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Endoscopic ultrasound (EUS), the primary procedure for the diagnosis of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer, is invasive. We aim to develop a liquid biopsy approach using plasma cell-free messenger RNA to stratify patients prior to EUS and assist in the precision diagnosis of PDAC. We found a set of plasma cell-free messenger RNA biomarkers and a set of robust reference genes to classify PDAC patients from intermediary pancreatic pathologies such as: benign cases, pancreatitis, and intraductal papillary mucinous neoplasm (IPMN) with reproducible results validated in separate cohorts. Our results demonstrate a non-invasive liquid biopsy approach for stratifying patient groups before invasive and definitive EUS screening. Citation Format: Travis Moore, Elias Spiliotopolous, Rowan Callahan, Ward Kirschbaum, Hyun Ji Kim, Dove Keith, Aaron Grossberg, Paul T. Spellman, Gordon Mills, Rosalie C. Sears, Terry Morgan, Thuy Ngo. Cell free RNA for prediction of PDAC in de novo symptomatic patients presenting for EUS-FNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB178.

The role of neoadjuvant chemoradiotherapy and/or chemotherapy (neoCHT) in patients with pancreatic ductal adenocarcinoma (PDAC) is poorly defined. We hypothesized that patients who underwent neoadjuvant therapy (NAT) would have improved systemic therapy delivery, as well as comparable perioperative complications, compared to patients undergoing upfront resection. This is an IRB-approved retrospective study of potentially resectable PDAC patients treated within an academic quaternary referral center between 2011 and 2018. Data were abstracted from the electronic medical record using an institutional cancer registry and the National Surgical Quality Improvement Program. Three hundred and fourteen patients were eligible for analysis and eighty-one patients received NAT. The median overall survival (OS) was significantly improved in patients who received NAT (28.6 vs. 20.1 months, p = 0.014). Patients receiving neoCHT had an overall increased mean duration of systemic therapy (p < 0.001), and the median OS improved with each month of chemotherapy delivered (HR = 0.81 per month CHT, 95% CI (0.76–0.86), p < 0.001). NAT was not associated with increases in early severe post-operative complications (p = 0.47), late leaks (p = 0.23), or 30–90 day readmissions (p = 0.084). Our results show improved OS in patients who received NAT, driven largely by improved chemotherapy delivery, without an apparent increase in early or late perioperative complications compared to patients undergoing upfront resection.

TPS776 Background: Neoadjuvant chemotherapy (NAC) and/or chemo-RT may confer benefit to patients with localized PDAC, by better tolerability, tumor down-staging, and increased R0 resections. mFFX or GA are the current NAC backbones; however, a lack of robust predictive biomarker(s) hampers identification of patients most likely to benefit from mFFX or GA. Further, desmoplastic stroma/poor vascularity compromise NAC efficacy, but angiotensin II receptor inhibitor, losartan, might remodel vascular perfusion to enhance chemotherapy activity. We designed the NeoOPTIMIZE trial for patients with newly diagnosed localized PDAC to provide a flexible clinical platform to: 1) evaluate the feasibility and efficacy of early switching of mFFX to GA, and 2) establish a robust biomarker/imaging discovery platform to optimize the NAC backbone. Methods: NeoOPTIMIZE (NCT04539808) is an open-label, non-randomized, phase II trial assessing the preliminary efficacy of an adaptive treatment strategy that allows for early switching of NAC in patients with localized PDAC. Sixty patients (n = 40 resectable/BRCP; n = 20 locally advanced unresectable [uLAPC]) will be enrolled to receive 2 months of preoperative mFFX (oxaliplatin, 85 mg/m2; folinic acid, 400 mg/m2; irinotecan, 150 mg/m2; 5-FU, 2400 mg/m2), then restaging by a multidisciplinary tumor board (multiD-TB). Absent progression (by panc protocol CT and CA19-9 decline/increase < 30% from baseline), patients continue mFFX (4 cycles). If progression (by panc protocol CT; CA19-9 increase > 30%), patients switch to GA (nab-paclitaxel, 125 mg/m2; gemcitabine, 1000 mg/m2) for 2 months. After 4 months of mFFX or mFFX/GA, another restaging multiD-TB will decide to proceed with: a) RT (if vascular involvement) then resection, b) resection, or c) continued chemo (if unresectable). Losartan (50 mg PO QD) is given throughout NAC and RT regimens. The primary endpoint estimates the proportion of resectable/BRPC patients with R0 resection. Assuming that the proportion of R0 is 60%, a sample size of 32 will provide a 95% CI (0.41, 076). To account for a 20% dropout, 40 patients will be enrolled towards primary endpoint. A separate exploratory cohort of 20 uLAPC patients will be enrolled. Secondary endpoints include DFS, PFS, OS, and AEs. Exploratory objectives include correlating clinical outcomes data with changes in blood-based biomarkers (CA19-9, ctDNA, circulating tumor cells etc.) and research DCE-MRI. To date, the trial has enrolled 19 patients: 8 resectable, 7 BRCP, and 4 uLAPC. Clinical trial information: NCT04539808 .

