Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) and endoscopic ultrasound-guided ethanol ablation (EUS-EA) of pancreatic neuroendocrine tumors and adenocarcinoma: a prospective multicenter study

IntroductionRFA and EUS-EA are emerging novel methods for managing non-functioning and functioning pNET and adenocarcinoma in the pancreas. We aim to assess the safety profile, feasibility, and outcomes of EUS-RFA...

Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial

Over the last twenty years, there is a limited number of effective cytotoxic or biological agents that managed to get approval in advanced pancreatic ductal adenocarcinoma. Despite numerous trials, investments in translational research and generally in health care, the survival of pancreatic cancer patients has improved by a few only months. This disappointing reality necessitates a better understanding of the pathogenesis of this disease and the identification of targetable alterations which might lead to development of more effective drugs or better combinations. At the 2013 Annual Meeting of the American Society of Clinical Oncology, few novel agents and new therapeutic concepts, tested in phase I studies in advanced pancreatic ductal adenocarcinoma, were presented. The first notable phase I study referred to the combination of chemotherapy with local delivery of silencing RNA against the K-ras mutation G12D, in advanced pancreatic ductal adenocarcinoma, which was well tolerated and promising (Abstract #4037). The second one referred to a combination of gemcitabine with pegylated recombinant human hyaluronidase (PEGPH20), an inhibitor of hyaluronan which as a matrix glycosaminoglycan is believed to play role in the reduced drug delivery to cancer (Abstract #4010). The other notable abstract was related to an early phase study which tested the safety and toxicity of arctigenin, a traditional herbal agent found in Arctium lappa Linné, administered as an oral formulation (GMS-01) in pancreatic ductal adenocarcinoma patient resistant to standard chemotherapy (Abstract #2559). The aforementioned early phase studies open new therapeutic approaches which deserve further testing in advanced pancreatic cancer.

315 Background: Metastatic PA is a lethal malignancy with poor prognosis and limited therapeutic options. We hypothesized that a comprehensive next-generation sequencing (NGS) assay could identify novel therapy targets not routinely explored in PA patients. Methods: We included patients with advanced pancreatic adenocarcinoma (PA) with accessible lesion for biopsy. Paraffin-embedded tumor tissues were evaluated by the method of NGS (Foundation Medicine, Cambridge, MA, USA). Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50 ng of DNA extracted from 10 PA specimens and sequenced to high, uniform coverage. Genomic alterations (GAs), were characterized and reported for each patient sample. Actionable GAs were defined as those identifying anti-cancer targeted therapies either available on the market or in registered clinical trials. Results: A total of 10 PA patients were included. Median age was 56 years (range 31-79). All cases harbored at least one GA with a mean of 2.7 actionable GAs per tumor. The most common actionable GAs were KRAS (90%), PTCH1 (20%), STK11 (10%) and GNAS (10%). KRAS mutations potentially treatable with MEK-inhibitor were identified in 9 patients. However, none of them received a MEK-inhibitor. Activating STK11 point mutations not detectable by IHC/FISH, potentially targetable with m-Tor inhibitor therapies were identified in 1 patient, who received everolimus and had a long-lasting (> 6 months) partial response. Conclusions: NGS of PA was able to reveal genomic alterations that may be potentially responsive to available targeted therapy. We are just at the dawn of exploring this strategy and NGS can effectively contribute for increasing the understanding of the disease.

