Faculty Bibliography

Background: Non-Hispanic African Americans (AA) have a higher incidence of ESRD but lower rates of kidney transplant (KT), and poorer quality of life (QOL) compared to non-Hispanic whites (WH). Disparities persist after adjusting for medical factors (e.g., comorbidity, dialysis). We assessed whether race disparities in QOL would persist in patients evaluated for KT after adjusting for medical and social determinants, including demographic (e.g., age, income), cultural (e.g., perceived discrimination, medical mistrust), psychosocial (e.g., social support, emotional distress), and knowledge (e.g., knowledge, learning activities) factors.
Method(s): We conducted a longitudinal cohort study with 1035 (AA=260; WH=775) patients undergoing KT evaluation at the UPMC Starzl Transplant Institute. Patients completed an interview after initiating KT evaluation to assess social determinants; and another interview after being accepted, rejected, or withdrawing from evaluation, to assess kidney-specific (symptoms/problems, sleep, lifestyle effects, burden, cognitive function, work, sexual function) and general QOL (mental and physical composite scores) using the Kidney Disease QOL scale. We built multivariable regression models to test the hypothesized relationships.
Result(s): Our sample was 38% female, mean age=57, 73% had family income < $50,000, 52% married, 35% public insurance, 27% private, and 38% public/private. Race differences in kidney-specific QOL outcomes were no longer significant when social determinants were included in the model. Instead, psychosocial (e.g., mastery, social support, emotional distress), transplant knowledge (e.g., concerns, learning activities, knowledge), and demographic (e.g., age, sex, income, insurance) factors were significant predictors. For general QOL outcomes, race continued to be a significant predictor even after we identified several significant psychosocial, transplant knowledge, and demographic predictors (all predictors significant at p<.05).
Conclusion(s): A combination of social determinants predicted QOL outcomes for KT patients, which mediated race differences, especially for kidney-specific QOL. Transplant centers may help ensure better QOL in their patients as they await KT by promoting psychosocial support, and ensuring candidates' understanding of KT

Background: During their lifetime about 8% of patients with single primary cutaneous melanoma (SPM) will develop multiple primary melanomas (MPM), which are associated with significantly higher mortality compared to patients with SPM. Based on the evidence that the immune system plays a role in regulating melanoma progression we explored whether germline genetic variants controlling the expression of immunomodulatory genes (immunomodulatory quantitative trait loci, eQTLs) discern risk of MPMcompared to patients with SPM or healthy controls.
Method(s): Previously, we identified 50 eQTLs significantly associated with the expression of 265 immunomodulatory genes using the MuTHer twin cohort. These 50 SNPs were genotyped in 837 SPM and 104MPM individuals using MassARRAY system. 1047 healthy controls were obtained from a publically available GWAS on CMascertained at MDAnderson (phs000187.v1.p1). We employed multivariate logistic regression to test the association of SNPs withMPM vs cancer-free controls andMPMvs SPM.
Result(s): When comparing MPMvs SPM, rs2071304, previously linked to expression of SPI1 in MuTHer data, showed a strong association with reduction ofMPM risk (OR=0.60; 95% CI=0.45-0.81; p=0.0007). Intriguingly, this variant also trended toward significance when comparing MPM vs controls (OR=0.61; 95% CI: 0.44-0.85; p=0.003). Finally, our most significant association when comparingMPM to controls was for rs2276645 (OR=0.60; 95% CI=0.45-0.81; p=0.0008), an eQTL associated with Zap-70 expression.
Conclusion(s): Our data, for the first time, indicate that the inherited host immunity impacts risk ofMPMin individuals with SPM, highlighting an importance of immune involvement in melanoma progression. The MPMrisk-predicting genetic variants identified here or in expanded efforts, currently underway, may eventually lead to a diagnostic tool allowing for enhanced screening and clinical management of patients at risk of MPM, hence reducing elevated MPM-associated mortality. Additionally, our results further support thatMPM and SPM may have different genetics underpinnings and should be treated as separate clinical entities

