Alberts, Steven

Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. Conclusions: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

4044 Background: To aid in decisions regarding adjuvant therapy (AT) for resected high-risk CC, two prog models are in common use: the Mayo Clinic NUM calculator developed from a pooled data analysis of 7 randomized 5FU-based AT trials, and ADJ! developed using SEER data. This study examines the accuracy of NUM and ADJ! utilizing a cohort of patients (pts) referred to the BC Cancer Agency (BCCA). Methods: Demographic, disease and treatment data for pts with stage II/III CC referred to the BCCA from 1995–1996 + 1999–2003 were collected. Observed (obs) 5-year relapse free survival (RFS) and overall survival (OS) were compared to predicted estimates (pred) using NUM and ADJ!, both overall and for all prog subgroups with ≥ 10pts, as stratified by T stage, N stage, tumor grade and age. Data are presented in a descriptive manner and using confidence intervals. Results: Median follow-up was 5.6 yrs for 2,033 pts - 53% male, median age 68y, 40% N0. The mean percentages of 5 year pred outcomes for each of the two models and the actual Kaplan Meier mean survivals are presented in the table . The percentage correct predictions of 5 y status is also presented, with correctness deemed accurate if the pt was alive and predicted to be alive by ≥ 50% as determined by each model or dead while the respective tool predicted < 50% possibility of being alive. For surgery alone pts, ADJ!pred were more often closer to what was observed, as compared to NUMpred, in the prog subgroups (for RFS 56%, OS 88%). For surgery + 5-FU pts, within these subgroups, NUMpred were more often closer to what was observed, as compared to ADJ!pred, for RFS (62%) and for OS (55%). Conclusions: In this independent population-based validation, NUM and ADJ! have acceptable and similar reliability with modest over-estimations of 5y RFS and OS. Both models thus appear to be useful adjuvant decision-aids. [Table: see text] No significant financial relationships to disclose.

Gastric cancer is an aggressive and heterogeneous malignancy that often varies in presentation and disease among racial and ethnic groups. The Alaska Native (AN) people have the highest incidence and mortality rates of gastric cancer in North America. This study examines molecular markers in solid tumor samples from eighty-five AN gastric adenocarcinoma patients using next-generation sequencing, immunohistochemistry, and in situ hybridization analysis. AN patients have a low mutation burden with fewer somatic gene mutations in their tumors compared to other populations, with the most common mutation being TP53. Epstein-Barr virus (EBV) was associated with 20% of AN gastric cancers, which is higher than the world average of 10%. The inflammation marker, cyclooxygenase-2 (COX-2), is highly expressed in patients with the lowest survival rates. Mismatch repair deficiency was present in 10% of AN patients and was associated with patients who were female, 50 years or older, gene mutations, and tumors in the distal stomach. Program death-ligand 1 (PD-L1) was expressed in 14% of AN patients who were more likely to have MMR deficiency, EBV-associated gastric cancers, and mutations in the PIK3CA gene, all of which have been linked to clinical response to PD-1 inhibitors. These studies suggest a portion of AN gastric cancer patients could be candidates for immunotherapy. Overall, this study highlights future avenues of investigation for clinical and translational studies, so that we can improve early detection and develop more effective treatments for AN patients.

Abstract Gastric cancer in the Alaska Native (AN) people occurs at a 3-fold higher incidence and 4-fold higher mortality rate compared to Non-Hispanic Whites (NHW), representing one of the largest cancer disparities in the AN population. We aimed to review the AN gastric cancer burden and identify clinicopathological factors that are associated with cancer outcomes. Patient information was collected from 132 AN gastric cancer patients diagnosed between 2006-2015 at the Alaska Native Medical Center. The Surveillance, Epidemiology and End Result database 18 was used to collect comparison United States NHW gastric cancer patient data. Compared to NHW patients, AN gastric cancer patients have a higher incidence rate, are significantly younger, 60 versus 69 years, and have a poorer 5-year overall survival rate of 10% compared to 22%. AN patients differ from NHW patients in gastric cancer anatomic location, subtype, and higher presence of signet ring cell carcinomas. Forty-one percent of AN patients were positive at the time of diagnosis for Helicobacter pylori, 77% had chronic gastritis, 30% had a family history of a first-degree relative with gastrointestinal cancers, and 82% were current or former tobacco users. Using univariate analysis, diminished overall survival was observed with anatomic site, increasing stage, no treatment, the number of lymph nodes examined during resection, blood type, and chronic gastritis. Multivariable analysis revealed stage and treatment type were independently associated with improved overall survival. AN gastric cancer cases vary in their clinical and epidemiologic features, relative to NHW. Citation Format: Holly Martinson, Steven Alberts, Matthew Olnes. Gastric cancer in Alaska Native people: A cancer health disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5284. doi:10.1158/1538-7445.AM2017-5284