e14580 Background: Combination chemotherapy provides modest benefit in patients with advanced pancreatic adenocarcinoma over single agent gemcitabine. Recent studies have suggested that new regimens that included taxanes may be active in this disease. One of the more promising regimens combines gemcitabine with docetaxel and capecitabine (GTX) reporting a median survival of greater than 1 year. We were interested in confirming these observations in our patient population. Methods: We performed a multicenter review of all patients with pathologically confirmed locally advanced or metastatic pancreatic adenocarcinoma who received treatment with GTX. Results: Clinical outcomes on 70 patients (36 locally advanced and 34 metastatic pancreatic adenocarcinoma) were collected. Patients had a mean age of 60.6 (range 39-81) and ECOG performance 0-1. Forty-seven percent of patients were deceased at time of this review. GTX was delivered every 21 days (gemcitabine 750 mg/m2 fixed dose rate D4 and D11, docetaxel 30 mg/m2 D4 and D11, capecitabine 1,000 mg bid D1-14) and used as the first-line therapy in 66% of cases. Median overall survival from the time of GTX initiation was 12.4 months, which improved to 14.3 months when used as a first-line regimen; one-year survival was 53% and 61% respectively. In patients with metastatic disease the median overall survival was 12.4 months with a one-year survival of 55%. More than half of patients with metastatic disease had at least a 50% drop in CA19-9. Response rate by RECIST criteria at one institution showed a 24.3% objective response rate (CR + PR) with one complete response, and the majority (70%) of patients exhibiting stable disease. Grade 3-4 hematological toxicities were neutropenia 40%, thrombocytopenia 12.5% and anemia 10%. Hospital admissions were required in 33% (23/70) of the patients while receiving GTX. There were no deaths attributed to toxicity from this regimen. Conclusions: GTX has a promising survival benefit of greater than 1 year in patients with advanced pancreatic adenocarcinoma when compared to studies using single agent gemcitabine or other combination chemotherapies. Randomized controlled studies in pancreatic cancer with GTX are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Concordia, Roche Concordia Bristol-Myers Squibb, Concordia, Genentech, Lilly

e16792 Background: To determine evaluate the safety and efficacy of nab-paclitaxe, gemcitabine (AG) and Recombinant Humanized Anti-PD-1 Monoclonal Antibody (JS001) for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Methods: This was a single-arm, open-label, phase 1b/2 clinical trial of nab-paclitaxel plus gemcitabine plus Anti-PD-1 Monoclonal Antibody in which 11 patients with previously untreated advanced PDAC were enrolled from December 2018. Patients were treated with nab-paclitaxel 125 mg/m2 on days 1 and 8 plus gemcitabine 1000 mg/m2 on days 1 and 8 plus fixed dose of JS001 240mg on day 1 of a 21-day cycle until progression or toxicity or receiving maintance therapy. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Results: 11 chemotherapy naïve PDAC patients with a median age of 52 years old were treated. 5 were men and all patients had an ECOG of 0 or 1. Grade 3/4 events were observed in 27.3% of patients (2 patients presented hematological toxicity ), and JS001 was discontinued because of asymptomatic elevated cardiac biomarkers and hypothyroidism as immunotherapy-related toxicities in a female patient, no patient was discontinued AG therapy because of chemotherapy-related adverse events. Of the 11 evaluable patients, the disease control rate (partial response [PR] + stable disease[SD]) was 81.8%. There were 2 patients with PR and 1 patient with complete response respectively, and overall response rate (ORR) was 27.3%. The median progression-free survival (PFS) was 7 months and all patients survive at the last following-up in Jan-2020. All patients were proficient mismatch repair (pMMR) status. Whole-exome sequencing was performed on 7 patients, no immunotherapy-associated gene was detected, and next comprehensive analysis of somatic alterations was ongoing. Conclusions: Combined JS001 and AG can be safely given to chemotherapy naïve PDAC patients. Efficacy appears to be promising over previously reported results for standard AG chemotherapy every 28 days gemcitabine and nab-paclitaxel dosing. Comprehensive data available was ongoing to analysis the potential effect to efficacy of the combination.

