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A woman in her 50s previously treated for early-stage breast cancer, parotid mucoepidermoid carcinoma and Caroli's disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDAC) metastatic to the liver and was found to harbour a

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Purpose: Emerging evidence implicates the microbiome in the development of pancreatic cancer. We investigated whether increased levels of microbial-related metabolites in circulation are associated with pancreatic cancer risk. Methods: We applied metabolomics profiling to sera from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cohort to quantify and build a model based on 14 microbial-related metabolites. The study involved samples collected from 172 subjects within five years prior to diagnosis and 863 matched controls. Data from five PLCO centers were used for training and from two centers for validation and model selection. The model was subsequently tested using samples from three independent centers. The contributions of non-microbial-associated metabolites as well as CA19-9 was also assessed. Results: A 3-marker microbial-related metabolite panel yielded in the PLCO testing set an AUC of 0.64 (95% CI: 0.53-0.76) for 5-year probability of pancreatic cancer. Five additional non-microbial metabolites were identified that when combined with the microbiome panel yielded an AUC of 0.79 (95% CI: 0.71-0.88) for 5-year probability of pancreatic cancer in the PLCO testing set. The combined metabolite panel and CA19-9 yielded an AUC of 0.86 (95% CI: 0.77-0.95) for 2-year probability of pancreatic cancer in the PLCO testing set, which was improved compared to CA19-9 alone (AUC: 0.70 (95% CI: 0.57-0.82), p< 0.001). Conclusion: We developed a metabolite panel derived in part from the microbiome for risk assessment of pancreatic cancer, which has relevance to prevention and early detection. Citation Format: Johannes F. Fahrmann, Ehsan Irajizad, Ana Kenney, Tiffany Tang, Jody Vykoukal, Ranran Wu, Jennifer B. Dennison, Marta Sans Escofet, James P. Long, Maureen Loftus, John A. Chabot, Michael D. Kluger, Fay Kastrinos, Lauren Brais, Ana Babic, Kunal Jajoo, Linda S. Lee, Thomas E. Clancy, Kimmie Ng, Andrea Bullock, Jeanine M. Genkinger, Anirban Maitra, Kim-Anh Do, Bin Yu, Brian M. Wolpin, Samir Hanash. Contribution of the microbiome to a metabolomic signature predictive of risk for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P076.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is often diagnosed in older adults. However, most published studies investigating chemotherapy for PDA include a predominantly younger population, and the standard of care for the older adult population is not defined. It is our goal to review the literature available about the safety and efficacy of combination chemotherapy for locally advanced or metastatic PDA in older adults ≥65 years. METHODS: We conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist. We searched PubMed, EMBASE and MEDLINE databases to identify retrospective and prospective studies published until October 2018 that assessed the survival outcomes and adverse events in patients 65 years and older diagnosed with PDA and treated with combination chemotherapy. RESULTS: A total of 1,479 studies were screened. Twenty-four full-text studies were assessed for eligibility. Nineteen were excluded due to wrong study design (n=4) or abstract only with no further publication (n=15). A total of 5 full text studies met eligibility and were included in the present review. Combination chemotherapy is associated with similar survival to that reported in younger populations with advanced PDA. The most common toxicities across studies included: sensory neuropathy and neutropenia. Two studies each reported one death related to treatment-associated sepsis. DISCUSSION: Papers examined in this systematic review concluded that the use of combination chemotherapy regimens is safe and effective for older adults with minimal comorbidities and adequate performance status. Prospective data is needed to confirm these findings, provided that the most significant limitation of these studies was a small sample size.

Background VT1021, a cyclic pentapeptide, reprograms myeloid-derived suppressor cells (MDSCs) and induces the production of thrombospondin-1 (Tsp-1) in the tumor microenvironment (TME). Tsp-1, via binding to CD36 and CD47, induces apoptosis in tumor and endothelial cells, blocks the ‘do-not-eat-me’ signal, increases the M1:M2 macrophage ratio and activates cytotoxic T lymphocytes (CTLs). Preclinical studies showed robust anti-tumor activities of VT1021 in multiple animal models. Methods This is a first-in-human, Ph 1/2, open-label, multicenter dose escalation and expansion study in advanced solid tumors. The primary objectives are to determine the recommended Phase 2 dose (RP2D) and characterize the safety and tolerability of VT1021. Secondary objectives are to characterize the adverse event (AE) profile, evaluate pharmacokinetics (PK), and describe preliminary efficacy. Exploratory objectives include evaluation of pharmacodynamic effects of VT1021 in tumor, TME, and peripheral blood. The expansion phase focuses on ovarian, pancreatic, triple negative breast cancer, glioblastoma, and a basket cohort with high CD36-expressing tumors. Results In the escalation phase, 46 subjects received between 0.5–15.6 mg/kg of VT1021 by IV infusion twice weekly. VT1021 has been well tolerated through all doses tested. One patient dosed at 1.0 mg/kg developed a grade 3 infusion reaction and 3 patients dosed at 1.0, 6.6, and 8.8 mg/kg respectively developed grade 2 infusion reactions. Other drug related AEs included grade 1–2 fatigue (n=7), nausea (n=4), constipation (n=2), increased aspartate aminotransferase (n=2) and blood bilirubin (n=2), hypomagnesaemia (n=2), and dizziness (n=2). Dose proportionality was observed in PK analysis. Among 28 evaluable subjects, one partial response (thymoma, 372+ days on treatment) and 11 stable disease (SD) in 9 different solid tumors have been observed for a disease control rate of 43%. Seven of eleven SDs had high CD36 AND high CD47 expression with an average duration of 162 days on study. VT1021 induced Tsp-1 production in peripheral blood cells at most dose levels. In addition, on-study biopsies exhibited increased Tsp-1 expression in the TME by activation of p53 in MDSCs, increased CTL infiltration, increased M1:M2 macrophage ratio, and reduced regulatory T cells in the TME. The RP2D was declared to be 11.8 mg/kg and enrollment in tumor-specific expansions is on-going. Conclusions Through all doses tested, VT1021 was safe and well tolerated, with dose proportional PK properties. In addition, VT1021 has demonstrated activities in reprogramming the TME which resulted in a high disease control rate in subjects with tumors expressing both high CD36 and high CD47. Trial Registration NCT03364400 Ethics Approval The study was approved by Northwestern University Medical School institutional review board (IRB), approval number 00000418, Horizon Oncology Center IRB, approval number 00001313, South Texas Accelerated Research Therapeutic IRB, approval number 00003657, University of Oklahoma Health Sciences Center IRB, approval number 00006075, Cleveland Clinic IRB, approval number 00000536, Florida Cancer Specialists IRB, approval number 00006075, Case Western IRB, approval number 00000536, Beth Israel Deaconess Hospital and Dana Farber Cancer Institute IRB, approval number 00000753 and MD Anderson IRB, approval number 00006023.

A woman in her 50s previously treated for early-stage breast cancer, parotid mucoepidermoid carcinoma and Caroli’s disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDAC) metastatic to the liver and was found to harbour aBRCA1germline mutation. She had palliative chemotherapy, initially with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin, and then FOLFIRI and capecitabine, achieving a sustained near-complete response for at least 86 months. Chemotherapy was eventually discontinued when she was diagnosed with a tongue squamous cell carcinoma. Despite withholding systemic therapy, she has maintained a durable response. This is the first report in the English literature showing a sustained duration of response in a patient with PDAC and BRCA1germline mutation.