Metastatic pancreatic adenocarcinoma (PDAC) is a rapidly lethal disease, with less than half of patients surviving 12 months, and 5-year survival approximately 3%. These outcomes are in large part due to a lack of effective medical and surgical therapies for metastatic PDAC. Herein, we present the case of a patient with oligometastatic liver recurrence of BRCA2-mutated PDAC following a curative-intent resection. Through a combination of systemic chemotherapy, metastasectomy, radiotherapy, and subsequent targeted therapy with olaparib, the patient is asymptomatic four years following metastatic diagnosis with stable low-volume disease. This patient’s excellent outcome is attributable to the multi-disciplinary care received, all aspects of which were informed by new evidence surrounding metastasectomy for metastatic PDAC, the unique biology and medical treatment of BRCA-mutated PDAC, and the role of radiotherapy in controlling locoregional recurrence. We provide a review of this evidence, while highlighting the importance of evaluating disease biology through somatic and germline genetic testing as well as monitoring response to systemic chemotherapy.

Background: One of the factors contributing to poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is thought to be the characteristically dense stroma and heterogeneous tumor microenvironment. The PDAC stroma involves multiple players, including cancer associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs). These stromal cells, when activated, promote extensive fibrosis in PDAC, which is associated with poor prognosis and chemoresistance. We have previously established that the RNA-binding protein Human Antigen R (HuR, ELAVL1) facilitates PDAC progression. In a tumor microarray of matched normal and malignant patient tissues, we found high active (i.e. cytoplasmic) HuR staining in 80% of PDAC tumors, while low or absent in adjacent normal tissues (n=80). Moreover, in both the orthotopic and the genetically engineered mouse models of PDAC, active HuR staining in tumors was dramatically higher than in normal pancreas. Pancreas-specific overexpression of HuR in a transgenic mouse model did not initiate tumorigenesis, but did increase fibrosis compared to control mice. We hypothesize that tumor intrinsic HuR regulates transcripts that are needed for tumor cells to activate the surrounding stroma. Methods: MiaPaCa-2 or PANC-1 human PDAC cells, either HuR-proficient or CRISPR-mediated knocked-out, were used in an orthotopic model where cells were injected into the tail of the pancreas. Both NRG and athymic mice were used. Resulting tumors underwent immunohistochemistry, immunofluorescence, or RNA-sequencing. Secreted proteins from cells in 2D culture were analyzed using a cytokine array. Results: HuR knockout tumors showed a decrease in CAF and PSC markers (i.e. podoplanin, alpha-SMA, desmin; >55% decrease, p RNA sequencing of PDAC tumors at various times during tumor development found that gene expression of stroma-activating ligands was significantly downregulated in HuR knockout tumors (e.g. TGFb, CCL2, PDGFA; -0.850% decrease, p Conclusions: We found inhibition of HuR led to a robust decrease in stroma activation (i.e. lack of collagen, CAFs, and PSCs). To our knowledge, this is the first report of PDAC tumor intrinsic HuR having an extrinsic effect on neighboring stromal cells. Specifically, we found loss of HuR results in a decrease of secreted stroma-activating ligands, likely to be the cause of the decreased fibrosis in HuR knockout tumors. With evidence that fibrosis is associated with poor survival rates and chemoresistance, inhibiting HuR may sensitize tumors to standard of care therapy. Citation Format: Grace A. McCarthy, Jennifer M. Finan, Aditi Jain, Roberto DiNiro, Aaron Grossberg, Jonathan R. Brody. Tumor intrinsic HuR promotes stroma activation in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3191.