BACKGROUND A prospective, randomized Phase III trial was performed to determine whether, compared with gemcitabine (GEM) alone, the addition of cisplatin (CDDP) to GEM was able to improve the time to disease progression and the clinical benefit rate in patients with advanced pancreatic adenocarcinoma. The objective response rate, overall survival rate, and toxicity patterns of patients in the two treatment arms were evaluated as secondary end points. METHODS Patients with measurable, locally advanced and/or metastatic pancreatic adenocarcinoma were randomized to receive GEM (Arm A) or a combination of GEM and CDDP (Arm B). In Arm A, a dose of 1000 mg/m2 GEM per week was administered for 7 consecutive weeks, and, after a 2-week rest, treatment was resumed on Days 1, 8, and 15 of a 28-day cycle for 2 cycles. In Arm B, CDDP was given at a dose of 25 mg/m2 per week 1 hour before GEM at the same dose that was used in Arm A. On Day 22, only GEM was administered. Patients were restaged after the first 7 weeks of therapy and then again after the other 2 cycles. RESULTS A total of 107 patients entered the trial: Fifty-four patients were randomized to Arm A, and 53 patients were randomized to Arm B. The median time to disease progression was 8 weeks in Arm A and 20 weeks in Arm B; this difference was statistically significant (P = 0.048). In Arm A, one complete response and four partial responses were recorded on the basis of an intent-to-treat analysis, with an overall response rate of 9.2% (95% confidence interval [95%CI], 3–20%). In Arm B, there were no complete responses, whereas 14 partial responses were achieved, with an overall response rate of 26.4% (95%CI, 15–40%). This difference in the overall response rates was statistically significant (P = 0.02). The tumor growth control rate (i.e., total number of patients who achieved complete responses, partial responses, and stable disease) was 42.6% (95%CI, 29–57%) in Arm A and 56.6% (95%CI, 42–70%) in Arm B. A clinical benefit was observed in 21 of 43 patients (49%) in Arm A and in 20 of 38 patients (52.6%) in Arm B without any significant difference. The median overall survival was 20 weeks for patients in Arm A and 30 weeks for patients in Arm B (P = 0.43). Toxicity was mild in both treatment arms, with no significant differences between the two groups except for the statistically higher incidence of Grade 1–2 asthenia in Arm B (P = 0.046). CONCLUSIONS The addition of CDDP to GEM significantly improved the median time to disease progression and the overall response rate compared with GEM alone. The clinical benefit rate was similar in both arms, whereas the median overall survival rate was more favorable for Arm B, although the difference did not attain statistical significance. The authors conclude that the combination of CDDP and GEM currently may be considered as an optimal treatment for patients with locally advanced and/or metastatic adenocarcinoma of the pancreas. Cancer 2002;94:902–10. © 2002 American Cancer Society. DOI 10.1002/cncr.10323

A prospective, randomized Phase III trial was performed to determine whether, compared with gemcitabine (GEM) alone, the addition of cisplatin (CDDP) to GEM was able to improve the time to disease progression and the clinical benefit rate in patients with advanced pancreatic adenocarcinoma. The objective response rate, overall survival rate, and toxicity patterns of patients in the two treatment arms were evaluated as secondary end points. Patients with measurable, locally advanced and/or metastatic pancreatic adenocarcinoma were randomized to receive GEM (Arm A) or a combination of GEM and CDDP (Arm B). In Arm A, a dose of 1000 mg/m(2) GEM per week was administered for 7 consecutive weeks, and, after a 2-week rest, treatment was resumed on Days 1, 8, and 15 of a 28-day cycle for 2 cycles. In Arm B, CDDP was given at a dose of 25 mg/m(2) per week 1 hour before GEM at the same dose that was used in Arm A. On Day 22, only GEM was administered. Patients were restaged after the first 7 weeks of therapy and then again after the other 2 cycles. A total of 107 patients entered the trial: Fifty-four patients were randomized to Arm A, and 53 patients were randomized to Arm B. The median time to disease progression was 8 weeks in Arm A and 20 weeks in Arm B; this difference was statistically significant (P = 0.048). In Arm A, one complete response and four partial responses were recorded on the basis of an intent-to-treat analysis, with an overall response rate of 9.2% (95% confidence interval [95%CI], 3-20%). In Arm B, there were no complete responses, whereas 14 partial responses were achieved, with an overall response rate of 26.4% (95%CI, 15-40%). This difference in the overall response rates was statistically significant (P = 0.02). The tumor growth control rate (i.e., total number of patients who achieved complete responses, partial responses, and stable disease) was 42.6% (95%CI, 29-57%) in Arm A and 56.6% (95%CI, 42-70%) in Arm B. A clinical benefit was observed in 21 of 43 patients (49%) in Arm A and in 20 of 38 patients (52.6%) in Arm B without any significant difference. The median overall survival was 20 weeks for patients in Arm A and 30 weeks for patients in Arm B (P = 0.43). Toxicity was mild in both treatment arms, with no significant differences between the two groups except for the statistically higher incidence of Grade 1-2 asthenia in Arm B (P = 0.046). The addition of CDDP to GEM significantly improved the median time to disease progression and the overall response rate compared with GEM alone. The clinical benefit rate was similar in both arms, whereas the median overall survival rate was more favorable for Arm B, although the difference did not attain statistical significance. The authors conclude that the combination of CDDP and GEM currently may be considered as an optimal treatment for patients with locally advanced and/or metastatic adenocarcinoma of the pancreas.

