES: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. METHODS: 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. RESULTS: Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, p = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (p < 0.001), irrespective of stratification by trial status or therapy. CONCLUSION: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.

The next generation sequencing technology generates ultra high dimensional data. However, it is computationally impractical to estimate an entire Directed Acyclic Graph (DAG) under such high dimensionality. In this paper, we discuss two different types of problems to estimate subnetworks in ultra high dimensional data. The first problem is to estimate DAGs of a subnetwork adjacent to a target gene, and the second problem is to estimate DAGs of multiple subnetworks without information about a target gene. To address each problem, we propose efficient methods to estimate subnetworks by using layer-dependent weights with BIC criteria or by using community detection approaches to identify clusters as subnetworks. We apply such approaches to the gene expression data of breast cancer in TCGA as a practical example.

Diabetes mellitus (diabetes) is associated with significantly increased risk of peripheral vascular disease. Diabetes is classified as a coronary heart disease (CHD) risk equivalent, but it is unknown whether diabetes is a CHD risk equivalent for peripheral vascular disease. The objective was to evaluate the odds of peripheral arterial disease (PAD) or carotid artery stenosis (CAS) among participants with diabetes, CHD, or both, compared with participants without diabetes or CHD, in a nationwide vascular screening database. We hypothesized that diabetes and CHD would confer similar odds of PAD and CAS. METHODS: A cross-sectional analysis of all eligible Life Line Screening Inc participants age 30 to 90 years with ankle brachial indices for PAD (ankle brachial index <0.9 in either leg) and carotid artery duplex ultrasonographic imaging for CAS (internal CAS >/=50%) was performed (N=3,522,890). RESULTS: Diabetes and CHD were present in 372,330 (10.7%) and 182,760 (5.8%) of participants, respectively; PAD and CAS were present in 155,000 (4.4%) and 130,347 (3.7%) of participants. After multivariable adjustment, PAD odds were 1.56 (95% CI 1.54-1.59) and 1.69 (95% CI 1.65-1.73) for participants with diabetes or CHD, respectively. Participants with both diabetes and CHD had 2.75-fold increased odds of PAD (95% CI 2.66-2.85). Findings were similar for CAS; compared with no diabetes or CHD, CAS odds increased for participants with diabetes alone (1.53, 95% CI 1.50-1.56), CHD alone (1.72, 95% CI 1.68-1.76), and both diabetes and CHD (2.57, 95% CI 2.49-2.66). Findings were consistent for women and men. CONCLUSION: In a large database of more than 3.5 million self-referred participants, diabetes was a CHD risk equivalent for PAD and CAS, and participants with comorbid diabetes and CHD had an especially robust association with PAD and CAS. Counseling regarding screening and prevention of peripheral vascular disease may be useful for patients with diabetes.

Patients with stage IB melanoma have a 10% risk of melanoma-specific mortality within five years. The current prognostic paradigm, however, is insufficient to predict which of these patients are most likely to recur. Additional prognostic characteristics of stage IB melanoma are needed to identify this patient subset who are at highest risk of recurrence, and may benefit from closer follow-up. We evaluated a prospective cohort of stage IB patients (n = 655) treated at NYU Langone Medical Center. In a research subset (n = 149) composed of patients with recurrent (n = 63) and nonrecurrent (n = 86) disease matched for age, sex, thickness, ulceration and mitoses, primary tumors were independently reviewed for digitally calculated area, manually calculated area (depth x width), width, and conformation (contiguous versus noncontiguous) using computer-assisted histopathological analysis (Aperio, Vista, CA USA). We tested the association between histologic variables and recurrence-free survival (RFS) using Cox univariate analysis. Increasing digital area (HR 1.08, P < 0.01), tumor width (HR 1.17, P = 0.01), and non-contiguous conformation (HR 0.57, P = 0.05) were independently prognostic of RFS. Linear regression analysis showed a significant correlation between the manual and digital area (estimate 0.64, P < 0.01), which became even stronger when restricted to patients with contiguous tumors (estimate 0.75, P < 0.01), suggesting manually calculated tumor area may also provide useful prognostic information for providers without access to similar software. Computer-assisted measurement of cross-sectional tumor area, width, and contiguity may help risk-stratification in stage IB patients. Independent validation of these primary tumor characteristic is needed to fully comprehend their prognostic role in stage IB melanoma

Melanoma patients with BRAFV600E -mutant tumors display striking responses to BRAF inhibitors (BRAFi); however, almost all invariably relapse with drug-resistant disease. Here we report that microRNA-125a (miR-125a) expression is upregulated in human melanoma cells and patient tissues upon acquisition of BRAFi resistance. We show that miR-125a induction confers resistance to BRAFV600E melanoma cells to BRAFi by directly suppressing pro-apoptotic components of the intrinsic apoptosis pathway, including BAK1 and MLK3. Apoptotic suppression and prolonged survival favor reactivation of the MAPK and AKT pathways by drug-resistant melanoma cells. We demonstrate that miR-125a inhibition suppresses the emergence of resistance to BRAFi and, in a subset of resistant melanoma cell lines, leads to partial drug re-sensitization. Finally, we show that miR-125a upregulation is mediated by TGFbeta signaling. In conclusion, the identification of this novel role for miR-125a in BRAFi resistance exposes clinically relevant mechanisms of melanoma cell survival that can be exploited therapeutically