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New Systematic Therapies and Trends in Cutaneous Melanoma Deaths Among US Whites, 1986-2016

Berk-Krauss, Juliana; Stein, Jennifer A; Weber, Jeffrey; Polsky, David; Geller, Alan C
Objectives. To determine the effect of new therapies and trends toward reduced mortality rates of melanoma.Methods. We reviewed melanoma incidence and mortality among Whites (the group most affected by melanoma) in 9 US Surveillance, Epidemiology, and End Results registry areas that recorded data between 1986 and 2016.Results. From 1986 to 2013, overall mortality rates increased by 7.5%. Beginning in 2011, the US Food and Drug Administration approved 10 new treatments for metastatic melanoma. From 2013 to 2016, overall mortality decreased by 17.9% (annual percent change [APC] = -6.2%; 95% confidence interval [CI] = -8.7%, -3.7%) with sharp declines among men aged 50 years or older (APC = -8.3%; 95% CI = -12.2%, -4.1%) starting in 2014. This recent, multiyear decline is the largest and most sustained improvement in melanoma mortality ever observed and is unprecedented in cancer medicine.Conclusions. The introduction of new therapies for metastatic melanoma was associated with a significant reduction in population-level mortality. Future research should focus on developing even more effective treatments, identifying biomarkers to select patients most likely to benefit, and renewing emphasis on public health approaches to reduce the number of patients with advanced disease. (Am J Public Health. Published online ahead of print March 19, 2020: e1-e3. doi:10.2105/AJPH.2020.305567).
PMID: 32191523
ISSN: 1541-0048
CID: 4353672

Validation of Circulating Tumor DNA Assays for Detection of Metastatic Melanoma

Syeda, Mahrukh M; Wiggins, Jennifer M; Corless, Broderick; Spittle, Cindy; Karlin-Neumann, George; Polsky, David
The detection of cell-free, circulating tumor DNA (ctDNA) in the blood of patients with solid tumors is often referred to as "liquid biopsy." ctDNA is particularly attractive as a candidate biomarker in the blood. It is relatively stable after blood collection, can be easily purified, and can be quantitatively measured with high sensitivity and specificity using advanced technologies. Current liquid biopsy research has focused on detecting and quantifying ctDNA to (1) diagnose and characterize mutations in a patient's cancer to help select the appropriate treatment; (2) predict clinical outcomes associated with different treatments; and (3) monitor the response and/or progression of a patient's disease. The diagnostic use of liquid biopsies is probably greatest in tumors where the difficulty and/or risk of obtaining a tissue specimen for molecular diagnostics is high (e.g., lung, colon). In metastatic melanoma, however, obtaining a tissue sample for molecular diagnostics is not typically a major obstacle to patient care plans; rather predicting treatment outcomes and monitoring a patient's disease course during therapy are considered the current priorities for this cancer type. In this chapter we describe an approach to the validation of ctDNA detection assays for melanoma, focusing primarily on analytical validation, and provide methods to guide the use of droplet digital PCR assays for measuring ctDNA levels in plasma samples.
PMID: 31502151
ISSN: 1940-6029
CID: 4115372

Circulating tumor DNA (ctDNA) kinetics and survival outcomes in patients (pts) with metastatic melanoma (MM) and brain metastases (BM) treated with dabrafenib (D)+ trametinib (T) in the COMBI-MB trial [Meeting Abstract]

