Faculty Bibliography

BACKGROUND:Immune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; however, not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events (irAEs). Identifying individuals who will develop irAEs is critical in order to improve the quality of care. Here, we prospectively demonstrate that the gut microbiome predicts irAEs in melanoma patients undergoing ICB. METHODS:Pre-, during, and post-treatment stool samples were collected from 27 patients with advanced stage melanoma treated with IPI (anti-CTLA-4) and NIVO (anti-PD1) ICB inhibitors at NYU Langone Health. We completed 16S rRNA gene amplicon sequencing, DNA deep shotgun metagenomic, and RNA-seq metatranscriptomic sequencing. The divisive amplicon denoising algorithm (DADA2) was used to process 16S data. Taxonomy for shotgun sequencing data was assigned using MetaPhlAn2, and gene pathways were assigned using HUMAnN 2.0. Compositionally aware differential expression analysis was performed using ANCOM. The Cox-proportional hazard model was used to assess the prospective role of the gut microbiome (GMB) in irAES, with adjustment for age, sex, BMI, immune ICB treatment type, and sequencing batch. RESULTS:= 0.88, p < 0.001). CONCLUSIONS:We identified two distinct fecal bacterial community clusters which are associated differentially with irAEs in ICB-treated advanced melanoma patients.

BACKGROUND:Early reports on cancer patients with coronavirus disease 2019 (COVID-19) corroborated speculation that cancer patients are at increased risk for becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developing severe COVID-19. However, cancer patients are a heterogeneous population and their corresponding risk may be different. AIM/OBJECTIVE:To compare COVID-19 presentation in patients with active malignancy to those with a history of cancer to determine the impact of cancer status on COVID-19 outcomes in the two groups. METHODS AND RESULTS/RESULTS:Of the 6724 patients who were hospitalized at NYU Langone Health (3/16/20-7/31/20) and tested positive for SARS-CoV-2, 580 had either active cancer (n = 221) or a history of cancer (n = 359). We compared the baseline clinicodemographic characteristics and hospital courses of the two groups. We studied the relationship between cancer status and the rate of admission to the intensive care unit (ICU), use of invasive mechanical ventilation (IMV), and all-cause mortality. The two groups had similar laboratory results associated with COVID-19 infection, incidence of venous thromboembolism, and incidence of severe COVID-19. Active cancer status was not associated with the rate of ICU admission (p = .307) or use of IMV (p = .236), but was significantly associated with worse all-cause mortality in both univariate and multivariate analysis with odds ratios of 1.48 (95% confidence interval [CI]: 1.04-2.09; p = .028) and 1.71 (95% CI: 1.12-2.63; p = .014), respectively. CONCLUSION/CONCLUSIONS:Active cancer patients had worse survival outcomes compared to patients with a history of cancer despite similar COVID-19 disease characteristics in the two groups. Our data suggest that cancer care should continue with minimal interruptions during the pandemic to bring about response and remission as soon as possible.

Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd-5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.

BACKGROUND:In patients with advanced melanoma (MM), genomic profiling may guide treatment decisions in the frontline setting and beyond as specific tumor mutations can be treated with targeted therapy (TT). The range of panel sizes used to identify targetable mutations (TM) can range from a few dozen to whole exome sequencing (WES). AIM/OBJECTIVE:We investigated the impact of panel size and mutation status on first-line treatment selection and outcomes in MM. METHODS AND RESULTS/RESULTS:We analyzed data for 1109 MM patients from three cohorts: 169 patients at NYULH and profiled with the 50 gene Ion Torrent panel (IT), 195 patients at MSKCC, profiled with the 400-gene MSK-IMPACT panel (MSK-I) and 745 patients at seven different sites profiled with WES. Data for cohorts 2 and 3 were extrapolated from the publicly available cBioPortal. Treatment information was available for 100%, 25%, and 0% of patients in cohort 1, 2, and 3, respectively. BRAF and NRAS were among the top five most commonly mutated genes in the IT and MSK-I, whereas for WES only BRAF was a top five mutation. There was no significant difference in OS for BRAF MUT patients treated with immune checkpoint inhibitors (ICI) vs TT in cohort 1 (P = .19), nor for BRAF MUT patients from cohort 1 treated with ICI vs those from cohort 2 treated with TT (P = .762). CONCLUSION/CONCLUSIONS:Public datasets provide population-level data; however, the heterogeneity of reported clinical information limits their value and calls for data standardization. Without evidence of clear clinical benefit of a larger panel size, there is a rationale for adopting smaller, more cost effective panels in MM.