e16288 Background: The prognosis for advanced metastatic pancreatic adenocarcinoma remains dismal, highlighting the need for novel therapeutic agents. FOLFIRINOX (5-Fluorouracil + Oxaliplatin + Irinotecan) remains the standard of care frontline therapy for advanced disease, with historical objective response rate (ORR) of ~31%. Eryaspase is an investigational red blood cell product encapsulating L-asparaginase, which hydrolyzes and reduces asparagine levels in plasma, leading to cancer cell death. A phase III trial (Trybeca-1), which compared chemotherapy with or without eryaspase in the second line setting, did not reach its primary efficacy endpoint. However, there was a trend towards improved survival in the group receiving 5-fluorouracil and irinotecan plus eryaspase. We herein report the final results from our phase I front-line study of mFOLFIRINOX plus eryaspase. Methods: Patients with locally advanced or metastatic biopsy-proven pancreatic adenocarcinoma were treated with mFOLFIRINOX plus eryaspase in a standard 3 +3 dose escalation trial design. mFOLFIRINOX was given as 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus eryaspase 75 units/kg at dose level 0 or 100 units/kg at dose level 1. Key eligibility criteria included performance status of 0 or 1, locally advanced or metastatic disease, and adequate organ function. The primary objectives were to determine the maximum tolerated dose (MTD) and to determine the safety of this combination. Results: At completion of trial, eighteen patients were enrolled. Three patients were enrolled at dose level 0 and fifteen at dose level 1, with no dose limiting toxicities. Seventeen patients had imaging to evaluate best response: 24% (N=4) had partial response (PR), 65% (N=11) had stable disease (SD), and 11% (N=2) had progressive disease. The disease control rate (PR +SD) was 89%. Progression free survival (PFS) was 6.4 months (95% CI 3.21 – 16.79) and overall survival (OS) was 10.1 months (95% CI 7.18 – NR). There were select patients with very durable response (PFS>12 months and OS >18 months). There was one grade 5 (G5) sepsis adverse event (AE) and one G4 thromboembolic AE. G3 AEs were hypokalemia (22%), fatigue (11%), anemia (6%), hypotension (6%), diarrhea (6%), syncope (6%), and atrial fibrillation (6%). Pharmacokinetic and pharmacodynamic data are in process. Conclusions: The novel combination of mFOLFIRINOX plus eryaspase was well tolerated with no DLT and demonstrated signals of clinical activity in select patients. The MTD was declared with 5-FU 2400 mg/2, Oxaliplatin 85 mg/2, Irinotecan 150 mg/m2, and eryaspase 100 units/kg. Although the phase III Trybeca-1 trial did not meet the primary OS endpoint, both trials may suggest enhanced activity of eryaspase with regimens containing 5-Fluorouracil and Irinotecan. Clinical trial information: NCT04292743 .

581 Background: The prognosis for advanced metastatic pancreatic adenocarcinoma remains dismal with median survival of 12-15 months in most recent trials, highlighting the urgent need for novel therapeutic agents. mFOLFIRINOX remains the standard of care for the first line treatment of advanced disease, with historical objective response rate (ORR) of ̃31%. Eryaspase, L-asparaginase (ASPNase) encapsulated in red blood cells (RBCs), is an investigational product under development. Following infusion, asparagine is actively transported in RBCs where it is hydrolyzed by encapsulated ASPNase. The reduction in plasma concentration of this essential amino acid leads to cancer cell death. A second line pivotal randomized phase III trial (Trybeca-1), which compares chemotherapy (Gemcitabine + Nab-Paclitaxel or 5-Fluorouracil + Irinotecan) with or without Eryaspase, has completed enrollment with results pending (NCT03665441). Methods: Patients with locally advanced or metastatic biopsy-proven pancreatic adenocarcinoma were treated with the combination of mFOLFIRINOX plus Eryaspase. The design was a standard 3 +3 dose escalation. mFOLFIRINOX was given as 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus Eryaspase 75 units/kg at dose level 0 or 100 units/kg at dose level 1. Key eligibility criteria include performance status of 0 or 1, locally advanced or metastatic disease, and adequate organ function. The primary objectives were to determine the maximum tolerated dose (MTD) and to determine the safety of this combination. Results: To date, nine patients have been enrolled with a mean age of 70. Four patients had locally advanced disease and five had metastatic disease. Three patients were enrolled at dose level 0 and six at dose level 1, with no dose limiting toxicities (DLT). Eight patients have had imaging to evaluate response: the ORR was 50% with four partial responses (PRs); 50% (N = 4) had stable disease (SD); disease control rate (PR + SD) was 100%. There were no grade 4 adverse events (AEs). The most common grade 3 AEs were hypokalemia (33%), fatigue (11%), and hypotension (11%); but they were beyond the DLT period of 28 days. The most common grade 1/2 AEs were neuropathy (78%), elevated liver enzymes (78%), nausea (78%), anemia (66%), fatigue (66%), diarrhea (66%), and mucositis (44%). Conclusions: The novel combination of mFOLFIRINOX plus Eryaspase was well tolerated with no DLT and has encouraging signs of clinical activity. The MTD has been declared with 5-FU 2400 mg/2, Oxaliplatin 85 mg/2, Irinotecan 150 mg/m2, and Eryaspase 100 units/kg. We plan to expand enrollment to further look at efficacy and are in the process of designing a larger randomized study in the first line setting pending results from the Trybeca-1 trial. Clinical trial information: NCT04292743.

