Pancreatic Cancer Pts Research Articles

A single-arm, multicenter, phase II study of utidelone in advanced solid tumors: Efficacy data from screening and the expansion cohort assessing utidelone plus sintilimab and oxaliplatin for advanced gastric cancer.

e16055 Background: Treatment regimens for many advanced solid tumors are limited and alternative options are needed.Utidelone is approved for the treatment of advanced breast cancer in China. NCT04911907 is a single-arm, multicenter, phase II study to assess the efficacy and safety of utidelone in advanced cancer. Stage I of the trial, completed in October 2023, included patients (pts) with pretreated advanced solid tumors. Based on the stage I data, a stage II expansion cohort (USO-G) investigated utidelone plus sintilimab and oxaliplatin as first-line therapy for advanced gastric cancer (GC). Here, we report efficacy and safety data from stage I and stage II for interim analysis. Methods: Eligible pts aged 18–70 years with pretreated advanced solid tumors were enrolled in stage I and received utidelone monotherapy (35 mg/m2/day iv on days 1–5 every 21 days). In stage II, eligible pts with metastatic and/or unresectable HER2 negative GC received utidelone (30mg/m2/day iv on days 1–5 every 21 days) plus sintilimab (200 mg iv Q3W) and oxaliplatin (130 mg/m2/day Q3W for up to 6 cycles), until disease progression or unacceptable toxicity. Results: From March 18th 2021 to October 13th 2022, 79 pts were enrolled into 7 tumor cohorts and 54 pts were evaluable for efficacy. The best overall responses were 1 CR, 3 PRs and 3 SDs in 10 esophageal cancer pts, 3 PRs and 5 SDs in 15 GC pts, 1 PR and 3 SDs in 10 ovarian cancer pts, SD for all 4 cholangiocarcinoma pts, 3 SDs in 4 cervical cancer pts, 2 SDs in 3 pancreatic cancer pts and a PR in 1 neuroectodermal tumor patient. Grade 3/4 TRAEs occurred in 27.8% of pts in stage I, and included anemia (13.9%), peripheral neuropathy (11.4%) and neutropenia (7.6%). No treatment-related deaths occurred. Gastric cancer was chosen as the expansion cohort indication. As of February 1st 2024, 14 eligible pts with GC with a median age of 57 years (range, 41–69) were enrolled. The median follow-up was 5.5 months (range, 1.0–9.7) and the longest duration of response was 8.0 months. A total of 8 PRs and 3 SDs were achieved in the 11 pts evaluable for efficacy, and 6 pts including the 3 with SD were still receiving treatment. Grade 3/4 TRAEs occurred in 28.6% of pts including diarrhea (14.3%), fatigue (14.3%), neutropenia (14.3%), and vomiting (7.1%). Other AEs were all Grade 1 or 2, with no treatment-related deaths. Conclusions: Utidelone monotherapy showed antitumor activity and manageable toxicity in pts with advanced solid tumors. Utidelone plus sintilimab and oxaliplatin demonstrated promising efficacy and an acceptable safety profile as first-line treatment for pts with GC. Stage II of the USO-G study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT04911907 .

DIsCOvER: A multicenter, randomized, double-blind, placebo-controlled, phase III clinical trial to investigate the efficacy and safety of dronabinol in the improvement of chemotherapy-induced and tumor-related symptoms in patients with locally advanced or metastatic pancreas cancer during first-line chemotherapy.

TPS711 Background: Patients (pts) with pancreatic cancer suffer from multiple symptoms related to the tumor itself or induced by chemotherapy (ctx). The available supportive therapy is still not able to relief all symptoms caused by the cancer itself or by the antineoplastic therapy. Additionally, anorexia and weight loss often result in increased morbidity and mortality in this population as well as in psycho-social burden and suffering. These are unmet needs in pancreatic cancer pts. Dronabinol has shown beneficial effects observed in cancer pts. However, evidence from randomized, placebo controlled trials in the use of cannabinoids for the treatment of cancer related anorexia-cachexia syndrome are lacking. Aim of this phase III trial is to investigate the efficacy and safety of dronabinol (orally administered tetrahydrocannabinol (THC)) as adjuvant, individually titrated therapy to first-line standard chemotherapy in pts with metastatic pancreas cancer for improvement of ctx- and tumor-related symptoms. Methods: Locally advanced or metastatic pancreas cancer pts from Austria and Germany with age of ≥18 yrs tolerating FOLFIRINOX or gemcitabine/nab-paclitaxel based ctx are eligible for enrolment. Exclusion criteria are use of dronabinol, cannabis-based medicine with THC or marihuana or relevant psychiatric disorders. The study duration for each patient will be a maximum of 18 wks treatment. Eligible pts are randomized 1:1 for treatment with dronabinol oral solution (2.5%) or placebo oral solution stratified by underlying ctx. The primary endpoint variable is the standardized area under the curve of the EORTC QLQ-C30 symptom summary score over the on-treatment period. Secondary endpoints include: other quality of life parameters, changes in Glasgow Prognostic Score, mean time to critical weight-loss (5%), ctx dose intensity over the treatment of 18 wks, adverse events/reactions, PFS and OS. Changes from baseline for bioelectrical impedance analysis parameters (e.g. fat-free mass, total body water, fat mass and phase angle) and handgrip strength will be evaluated. Estimating a difference of 20% in the primary endpoint between the treatment groups with a power of 80% and an expected standard deviation of 30 a total sample size of 74 assuming a balanced design is required. A total sample size of 104 pts is needed with expected drop-out rate of 30 pts. Enrolment started in 2019 and continues until 2024. The DIsCOvER trial is the first randomized, placebo-controlled phase III trial that investigates the impact of individually dosed dronabinol in cancer pts (Registration: NCT03984214). Clinical trial information: NCT03984214 .