BACKGROUND:Although most patients with cutaneous melanoma are non-Hispanic whites (NHWs), minorities consistently suffer worse melanoma-specific survival (MSS). Much of the literature comes from analyses of registries from the 1990s and 2000s. OBJECTIVE:We sought to evaluate whether and to what degree racial disparity in MSS persists since 2010. METHODS:We analyzed 381,035 patients from the Surveillance, Epidemiology, and End Results registry. Race categories included Hispanic, NHW, non-Hispanic black (NHB), non-Hispanic Asian or Pacific Islander (NHAPI), and non-Hispanic American Indian/Alaska Native (NHAIAN). We evaluated the association between MSS and race in 3 time periods: before the year 2000, 2000 to 2009, and 2010 or later. NHW was the reference group for all analyses. RESULTS:Racial disparity worsened from before the year 2000 to 2010 or later for Hispanic (P < .001), NHB (P = .024), and NHAPI (P < .001) patients. Across all minority groups, patients with localized disease suffered increasing disparity (P = .010 for Hispanic, P < .001 for NHB, P = .023 for NHAPI, and P = .042 for NHAIAN patients). Among those with regional and distant disease, Hispanic patients were the only minority to experience worsening disparity (P = .001 and P = .019, respectively). LIMITATIONS/CONCLUSIONS:Lack of immunotherapy and targeted treatment information. CONCLUSIONS:Racial disparity in MSS is worsening. Improving postdiagnosis management for minorities with localized disease is imperative to mitigate disparity and improve survival.

Importance/UNASSIGNED:Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective/UNASSIGNED:To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants/UNASSIGNED:This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures/UNASSIGNED:Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results/UNASSIGNED:Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance/UNASSIGNED:In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

The Great Debate session at the 2020 Melanoma Bridge virtual congress (December 3rd-5th, Italy) featured counterpoint views from experts on five specific controversial issues in melanoma. The debates considered whether or not innate immunity is important in the response to cancer and immunotherapy, how useful are the revised American Joint Committee on Cancer (AJCC) classification for the staging of patients, the use of sentinel node biopsy for staging patients, the use of triplet combination of targeted therapy plus immunotherapy versus combined immunotherapy, and the respective benefits of neoadjuvant versus adjuvant therapy. As is usual with Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their own personal opinion.

Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, interobserver discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark's model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar's test and visually by an attending dermatopathologist. In total, 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (log-rank P < 0.001 for RFS; P = 0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84-1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83-0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n = 240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P > 0.05) when categorized as brisk, nonbrisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.

BACKGROUND:Tumor mutation burden (TMB) has been associated with melanoma immunotherapy (IT) outcomes, including survival. We explored whether combining TMB with immunogenomic signatures recently identified by The Cancer Genome Atlas (TCGA) can refine melanoma prognostic models of overall survival (OS) in patients not treated by IT. METHODS:Cox proportional-hazards (Cox PH) analysis was performed on 278 metastatic melanomas from TCGA not treated by IT. In a discovery and two validation cohorts Cox PH models assessed the interaction between TMB and 53 melanoma immunogenomic features to refine prediction of melanoma OS. RESULTS:Interferon-γ response (IFNγRes) and macrophage regulation gene signatures (MacReg) combined with TMB significantly associated with OS (p = 8.80E-14). We observed that patients with high TMB, high IFNγRes and high MacReg had significantly better OS compared to high TMB, low IFNγRes and low MacReg (HR = 2.8, p = 3.55E-08). This association was not observed in low TMB patients. CONCLUSIONS:We report a model combining TMB and tumor immune features that significantly improves prediction of melanoma OS, independent of IT. Our analysis revealed that patients with high TMB, high levels of IFNγRes and MacReg had significantly more favorable OS compared to high TMB patients with low IFNγRes and low MacReg. These findings may substantially improve current melanoma prognostic models.