3037 Background: Prognosis for advanced pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancer (BTC) remains poor, with limited treatment options available. Expression of claudin18.2 (CLDN18.2) has emerged as a potential target for anti-cancer treatment. Herein, we report preliminary safety and efficacy results of IBI343, an antibody-drug conjugate (ADC) consisting of anti-CLDN18.2 monoclonal antibody conjugated to exatecan (topoisomerase I inhibitor), in patients (pts) with advanced PDAC or BTC in a phase 1 study. Methods: Eligible pts who failed or were intolerant to standard treatment were enrolled. IBI343 were intravenously administered at 6 mg/kg or 8 mg/kg Q3W. In dose escalation, pts were enrolled regardless of CLDN18.2 expression. In dose expansion, pts were required to have CLDN18.2 expression ≥40% (1+/2+/3+ staining intensity by immunohistochemistry). Primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression free survival (PFS) assessed by investigator per RECIST v1.1. Results: As of December 19, 2023, 35 pts (1 pt in dose escalation and 34 pts in dose expansion) were enrolled from China and Australia (males: 57.1%, median age: 58.0 years, ECOG PS 1: 71.4%, stage IV: 91.4%, median lines of prior treatment: 2) including 28 PDAC pts and 7 BTC pts. Pts received IBI343 at 6 mg/kg (n=17) or 8 mg/kg (n=18). Median duration of treatment was 7.0 weeks (range: 3.0-23.6) with 23 (65.7%) pts still on treatment. In all pts, treatment-related adverse events (TRAEs) occurred in 28 (80.0%) pts including grade ≥3 TRAEs in 9 (25.7%) pts. Common TRAEs (≥20%) were anemia (42.9%), neutrophil count decreased (28.6%), nausea (25.7%), vomiting (25.7%) and white blood cell count decreased (22.9%). Serious TRAEs occurred in 4 (11.4%) pts. TRAEs leading to dose interruption and treatment discontinuation occurred in 7 (20.0%) pts and 1 (2.9%) pt respectively. No TRAE led to death. Safety profiles of IBI343 in PDAC and BTC were comparable with the whole study cohort and no new safety signal was observed. As of January 15, 2024, 25 pts at 6 mg/kg and 8 mg/kg were efficacy evaluable. Partial response (PR) was observed in 7 pts (5 PDAC and 2 BTC). The ORR was 28.0% (95%CI: 12.1-49.4) and DCR was 80.0% (95%CI: 59.3-93.2). In evaluable pts at 6 mg/kg with CLDN18.2 expression ≥60% (1+/2+/3+, n=13), 5 pts had PR with ORR of 38.5% (95%CI: 13.9-68.4) and DCR of 84.6% (95%CI: 54.6-98.1). Among 10 PDAC pts in this subgroup, ORR was 40% (95%CI: 12.2-73.8). DoR and PFS data were immature. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI343 was well tolerated with favorable safety profiles and encouraging efficacy in CLDN18.2-positive PDAC and BTC. Clinical trial information: NCT05458219 .

