Faculty Bibliography

Background: To examine the trends in clinicopathologic features, treatment, and survival of male breast cancer (MBC), utilizing the National Cancer Data Base (NC

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

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.

Background/Objective: In a time when clinicians are attempting to identify a cohort of patients with ductal carcinoma in situ (DCIS) who will benefit most from post-lumpectomy radiation therapy (RT), tools have been developed to quantify patients' risk for in-breast recurrence. These tools have not yet been integrated into standard use. At our institution, the recommendation for RT after lumpectomy for DCIS is guided by established clinicopathologic factors and reviewed by a multi-disciplinary group. The purpose of this study was to compare the clinicopathologic characteristics and outcomes of postlumpectomy DCIS patients with and without RT at our institution. Methods: The Institutional Breast Cancer Database was queried for all women who were diagnosed with DCIS from 2010-2016. Variables included age, method of presentation, risk factors, tumor and treatment characteristics, and ipsilateral breast tumor recurrence (IBTR). Statistical analyses included Pearson's Chi Square and Fisher's Exact Tests. Results: Of 480 women with pure DCIS and no prior history of breast cancer, 350 (73%) underwent lumpectomy. The median follow-up was 4 years, and median age was 60 years. Two hundred thirty-six (67%) women underwent RT following lumpectomy. Compared to women who did not undergo RT, these women were younger (p=0.003), had larger tumor size (p=0.0008), higher grade (p=0.0006), and comedo features (p=0.03). Women who underwent post-lumpectomy RT had an IBTR rate of 2% vs. 4% (p=0.32) with no RT. The 10 patients with early IBTR in both groups were younger (median age 54 years), and all had intermediate- or high-grade DCIS. Of the 114 patients who did not undergo adjuvant RT, 70 (61%) met the RTOG 9804 criteria for omission of adjuvant RT. Of the 44 patients who did not receive adjuvant RT and did not meet RTOG 9804 criteria, 20 declined RT, and 24 were not referred. Conclusions: Within a relatively short follow-up period, we found a very low overall rate (3%) of IBTR for our patients who underwent lumpectomy for DCIS. These results are consistent with previously published trials on post-lumpectomy RT in DCIS. RT at our institution is recommended based on wellestablished clinicopathologic factors and multidisciplinary care. Considering the low recurrence rates, we recommend continuing the current trend of using published criteria and multidisciplinary review. It remains to be seen to what extent the newly developed recurrence tools, such as Oncotype DX Breast DCIS ScoreTM, will improve upon these short-term recurrence rates

Patients with thick (>4 mm) primary melanomas have highly variable outcomes. Current staging criteria for these patients are based primarily on the presence of nodal disease, which often serves as the basis for adjuvant trial eligibility. Identification of novel biomarkers could help identify patients who may benefit from promising, new adjuvant therapies or, alternatively, spare patients with good prognoses the cost and potential toxicity of these drugs. We examined patients with thick primary melanoma to determine whether proliferation markers (mitotic index and Ki- 67) and other clinicopatholgical features were associated with survival. We studied 171 patients with thick primary melanomas; median thickness was 6.0 mm (median follow-up, 3.0 years). In clinically node-negative patients, Ki-67 expression was an independent predictor of worse RFS (HR 2.19, P = 0.024) and OS (HR 2.49, P = 0.028). In a separate model, moderate (>1 to <5 per mm²) and many (>5 per mm²) mitoses were each significantly associated with RFS (HR = 9.97, P = 0.035 and HR = 11.93, P = 0.025, respectively); and OS (HR = 12.79, P = 0.033 and HR = 18.68, P = 0.017, respectively). In the same model, natural log-transformed tumor thickness was also significantly associated with worse OS (HR 2.37, P = 0.009). In sum, we identified cell proliferation markers Ki-67 and mitotic index as independent predictors of survival in clinically nodenegative patients with thick primary melanoma. Greater tumor thickness was also an independent predictor of survival in this cohort. With further investigation, these measures may improve risk-stratification for patients with thick primary melanoma

Tumor infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host anti-tumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1241 primary melanoma patients to assess the association of absent, non-brisk, and brisk TIL grade with survival outcomes. We tested whether quantitative TIL counts using immunohistochemical lymphocyte markers CD3, CD45, and FOXP3 add prognostic value to TIL grading compared to histology alone in 15% of the cohort. To assess for inter-group immunologic heterogeneity among TIL grades, we investigated differential expression of 594 immunoregulatory genes in 67 primary melanomas. On histologic evaluation of 1241 primary melanomas, TILs were graded as absent (n=388, 31%), non-brisk (n=330, 27%), and brisk (n=523, 42%). Patients with brisk TILs had improved recurrence-free survival (RFS) (P=.025) and overall survival (OS) (P=.006) compared to patients with non-brisk and absent TILs, for which there were no differences in RFS (P=.40) or OS (P=.41). TIL quantitation by immunohistochemistry did not improve prognostication compared to TIL grading on hematoxylin and eosin stained sections. Melanomas with non-brisk and absent TILs share similar immunoregulatory gene expression profiles. In contrast, melanomas with brisk TILs demonstrate upregulation of T-cell activation pathways and inhibition of upstream immune checkpoint regulators. The presence of TILs in primary melanomas represents a heterogeneous group and caution in prognostic interpretation is warranted. Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile and improved prognosis compared to melanomas with non-brisk or absent TILs.