BACKGROUND:Patients with thick primary melanomas (≥4 mm) have highly variable survival outcomes. Cell proliferation marker Ki-67 has been identified as promising biomarker in thick melanoma but has not been evaluated since the wide spread adoption of sentinel lymph node biopsy. We revisit its prognostic relevance in the sentinel node era. METHODS:We studied patients with thick (≥4 mm) primary melanoma prospectively enrolled in a clinicopathological biospecimen database from 2002 to 2015, and evaluated the prognostic value of Ki-67 expression while controlling for features included in the existing staging criteria. RESULTS:We analyzed 68 patients who underwent lymph node sampling and who had an available tumor for Ki-67 immunohistochemical (IHC) staining. The median tumor thickness was 6.0 mm; the median follow-up was 2.6 years. In multivariable analysis including nodal status and primary tumor ulceration, Ki-67 expression was an independent predictor of worse recurrence-free survival (HR 2.19, P = 0.024) and overall survival (HR 2.49, P = 0.028). Natural log-transformed tumor thickness (ln [thickness]) was also significantly associated with worse OS (HR 2.39, P = 0.010). CONCLUSION/CONCLUSIONS:We identify Ki-67 and ln (thickness) as potential biomarkers for patients with thick melanoma who have undergone nodal staging. If validated in additional studies, these biomarkers could be integrated into the staging criteria to improve risk-stratification.

BACKGROUND:Cancer-testis antigen NY-ESO-1 is a highly immunogenic melanoma antigen which has been incorporated into adjuvant vaccine clinical trials. Three such early-phase trials were conducted at our center among patients with high-risk resected melanoma. We herein report on the pooled long-term survival outcomes of these patients in comparison to historical controls. METHODS:All melanoma patients treated at NYU Langone Health under any of three prospective adjuvant NY-ESO-1 vaccine trials were retrospectively pooled into a single cohort. All such patients with stage III melanoma were subsequently compared to historical control patients identified via a prospective institutional database with protocol-driven follow-up. Survival times were calculated using the Kaplan-Meier method, and Cox proportional hazard models were employed to identify significant prognostic factors and control for confounding variables. RESULTS:A total of 91 patients were treated with an NY-ESO-1 vaccine for the treatment of high-risk resected melanoma. Of this group, 67 patients were stage III and were selected for comparative analysis with 123 historical control patients with resected stage III melanoma who received no adjuvant therapy. Among the pooled vaccine cohort (median follow-up 61 months), the estimated median recurrence-free survival was 45 months, while the median overall survival was not yet reached. In the control cohort of 123 patients (median follow-up 30 months), the estimated median recurrence-free and overall survival were 22 and 58 months, respectively. Within the retrospective stage III cohort, NY-ESO-1 vaccine was associated with decreased risk of recurrence (HR = 0.56, p < 0.01) and death (HR = 0.51, p = 0.01). Upon controlling for sub-stage, the adjuvant NY-ESO-1 clinical trial cohort continued to exhibit decreased risk of recurrence (HR = 0.45, p < 0.01) and death (HR = 0.40, p < 0.01). CONCLUSIONS:In this small retrospective cohort of resected stage III melanoma patients, adjuvant NY-ESO-1 vaccine immunotherapy was associated with longer recurrence-free and overall survival relative to historical controls. These data support the continued investigation of adjuvant NY-ESO-1 based immunotherapy regimens in melanoma.