Objective: Cachexia, a wasting condition defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC) that negatively impacts quality of life and confers poor patient survival. Cachectic wasting cannot be abrogated by nutritional supplementation, and the mechanisms underlying this phenotype are unclear. Recent work demonstrates that human antigen R (HuR), an RNA-binding protein that regulates expression of genes involved in key cellular processes such as inflammation, stress response, and apoptosis, is also a major repressor of adipogenesis. Thus, we sought to elucidate the relative contributions of enhanced catabolism and impaired anabolism on fat wasting by investigating adipose tissue response to different nutritional contexts and HuR inhibition in cachectic mice. Methods: Adult C57BL/6J mice received orthotopic PDAC tumor injections (KrasG12D; p53R172H/+; Pdx1-cre) or sham injections. Mice were fed ad libitum, fasted 24h or fasted and refed 24h at mid-cachexia (9 days after injection). A separate cohort of PDAC mice were treated with the HuR inhibitor KH3 (100 mg/kg) at 6-, 8-, and 10-days post-injection and subjected to the same fast/refeed paradigm. Gross fat pads were weighed to assess anabolism. Adipose tissue mRNA levels were measured using RNAseq and validated with qPCR. Lipolytic rate was quantified as normalized quantity of glycerol released from inguinal (iWAT) and gonadal (gWAT) fat pads ex vivo. Results: PDAC and control mice exhibited equivalent loss of adipose tissue as a result of food restriction. Fat pads from PDAC mice displayed decreased lipolysis ex vivo and decreased lipase (Atgl & Lipe) mRNA expression. In the fast/refeed model, PDAC mice were unable to restore iWAT or gWAT mass after refeed compared to controls. RNAseq revealed 614 differentially expressed genes between gWAT from PDAC and control mice. Downregulated (n=111) genes were most closely associated with adipogenesis (adj p=5x10-3), and expression of adipogenesis master regulators Pparg and Cebpa were reduced in both iWAT and gWAT from PDAC mice. Inhibition of HuR by KH3 restored lipogenesis in refed animals with a concomitant increase in fat pad mass and associated genes regulating adipogenesis (Pparg, Cebpa, Retn, Adipoq, Fasn). Conclusion: Adipose tissue wasting during PDAC cachexia can result from impaired anabolism in the absence of excess lipolysis or malabsorption. Adipose anabolism in PDAC mice is mediated by increased HuR activity in adipocytes. Restoring anabolic potential in adipose tissue using the HuR inhibitor KH3 may provide a novel approach to alleviating PDAC cachexia. Citation Format: Beth L. Worley, Katherine Pelz, Grace McCarthy, Heike Mendez, Roberto Di Niro, Alex Chitsazan, Jonathan Brody, Aaron Grossberg. The RNA-binding protein HuR mediates impaired adipogenesis in pancreatic cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2373.

Background and Aims Pancreatic ductal adenocarcinoma is an aggressive disease most often diagnosed after local progression or metastatic dissemination, precluding resection and resulting in a high mortality rate. For individuals with elevated personal risk of the development of pancreatic cancer, EUS is a frequently used advanced imaging and diagnostic modality. However, there is variability in the expertise and definition of EUS findings among gastroenterologists, as well as lack of standardized reporting of relevant findings at the time of examination. Adoption of standardized EUS reporting, using a universally accepted and agreed upon terminology, is needed. Methods A consensus statement designed to create a standardized reporting template was authored by a multidisciplinary group of experts in pancreatic diseases that includes gastroenterologists, radiologists, surgeons, oncologists, and geneticists. This statement was developed using a modified Delphi process as part of the Pancreatic Cancer Early Detection Consortium (PRECEDE) and >75% agreement was required to reach consensus. Results We identified reporting elements and present standardized reporting templates for EUS indications, procedural data, EUS image capture, and descriptors of findings, tissue sampling, and for postprocedural assessment of adequacy. Conclusions Adoption of this standardized EUS reporting template should improve consistency in clinical decision making for individuals with elevated risk of pancreatic cancer by providing complete and accurate reporting of pancreatic abnormalities. Standardization will also help to facilitate research and clinical trial design by using clearly defined and consistent imaging descriptions, thus allowing for comparison of results across different centers.

BackgroundStereotactic body radiotherapy (SBRT) demonstrates excellent local control in early stage lung cancer, however a quarter of patients develop recurrence or distant metastasis. Transforming growth factor-beta (TGF-β) supports metastasis and treatment resistance, and angiotensin receptor blockade (ARB) indirectly suppresses TGF-β signaling. This study investigates whether patients taking ARBs while undergoing SBRT for early stage lung cancer exhibited improved overall survival (OS) or recurrence free survival (RFS) compared to patients not taking ARBs. MethodsThis was a single institution retrospective analysis of 272 patients treated with SBRT for early stage lung cancer between 2009-2018. Patient health data was abstracted from the electronic medical record. OS and RFS were assessed using Kaplan-Meier method. Log-rank test was used to compare unadjusted survival between groups. Univariable and multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs). ResultsOf 247 patients analyzed, 24 (10%) patients took ARBs for the duration of radiotherapy. There was no difference in mean age, median tumor diameter, or median biologic effective dose between patients taking ARBs or not. Patients taking ARBs exhibited increased OS (ARB=96.7 mo.; no ARB= 43.3 mo.; HR=0.25 [95% CI: 0.10 to 0.62, P = .003]) and increased RFS (median RFS, ARB=64.3 mo.; No ARB=35.1 mo.; HR=0.26 [95% CI: 0.10 to 0.63, P = .003]). These effects were not seen in patients taking angiotensin converting enzyme inhibitors (ACEIs) or statins. ConclusionsARB use while undergoing SBRT for early stage lung cancer may increase OS and RFS, but ACEI use does not show the same effect.