Syeda, M M; Wiggins, J; Davies, M A; Robert, C; Long, G V; Grob, J -J; Flaherty, K; Gasal, E; Squires, M; Garrett, J; Brase, J; Polsky, D
Nearly 50% of pts with MM are diagnosed with BM. Although baseline ctDNA levels and changes during treatment predict clinical outcome after targeted and immunotherapy, no prospective trials have evaluated pre-and on-treatment ctDNA kinetics in pts with BM. We measured BRAF V600E ctDNA at baseline and in longitudinally collected plasma samples before progression for up to 40 weeks in 38 pts with intracranial (IC) and extracranial (EC) disease enrolled in cohort A (asymptomatic MM with BM; no previous local brain therapy; ECOG PS <=1) of the phase 2 COMBI-MB trial (NCT02039947) evaluating D+T in pts with MM and BM. ctDNA was quantified using a validated mutation-specific droplet digital PCR assay (threshold, 0.25 copies/mL). Separately, 20 of 21 samples from 9 pts with isolated IC disease had no detectable ctDNA; those pts were excluded. Progression-free survival (PFS), overall survival (OS), and IC and EC RECIST responses were analyzed. Baseline ctDNA was detectable in 34 of 38 pts (89%); ctDNA copy numbers were correlated with EC (Pearson r = 0.48; p = 0.0042) but not with IC (Pearson r = 0.16; p = 0.3257) disease volume. Presence/absence of baseline ctDNA was not correlated with IC or EC best overall response (BOR); baseline ctDNA levels were significantly associated with PFS (HR, 1.17 [95%CI, 1.05-1.30]; p = 0.0024) and OS (HR, 1.21 [95%CI, 1.07- 1.38]; p = 0.0020). ctDNA zeroconversion over time (including all longitudinal on-treatment samples) was significantly correlated with EC BOR (OR, 5.8; p = 0.04) but less so with IC BOR. Although these analyses confirm recent findings that ctDNA is not a good biomarker for monitoring CNS responses and associated clinical outcome, we found some associations between baseline ctDNA levels and PFS/OS as well as ctDNA zeroconversion and EC response
ISSN: 1755-148x
CID: 4472792

Late-stage melanoma diagnosis in New York State (NYS) [Meeting Abstract]

Shah, P.; Bajaj, S.; Polsky, D.
ISSN: 0022-202x
CID: 4562182

Immunomodulatory germline variation associated with the development of multiple primary melanoma (MPM)

Ferguson, Robert; Archambault, Alexi; Simpson, Danny; Morales, Leah; Chat, Vylyny; Kazlow, Esther; Lax, Rebecca; Yoon, Garrett; Moran, Una; Shapiro, Richard; Pavlick, Anna; Polsky, David; Osman, Iman; Kirchhoff, Tomas
Multiple primary melanoma (MPM) has been associated with a higher 10-year mortality risk compared to patients with single primary melanoma (SPM). Given that 3-8% of patients with SPM develop additional primary melanomas, new markers predictive of MPM risk are needed. Based on the evidence that the immune system may regulate melanoma progression, we explored whether germline genetic variants controlling the expression of 41 immunomodulatory genes modulate the risk of MPM compared to patients with SPM or healthy controls. By genotyping these 41 variants in 977 melanoma patients, we found that rs2071304, linked to the expression of SPI1, was strongly associated with MPM risk reduction (OR = 0.60; 95% CI = 0.45-0.81; p = 0.0007) when compared to patients with SPM. Furthermore, we showed that rs6695772, a variant affecting expression of BATF3, is also associated with MPM-specific survival (HR = 3.42; 95% CI = 1.57-7.42; p = 0.0019). These findings provide evidence that the genetic variation in immunomodulatory pathways may contribute to the development of secondary primary melanomas and also associates with MPM survival. The study suggests that inherited host immunity may play an important role in MPM development.
PMID: 31308438
ISSN: 2045-2322
CID: 3977742

Towards automated melanoma detection with deep learning: Data purification and augmentation

Chapter by: Bisla, Devansh; Choromanska, Anna; Berman, Russell S.; Stein, Jennifer A.; Polsky, David
in: IEEE Computer Society Conference on Computer Vision and Pattern Recognition Workshops by
[S.l.] : IEEE Computer, 2019
pp. 2720-2728
ISBN: 9781728125060
CID: 4421152

