Citations

3599 Background: Existing tools for post-treatment CRC surveillance and monitoring are insensitive and expensive. MDMs are broadly informative for early detection of CRC but have not been extensively studied for disease monitoring. As a first step, we sought to assess the concordance of novel CRC-associated MDMs in pCRC and mCRC. Methods: A panel of 14 MDMs previously identified to be highly discriminant for pCRC was selected on the basis of high median fold-change of MDM levels relative to buffy coat (682 (IQR: 132-19347)). Surgically resected pCRC and paired mCRC were identified from institutional pathology databases. Quantitative methylation-specific PCR was used to assay MDMs. 30 paired samples per metastatic subtype were calculated to be sufficient. MDM levels were compared using two-sample and paired Wilcoxon rank sum tests. Results: 87 patients with paired pCRC and mCRC including 57 synchronous and 30 metachronous metastases were included. 41/87 (47%) had neoadjuvant and 59/87 (68%) had adjuvant chemotherapy. All synchronous metastases were to liver. Metachronous metastases were to liver in 19/30 (63%) and to lung in 11/30 (37%). The levels of 14 selected MDMs were remarkably similar between paired pCRC and mCRC (Table). Individual MDM levels and the average level of all MDMs combined were not significantly different ( p> 0.0018 by Bonferroni correction). Conclusions: MDM levels are highly concordant in pCRC and mCRC. Thus, MDMs discovered from pCRC should be further studied for non-invasive surveillance after surgical resection and monitoring of treatment response in mCRC. [Table: see text]

3101 Background: PDO is a promising translational tool that recapitulates the biology and drug response of donor cancer patient. However, an unmet need is to have PDO drug-screening data available for treatment decision making in clinic. We conducted a pilot study to determine whether PDO testing results will be available at critical treatment decision points in metastatic GI cancer patients. Methods: Metastatic GI cancer patients undergoing core-needle biopsy were eligible. Tumor cells isolated from ≤4 fresh biopsy tissues were grown in a Matrigel-based culture. PDO response to anti-cancer drugs were evaluated; and when available, correlated with donors’ clinical response to the same agent(s). PDO response was defined as IC50 < 0.1 × published Cmax of the drug clinically; stable as IC50 between 0.1 to 10 × Cmax. Radiographic response was per RECIST criteria. Results: We enrolled 27 refractory metastatic GI cancer patients (9 colorectal [CRC], 9 pancreas, and 9 biliary tract). Median lines of therapy were 4, 2, and 2; the success rate of organoid establishment was 89%, 44%, and 55%, respectively. The median time from biopsy to availability of drug-testing data was 64 days (range: 24 to 93 days). The median time from biopsy to next CT re-staging in donors was 64 days. The established PDOs shared histological and genomic features with donor clinical tissue. PDO and clinical responses to the same agent(s) were correlated in 2 CRC donors including (1) BRAFV600E-mutated PDO responded to vemurafenib + panitumumab, as did the donor who had partial response (PDO drug-testing data were available 55 days post-biopsy, 23 days prior to restaging scan); (2) KRAS/FGF-dual amplified PDO had stable disease status to regorafenib, as did the biopsied lesion from the donor (73 days post-biopsy, 5 days post-scan). Conclusions: We showed the feasibility of completing PDO drug sensitivity testing in metastatic GI cancer patients within a short time that could impact clinical decision making, particularly in CRC. PDO drug response showed correlation with clinical response. With further refinement, PDO can be a powerful tool for personalizing cancer therapy in metastatic GI cancer patients.

The Hedgehog/GLI signaling pathway plays an important role in normal embryonic tissue development and has been implicated in the pathogenesis of various human cancers. In this review article, we summarize pre-clinical evidence supporting the suitability of targeting this signaling pathway in cancers. We review agents blocking both the ligand-dependent and ligand-independent cascades, and discuss the clinical evidence, which has led to the FDA approval of Hedgehog receptor Smoothened inhibitors, vismodegib, and sonidegib, in different malignancies. Finally, we provide an overview of published and ongoing clinical trial data on single agent or combination therapeutic strategies, targeting Hedgehog/GLI signaling pathway, in both advanced solid tumors and hematologic malignancies.

322 Background: The role of perioperative systemic therapy (PST) is unclear in the management of localized pancreatic neuroendocrine tumor (pNET). We aim to evaluate the benefit of PST compared to surgical resection alone in localized pNET. Methods: We identified patients with stage I–III pNET who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who underwent PST and surgical resection were matched with patients who received surgery alone by propensity score at 1:1 ratio with nearest neighbor method. Factors predicting the use of PST were identified from logistic regression. Survival was estimated with Kaplan-Meier method and compared with Cox proportional hazards regression. Results: 4919 patients were included in this study with median age of 60 years. 1397 (28%) patients had pNET at the head of pancreas. 2708 (55%) patients had pNET at pancreas body and tail. 334 (6.8%) patients received PST. Factors associated with significant more use of PST compared to surgery alone were age < 65 years, low income, community medical facilities, grade 3/4 tumor, tumor at the head of pancreas, T3-4 tumor and N1 tumor. 310 patients in PST group were matched with 310 patients in surgery alone group, with no significant difference for all covariates after match. For those in PST group, 64 (21%) patients received neoadjuvant systemic therapy, 173 (56%) patients received adjuvant systemic therapy, 7 (2.3%) patients received both, and 66 (21%) patients received PST without clear sequence. In the matched cohort, PST group had significantly shorter overall survival (OS) compared to surgery alone group (median OS 91.1 months versus not reached, p = 0.04). This finding was confirmed by multivariable Cox proportional hazards regression in unmatched cohort with HR 1.5 (95% CI 1.2 – 1.9, p = 0.002). Subgroup analysis in patients with grade 3/4 tumor demonstrated PST group has a trend of shorter OS compared to surgery alone group (median OS 34.1 versus 54.4 months, p = 0.1). Conclusions: PST compared to surgery alone is associated with worse OS in patients with localized pNET. This finding suggests that we may use PST in localized pNET with caution in the absence of solid clinical trial data.

Pancreatic cancer is the eleventh most common cancer, yet it is the third leading cause of mortality. It is also largely a disease of older adults, with the median age of 71 at diagnosis in the US, with <1% of diagnoses occurring prior to age 50. Current NCCN guidelines recommend surgery for localized disease, followed by adjuvant therapy and/or consideration of enrollment in a clinical trial. For metastatic disease, current guidelines recommend clinical trial enrollment or systemic chemotherapy based on results from the landmark ACCORD-11 and MPACT trials. However, these trials focused heavily on younger, more fit patients, with the ACCORD-11 trial excluding patients over age 75 and the MPACT trial having 92% of its patients with a Karnofsky performance score >80. This article summarizes the available evidence in current literature in regards to the best treatment options for older adults, who represent the majority of pancreatic cancer diagnoses.

Objectives: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. Materials and Methods: Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8, capecitabine 1300 mg/m² oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. Results: A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. Conclusions: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.