Purpose: Well-established risk factors for breast cancer include family history (FH), BRCA mutations and biopsies with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS). Several mathematical models, including the Gail and Tyrer-Cuzick models, have been developed to quantify a patient's risk for developing breast cancer. These models all differ in the list of variables and risk factors that are included in risk calculations. As a result, there is no single model that best estimates the risk for all high risk patients. The purpose of this study is to examine the application of the Gail and Tyrer-Cuzick models in a contemporary cohort of women who are enrolled in a comprehensive high-risk breast cancer database. Methods: The institutional High Risk Breast Cancer Consortium (HRBCC) was established in January 2011. Patients who were at high risk for developing breast cancer based on family history (maternal and paternal), BRCA mutations, AH and LCIS were eligible to enroll in the database. The following variables were included in this analysis: age, family history, genetic testing results, reproductive history, AH, LCIS, Gail and Tyrer-Cuzick scores, risk reduction strategies, and outcomes. All clinical data are obtained from detailed questionnaires filled out by patients who consent to the database studies and from a review of electronic medical records. Descriptive statistics were performed. Results: A total of 604 women were enrolled between 1/2011-2/2016. The median age was 51 years (range 20-87). The majority of women were Caucasian (83%). 52% had a strong FH, 13% were BRCA1 and 2 positive, 48% had AH, and 22% had LCIS. 47% of patients in our high risk program were not eligible for Gail model analysis (age <35 years, BRCA mutation carriers, history of LCIS). Only one patient was not eligible for Tyrer-Cuzick model calculation based on age >84 years. For patients who were eligible for Gail model analysis, 26 (8%) women did not meet criteria (5-year risk >=1.7%) for being designated as high risk for breast cancer. 34 (6%) of our patients did not have Tyrer- Cuzick scores over 20% (criterion for high risk). Notably, majority of the patients (69%) who were not defined as high-risk based on Gail scores >=1.7% or Tyrer-Cuzick scores >=20%, had a strong family history of breast cancer. Only 14 (2%) patients developed breast cancer during our study period, and the majority (93%) of the cancers were early stage (stage 0, I). Conclusions: Our institutional high-risk database includes women who are at high risk based on well-established risk factors for developing breast cancer (FH, BRCA mutations, AH, LCIS). Current mathematical models including the Gail and Tyrer-Cuzick models did not capture the increased risk of breast cancer in 8% of our population. While the models are helpful, in clinical practice they are not necessarily the be-all and end-all. Using heuristic risk factors is more time efficient and comprehensive risk assessment allows the clinicians and patients to better understand risk. Identifying patients as high risk and enrolling them in a high-risk database and program allow us to capture long term follow up, recommend surveillance for early detection, and better understand the effectiveness of different risk reduction and management strategies for this population

PURPOSE: The purpose of this study was to compare and contrast the clinical characteristics of the triple negative breast cancer (TNBC) and non-TNBC patients, with a particular focus on genetic susceptibility and risk factors prior to diagnosis. METHODS: Our institutional database was queried for all patients diagnosed with invasive breast cancer between January 2010 and May 2016. RESULTS: Out of a total of 1964 patients, 190 (10%) patients had TNBC. The median age for both TNBC and non-TNBC was 59 years. There was a significantly higher proportion of African American and Asian patients with TNBC (p = 0.0003) compared to patients with non-TNBC. BRCA1 and BRCA2 were significantly associated with TNBC (p < 0.0001, p = 0.0007). A prior history of breast cancer was significantly associated with TNBC (p = 0.0003). There was no relationship observed between TNBC and a history of chemoprevention or patients who had a history of AH or LCIS. CONCLUSIONS: We found that having Asian ancestry, a prior history of breast cancer, and a BRCA1 or BRCA2 mutation all appear to be positively associated with TNBC. In order to develop more effective treatments, better surveillance, and improved prevention strategies, it is necessary to improve our understanding of the population at risk for TNBC.

Introduction: The treatment of ductal carcinoma in situ (DCIS) remains controversial, and treatment approaches include surgery, post-lumpectomy radiation therapy (RT), and/or hormonal therapy for prevention of recurrent disease. These decisions may be particularly difficult for patients with minimal disease. There is a dearth of information regarding patients who have been diagnosed with DCIS on core-needle biopsy (CNB) who have no residual disease in the area at surgery. The purpose of this study was to explore the frequency of this presentation and short-term outcomes in these patients. Methods: Our institutional Breast Cancer Database was queried for all women who were diagnosed with pure DCIS from 2010-2016. Variables included age, method of presentation, risk factors, tumor characteristics and outcomes. Statistical analyses included Pearson's Chi Square and Fisher's Exact Tests. Results: Out of a total of 548 patients with pure DCIS, 55 (10%) had DCIS on CNB alone with no residual in the surgical specimen. The median age was 55 years (range 36-83). Of the patients with DCIS on CNB alone, 6 (11%) were treated with mastectomies. 14 (25%) had lumpectomy and RT, while 35 (64%) had lumpectomy without RT. The median follow up was 4 years. There were three ipsilateral recurrences in women who were treated by lumpectomy alone. One of these recurrences was invasive carcinoma, and the other two were recurrent pure DCIS. None of the patients who recurred had taken hormonal therapy. There were no contralateral second primaries detected in the study period in this cohort. Conclusions: Despite the minimal extent of disease exhibited in these cases, 3 of 35 patients with DCIS on CNB with no residual disease at surgery and no RT had ipsilateral recurrence at a median follow up of 4 years. These data suggest that even minimal DCIS represents a significant risk of recurrence to the patient. Additional information provided by genomic analysis may better stratify the risk for recurrence in this group and help identify the population that would most benefit from post-lumpectomy RT