Impact of initial stage on metastatic melanoma survival

Wilson, Melissa A; Zhong, Judy; Rosenbaum, Brooke E; Utter, Kierstin; Moran, Una; Darvishian, Farbod; Polsky, David; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Osman, Iman
Patients diagnosed with metastatic melanoma have varied clinical courses, even in patients with similar disease characteristics. We examine the impact of initial stage of melanoma diagnosis, BRAF status of primary melanoma, and receiving adjuvant therapy on postmetastatic overall survival (pmOS). We studied melanoma patients presenting to Perlmutter Cancer Center at New York University and prospectively enrolled in New York University melanoma biospecimen database and followed up on protocol-driven schedule. Patients were stratified by stage at initial melanoma diagnosis as per AJCC 7th ed. guidelines. pmOS was determined using the Kaplan-Meier method and Cox's proportional hazards models were used to assess hazard ratios (HRs). Three hundred and four out of 3204 patients developed metastatic disease over the time of follow-up (median follow-up 2.2 years, range: 0.08-35.2 years). Patients diagnosed with stage I (n=96) melanoma had longer pmOS (29.5 months) than those diagnosed with stage II (n=99, pmOS 14.9 months) or stage III (n=109, pmOS 15.1 months) melanoma (P=0.036). Initial stage of diagnosis remained significant in multivariate analysis when controlling for lactate dehydrogenase and site of metastases [primary diagnosis stage II (HR 1.44, P=0.046), stage III (HR 1.5, P=0.019)]. Adjuvant treatment was associated with better survival but BRAF mutation status did not show an association. Our data challenge the general assumption that primary melanomas converge upon diagnosis of metastatic disease and behave uniformly. Primary stage of melanoma at the time of diagnosis may be prognostic of outcome, similar to lactate dehydrogenase and metastatic disease sites.
PMID: 31026246
ISSN: 1473-5636
CID: 3821792

Development of Novel Mutation-Specific Droplet Digital PCR Assays Detecting TERT Promoter Mutations in Tumor and Plasma Samples

Corless, Broderick C; Chang, Gregory A; Cooper, Samantha; Syeda, Mahrukh M; Shao, Yongzhao; Osman, Iman; Karlin-Neumann, George; Polsky, David
Detecting mutations in the plasma of patients with solid tumors is becoming a valuable method of diagnosing and monitoring cancer. The TERT promoter is mutated at high frequencies in multiple cancer types, most commonly at positions -124 and -146 (designated C228T and C250T, respectively). Detection of these mutations has been challenging because of the high GC content of this region (approximately 80%). We describe development of novel probe-based droplet digital PCR assays that specifically detect and quantify these two mutations, along with the less common 242-243 CC>TT mutation, and demonstrate their application using human tumor and plasma samples from melanoma patients. Assay designs and running conditions were optimized using cancer cell line genomic DNAs with the C228T or C250T mutations. The limits of detection were 0.062% and 0.051% mutant allele fraction for the C228T and C250T assays, respectively. Concordance of 100% was observed between droplet digital PCR and sequencing-based orthogonal methods in the detection of TERT mutant DNA in 32 formalin-fixed, paraffin-embedded melanoma tumors. TERTmutant DNA was also identified in 21 of 27 plasma samples (78%) from patients with TERTmutant tumors, with plasma mutant allele fractions ranging from 0.06% to 15.3%. There were no false positives in plasma. These data demonstrate the potential of these assays to specifically detect and quantify TERTmutant DNA in tumors and plasma of cancer patients.
PMID: 30827467
ISSN: 1943-7811
CID: 3722502

Primary Melanoma Histologic Subtype: Impact on Survival and Response to Therapy

Lattanzi, Michael; Lee, Yesung; Simpson, Danny; Moran, Una; Darvishian, Farbod; Kim, Randie H; Hernando, Eva; Polsky, David; Hanniford, Doug; Shapiro, Richard; Berman, Russell; Pavlick, Anna C; Wilson, Melissa A; Kirchhoff, Tomas; Weber, Jeffrey S; Zhong, Judy; Osman, Iman
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.
PMID: 29912415
ISSN: 1460-2105
CID: 3158042

Plasma cell-free circulating tumor DNA (ctDNA) detection in longitudinally followed glioblastoma patients using TERT promoter mutation-specific droplet digital PCR assays

Cordova, Christine; Syeda, Mahrukh M; Corless, Broderick; Wiggins, Jennifer M; Patel, Amie; Kurz, Sylvia Christine; Delara, Malcolm; Sawaged, Zacharia; Utate, Minerva; Placantonakis, Dimitris; Golfinos, John; Schafrick, Jessica; Silverman, Joshua Seth; Jain, Rajan; Snuderl, Matija; Zagzag, David; Shao, Yongzhao; Karlin-Neumann, George Alan; Polsky, David; Chi, Andrew S
ISSN: 1527-7755
CID: 4032352