Increasing cancer genetic referrals via best practice alerts (BPA).

565 Background: Germline genetic testing (GT) is recommended for all patients (pts) with pancreatic cancer (PC). However, genetic referral (GR) rates for PC are low even at academic centers; there is a paucity of literature at safety-net hospitals (SNH) which often treat higher percentages of cancers at advanced stages. Providers focused on the challenging treatment of PC and may not prioritize GT referrals. Technology can be adapted to aid in this process. Best practice alerts (BPA) built in Electronic Medical Records (EMR) can prompt providers to place GR order. We initiated BPA at John Peter Smith (JPS) hospital, a SNH in Texas, and evaluated if the BPA improved referral patterns. Methods: A retrospective review was conducted using JPS tumor registry data. We studied pts diagnosed with pancreatic adenocarcinoma (AC) or neuroendocrine tumors (NET) from 1/1/2018 to 4/30/2023 at JPS. BPA go-live date was 10/19/2022. Data Analytics team queried EMR regarding GR, if pts completed their genetics encounter (GE), and GT. Statistical analysis using a two-tailed T test was performed. Results: 162 PC pts were identified: 155 (96%) AC and 7 (4%) NET, and the median age was 59 years. A majority of patients were diagnosed in house (114/162, 70%), while the rest were referred to JPS after diagnosis elsewhere. A total of 57 pts were excluded due to being placed on hospice, death within 3 months of diagnosis, or refusing oncology services at JPS. 105 pts were included for analyses: 96 were diagnosed with PC before the BPA go-live date (pre-BPA) and 9 after the BPA go-live date (post-BPA). 36 (38%) pts were referred pre-BPA. 23 pre-BPA pts completed GE, median of 15 days from referral. 7 out of 9 (78%) pts received GR post-BPA. Post-BPA pts were all referred due to BPA triggers being fired. 2 post-BPA pts completed GE with a median time of 27.5 days from GR. Since launching the BPA, a statistically significant increase in GR has been observed (p=0.0187). 2 pre-BPA pts who completed GT were found to have a pathogenic variant. Conclusions: BPA has shown a significant improvement in GR for PC. Our study population is limited by rarity of PC, and the BPA alert is set to only fire for pts receiving oncology care at JPS. We noted a large number of pre-BPA pts that have yet to be referred and remain at risk. Updates to the BPA build are needed to capture previously diagnosed pts who are receiving JPS oncology services. For future studies, we will analyze pts with other cancer diagnoses to continue to improve upon the GR process.[Table: see text]

Real-world impact of olaparib use in patients (pts) with advanced pancreatic cancer (PC) harboring germline BRCA1/2 (gBRCA) mutations.