BACKGROUND: Metastatic melanoma of unknown primary (MUP) is uncommon, biologically ill defined, and clinically understudied. MUP outcomes are seldom reported in clinical trials. In this study, we analyze responses of MUP patients treated with systemic therapy in an attempt to inform treatment guidelines for this unique population. METHODS: New York University (NYU)'s prospective melanoma database was searched for MUP patients treated with systemic therapy. PubMed and Google Scholar were searched for MUP patients treated with immunotherapy or targeted therapy reported in the literature, and their response and survival data were compared to the MUP patient data from NYU. Both groups' response data were compared to those reported for melanoma of known primary (MKP). RESULTS: The MUP patients treated at NYU had better outcomes on immunotherapy but worse on targeted therapy than the MUP patients in the literature. The NYU MUP patients and those in the literature had worse outcomes than the majority-MKP populations in 10 clinical trial reports. CONCLUSIONS: Our study suggests that MUP patients might have poorer outcomes on systemic therapy as compared to MKP patients. Our cohort was small and limited data were available, highlighting the need for increased reporting of MUP outcomes and multi-institutional efforts to understand the mechanism behind the observed differences.

Background: Efforts to identify targeted therapies that can improve treatment outcome in metastatic ALM have been unsuccessful. In a previous genomic screening, we identified copy number amplification of the histone methyltransferase EZH2 in 47% of ALM cases, a higher frequency than previously reported in cutaneous melanomas (CM) (5%). Here, we tested the hypothesis that increased EZH2 expression contributes to ALM progression and may confer selective sensitivity to EZH2 inhibition. Methods: EZH2 expression was examined by immunohistochemistry (IHC) in 51 primary (21 stage I, 13 Stage II and 17 Stage III) and 23 metastatic (11 in transit, 8 nodal and 4 visceral) ALM cases with extensive clinicopathological data and protocol-driven follow up. Colony formation and cell proliferation was assessed following treatment of ALM and CM cell lines with three EZH2 inhibitors, including GSK126, currently in clinical trials. The effect of GSK126 on H3K27me3 and downstream EZH2 targets was analyzed by western blotting. Results: EZH2 is commonly overexpressed in both primary (30/51; 65%) and metastatic (20/23; 87%) ALM cases, with a significant increase in mean IHC score between primary and metastatic tumors (1.9 vs. 2.7, respectively, p = 0.047). EZH2 expression increased in 6/10 metastatic ALM tumors compared to their matched primary tumors. ALM tumors with EZH2 gene amplification showed increased EZH2 protein expression; however more cases showed overexpression with no amplification suggesting a potential epigenetic component of EZH2 regulation. GSK126 significantly suppressed ALM colony formation at lower doses compared to CM (1 muM vs. 5 muM, respectively). EZH2 inhibition also increased expression of the downstream tumor suppressor E-cadherin in ALM but not in CM cell lines. Finally, ALM cell lines had significantly lower basal H3K27me3 levels than CM cell lines, suggesting an additional, histone methyltransferase-independent function of EZH2 in ALM. Conclusions: Our data demonstrate thatEZH2 upregulation is common in ALM, and suggest that it may play a role in ALM's metastatic progression that requires further investigation. Selective sensitivity of ALM cell lines to EZH2 inhibitors supports the therapeutic potential of EZH2-targeted therapy in ALM