In a retrospective analysis, we found that despite similar rates of colorectal tumor analysis, minority patients are less likely to be recommended for genetic evaluation or to undergo germline testing for Lynch syndrome. Improvements in institutional practices in follow up after tumor testing could reduce barriers to diagnosis of Lynch diagnosis in minorities.

Abstract. Disruption of cell-cell junctions and the concomitant loss of polarity, downregulation of tumor-suppressive adherens junctions and desmosomes represent hallmark phenotypes for several different cancer cells. Moreover, a variety of evidence supports the argument that these two common phenotypes of cancer cells directly contribute to tumorigenesis. In this study, we aimed to determine the status of intercellular junction proteins expression in JJ012 human malignant chondrosarcoma cells and investigate the effect of the antitumorigenic cytokine, proline-rich polypeptide-1 (PRP-1) on their expression. The cell junction pathway array data indicated downregulation of desmosomal proteins, such as desmoglein (1,428-fold), desmoplakin (620-fold) and plakoglobin (442-fold). The tight junction proteins claudin 11 and E-cadherin were also downregulated (399-and 52-fold, respectively). Among the upregulated proteins were the characteristic for tumors gap junction β-5 protein (connexin 31.1) and the pro-inflammatory pathway protein intercellular adhesion molecule (upregulated 129-and 43-fold, respectively). We demonstrated that PRP-1 restored the expression of the abovementioned downregulated in chondrosarcoma desmosomal proteins. PRP-1 inhibited H3K9-specific histone demethylase activity in chondrosarcoma cells in a dose-dependent manner (0.5 µg/ml PRP, 63%; 1 µg/ml PRP, 74%; and 10 µg/ml PRP, 91% inhibition). Members of the H3K9 family were shown to transcriptionally repress tumor suppressor genes and contribute to cancer progression. Our experimental data indicated that PRP-1 restores tumor suppressor desmosomal protein expression in JJ012 human chondrosarcoma cells and inhibits H3K9 demethylase activity, contributing to the suppression of tumorigenic potential in chondrosarcoma cells.

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Introduction: An increasing incidence of colorectal cancer (CRC) in young patients has been well noted. The risk of metachronous advanced neoplasia (AN) in younger patients with CRC in the absence of hereditary syndromes in comparison to older patients is not well defined. Identifying high risk subgroups would provide a customized surveillance strategy which would increase cost-effectiveness. Therefore, this study aims to identify CRC patients at increased risk for metachronous AN for surveillance risk stratification. The primary aim was to compare metachronous AN free survival at any surveillance colonoscopy between patients 50 and >50 while the secondary aim was to evaluate risk factors of metachronous AN. Methods: We retrospectively reviewed colonoscopy and pathology records of patients diagnosed with CRC undergoing curative resection between 2006 and 2016 at 3 medical centers. Exclusion criteria included first surveillance performed at > 3 years, hereditary CRC, IBD, poor bowel prep, total colectomy, and obstructive carcinoma without clearance colonoscopy. Information on race, age, sex, sidedness of cancer, smoking history, aspirin use, and number, size, and histology of adenomas were collected from each patient. Advanced neoplasia was defined as > 10 mm, villous histology, or high-grade dysplasia. Kaplan-Meier curves were used to display time to metachronous AN between groups. Log-rank tests were used to compare the time-to-event endpoint across groups. Risk factors associated with hazard of metachronous AN were evaluated by Cox regression. A two-sided alpha of 0.05 was considered statistically significant. Results: 794 patients were included in analysis with 123 patients 50 and 368 patients 60. The rate of metachronous AN in patients >60 compared to 60 was 13.6% and 9.7%, respectively. The rate of metachronous AN in patients >50 compared to 50 was 12.2% and 7.3%, respectively, while it was 8.6% and 5.7% in first surveillance colonoscopy only. In Kaplan-Meier survival analysis with log-rank test, age >60 (pZ0.03), presence of synchronous adenoma (pZ0.01), and presence of synchronous AN (p<0.0001) were found to be significantly associated with higher recurrence of AN. Age >50 approached significance (pZ0.08). In Cox regression, age >60 was found to be a predictor of metachronous AN (HR 2.12, CI 1.03-4.35) while age >50 was not (HR 1.03, CI 0.36-2.92). Of 17 metachronous CRC, 3 occurred in patients 50 of which 2 had no synchronous AN. Discussion: The risk of metachronous AN in CRC patients is not elevated in patients 50. The risk is significantly higher in older patients >60 at diagnosis. Synchronous AN is also a risk factor for metachronous AN. This study does not support more intensive surveillance in young patients with a diagnosis of CRC.

266 Background: Germline genetic testing and somatic genomic profiling using commercial multigene panels are now routine in mPDAC. A subset of these patients have deleterious alterations in genes involved with DDR. Herein we investigate the role of daDDR as a predictive biomarker for response to first-line platinum-based chemotherapy. Methods: Utilizing the IRB-approved pancreas cancer and genetics clinic databases at the University of Miami, we identified all patients with mPDAC who had germline and/or somatic mutation testing. We performed a retrospective chart review to extract demographic and clinical characteristics including treatments received, response and survival. Results: Between 2012 and 2018, 116 patients with mPDAC underwent germline (using Invitae, Ambry Counsyl or Myriad) and/or somatic testing (using FoundationOne CDx). Among these, 40 received first-line therapy with FOLFIRINOX (95%) or gemcitabine/cisplatin (5%). The median age was 59 years and 15 (38%) were female. The majority (70%) were Hispanic and 63% had de-novo mPDAC (treatment-naïve). Germline testing revealed daDDR in 5 patients and somatic NGS found an additional 4 patients with daDDR (total of 9 (23%), including 5 with BRCA2, one each with BRCA1, RAD51C, ATM and MUTYH). The median progression-free survival (PFS) was significantly longer in patients with daDDR than without (17.3 vs 7.8 months, log-rank p = 0.01). The median overall survival (OS) was not statistically different between the two groups. Three patients with daDDR had complete or near-complete radiological and tumor marker responses to FOLFIRINOX and were treated with olaparib (a PARP inhibitor) as maintenance and remain progression-free after 7, 12.4 and 13.6 months respectively. Conclusions: daDDR appears to define a subset of patients with mPDAC who may be more sensitive to platinum agents. There are currently no biomarkers for selection of first-line therapy in patients with mPDAC and we demonstrate that this composite biomarker which is easily done via commercially available assays may be able to inform treatment selection.

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