Circulating microRNAs as dynamic biomarkers of response to treatment with FOLFIRINOX combination therapy in advanced pancreatic ductal adenocarcinoma

Survival impact on triple-modal strategy comprising hyperthermia, external radiation, and chemotherapy for unresectable locally advanced (UR-LA) pancreatic ductal adenocarcinoma

2509 Background: As a promising approach for some cancers, chimeric antigen receptor T cell therapy has limited success in solid tumors. Claudin18.2 (CLDN 18.2) is a stomach-specific isoform of Claudin-18, and highly expressed in gastric and pancreatic adenocarcinoma, the advanced form of both of which have urgent unmet medical needs. We previously developed and demonstrated ability of CLDN 18.2-specific CAR (CAR-CLDN18.2) T cells to eradicate CLDN 18.2-positive gastric cancer xenografts without obvious on-target off-tumor toxicity (Huang J. JNCI 2018). Methods: In this single-arm, open-label, first-in-human phase I pilot study (NCT03159819) to investigate the safety and explore the efficacy of the autologous CAR-CLDN18.2 T cells, patients with confirmed CLDN 18.2 positive advanced gastric or pancreatic adenocarcinoma aged 18 to 70 years received 1 or more cycles of CAR-CLDN18.2 T cell infusion(s) after lymphodepletion pretreatment (fludarabine and cyclophosphamide, with or without nab-paclitaxel) until disease progression or presence of intolerable toxicity. Adverse Event (AE) grade categorization is according to CTCAE 4.0, and tumor response was assessed per RECIST 1.1. Results: As of November 30th, 2018, 12 subjects with metastatic adenocarcinoma (7 gastric and 5 pancreatic) were treated with 1–5 cycles (total of 0.5 - 55 X 108) of CAR-positive T cells infusions. There were no serious adverse events, treatment-related death or severe neurotoxicity occurred in the study. No grade 4 AEs except for decreased lymphocytes, neutrophils and white blood cells. All cytokine release syndromes observed were grade 1 or 2. Among the 11 evaluable subjects, 1 achieved a complete response (gastric adenocarcinoma), 3 had partial responses (2 gastric adenocarcinomas and 1 pancreatic adenocarcinoma), 5 had stable disease and 2 had progression of disease. The total objective response rate was 33.3%, with median PFS of 130 days estimated using Kaplan-Meier method [95% CI (38, 230)]. Conclusions: This clinical study indicated that CAR-CLDN18.2 T cell therapy were safe and well tolerated and may have promising therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma. Clinical trial information: NCT03159819.

<div>Abstract<p><b>Purpose:</b> Despite recent therapeutic advances, prognosis of patients with pancreatic adenocarcinoma remains poor. Analyses from tumor tissues present limitations; identification of informative marker from blood might be a promising alternative. The aim of this study was to assess the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma.</p><p><b>Experimental Design:</b> From 2011 to 2015, blood samples were prospectively collected from all consecutive patients with pancreatic adenocarcinoma treated in our center. Identification of ctDNA was done with next-generation sequencing targeted on referenced mutations in pancreatic adenocarcinoma and with picoliter droplet digital PCR.</p><p><b>Results:</b> A total of 135 patients with resectable (<i>n</i> = 31; 23%), locally advanced (<i>n</i> = 36; 27%), or metastatic (<i>n</i> = 68; 50%) pancreatic adenocarcinoma were included. In patients with advanced pancreatic adenocarcinoma (<i>n</i> = 104), 48% (<i>n</i> = 50) had ctDNA detectable with a median mutation allelic frequency (MAF) of 6.1%. The presence of ctDNA was strongly correlated with poor overall survival (OS; 6.5 vs. 19.0 months; <i>P</i> < 0.001) in univariate and multivariate analyses (HR = 1.96; <i>P</i> = 0.007). To evaluate the impact of ctDNA level, patients were grouped according to MAF tertiles: OS were 18.9, 7.8, and 4.9 months (<i>P</i> < 0.001). Among patients who had curative intent resection (<i>n</i> = 31), 6 had ctDNA detectable after surgery, with an MAF of 4.4%. The presence of ctDNA was associated with a shorter disease-free survival (4.6 vs.17.6 months; <i>P</i> = 0.03) and shorter OS (19.3 vs. 32.2 months; <i>P</i> = 0.027).</p><p><b>Conclusions:</b> ctDNA is an independent prognostic marker in advanced pancreatic adenocarcinoma. Furthermore, it arises as an indicator of shorter disease-free survival in resected patients when detected after surgery. <i>Clin Cancer Res; 23(1); 116–23. ©2016 AACR</i>.</p></div>