e16278 Background: g BRCA mutations are found in approximately 8% of Italian PC pts screened within 3 months from diagnosis. g BRCA PC pts display enhanced sensitivity to platinum-based chemotherapy (CHT) and PARP inhibitors, such as olaparib. In metastatic g BRCA PC pts, maintenance olaparib after platinum-based CHT doubled PFS and resulted in twice as many long-term (3-yr) survivors (34% versus 18%) in the randomized POLO trial. However, despite guideline recommendations, olaparib is currently not reimbursed in Italy in metastatic g BRCA PC pts, based on the absence of significant differences in median OS. Methods: We analyzed the impact of exposure to olaparib on OS from the start of I-line treatment in a cohort of 114 Italian g BRCA PC pts, whose clinical characteristics and outcomes in response to first () and subsequent chemotherapy lines have been previously reported ( 10.1016/j.esmoop.2021.100238 ; 10.1038/s41416-022-02086-w ). Results: Clinical characteristics of patients who did or did not receive olaparib were well balanced, except for baseline CA19.9 levels (significantly lower in patients who received olaparib, p=0.043) and exposure to platinum-containing chemotherapy (significantly less in patients who did not receive olaparib, p<0.0001). In the entire cohort of g BRCA PC pts, OS from the start of I-line treatment for metastatic disease was significantly (p=0.02) longer in pts who had been exposed to olaparib in any treatment line (n=53). Since previous surgery and response to I-line chemotherapy were strong independent predictors of OS at multivariate analysis, we analyzed pts who were diagnosed with stage IV (M+, n=87) disease and pts who did not experience PD as best response to I-line chemotherapy (no PD, n=94), separately. A statistically significant difference in OS favoring g BRCA PC pts who were exposed to olaparib in any line of treatment was observed in the M+ cohort (p=0.0025), in the no PD cohort (p=0.049), but not in the M+/no PD cohort (n=73, p=0.057) or in the POLO-like population (I-line maintenance; n=60, p=0.334). Conclusions: In g BRCA PC pts, exposure to olaparib in any line of treatment in a real-world setting significantly impacts on OS; timing and setting of administration remain to be determined in order to optimize survival advantage. [Table: see text]

Abstract 5603: Functional studies on viable circulating tumor cells (v-CTCs) and frequent expression of PD-L1 on v-CTCs in pancreatic cancer

Abstract Introduction: The analysis of CTCs as liquid biopsies provides the possibility to avoid invasive tissue biopsies, with obvious implications in cancer diagnostics and treatments. We tested new methods for v-CTCs detection in patients (pts) with pancreatic cancer (PC), and investigated the clinical potential of v-CTCs in prognosis. We analyzed the PD-L1(L1) expression in primary PC tumors, metastatic lymph nodes (LN) and v-CTCs. Pts and Methods: 7.5 ml of venous blood was collected from 39 PC pts, either upfront surgery (U group) or pre-treatment, consisted of Gem:800mg/m2; and S-1:80mg/m2 given concurrently with IMRT to 60Gy ((NACRT:N group). To detect v-CTCs, we employed a telomerase-specific replication-selective adenovirus expressing GFP. For U group, samples were obtained before/after resection. For N group, samples were obtained before/after NACRT and after resection. To distinguish between leucocyte and cells with either epithelial or mesenchymal origin, cells were stained by anti-CD45, anti-Cytokeratin and anti-Vimentin Abs. GFP-positive and CD45-negative cells were counted as v-CTCs. To assess L1 expression in PC tissues (PC tumors and LN) and on v-CTCs, L1 IHC kit (22C3, for tissues) and anti-human L1 mAb(MIH1, for CTCs) were employed. Results: U group: 24 pts aged 53~85 years (male/female=12/12) were enrolled. 24 pts underwent curative resection. No v-CTCs were detected in 6 pts at both before and after resection, and 5 of 6 pts survived without recurrence. V-CTCs were identified in 18 of 24 pts, and 13 of 18 pts developed liver metastasis. Marked decrease of CTC counts were seen after resection in 10 of 18 pts, but 9 pts developed recurrences. N group: 15 PC pts aged 44~77 years (male/female=4/11) were enrolled. 15 pts underwent curative resection. No v-CTCs at 3 sampling points were detected in 5 pts, and 5 pts survived without recurrences. V-CTCs was identified in 10 of 15 pts, and 4 out of 10 pts developed disease recurrence. Marked increase in CTC counts was observed after NACRT in 5 of 6 CTC-positive pts before NACRT, and 3 of 5 pts developed liver metastasis and died. NACRT may induce tumor cell dissemination into the blood circulation for CTC-positive pts. PD-L1 expression: L1 expression were assessed for 21 pts (U group:18, N group: 3). For PC tumors, L1 molecules were expressed in 12 pts and expression level of these pts were all low (57%, ≥50% [high]=0 pts, 1-49% [low]=12 pts {10%=6, 20%=4, 40%=2}, <1% [negative]=9 pts). For metastatic LNs, metastatic LNs were observed in 14 pts and L1-positive expression in these LNs were detected in only 4 pts (28%, all low expression). On the contrary, the majority of detected v-CTCs clearly expressed L1 molecule (92 CTCs out of 103 detected CTCs were L1-positive=89 %). Conclusions: Viable CTC detection appears as a good prognostic marker. Immunotherapy with anti-PD-1/PD-L1 Abs may target v-CTCs, resulted in improvement of poor prognosis. Citation Format: Masahiro Tanemura, Masaki Kashiwazaki, Kenichi Matsumoto, Kenta Furukawa, Manabu Mikamori, Tadafumi Asaoka, Daisaku Yamada, Shogo Kobayashi, Hidetoshi Eguchi. Functional studies on viable circulating tumor cells (v-CTCs) and frequent expression of PD-L1 on v-CTCs in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5603.

Interim analysis results of gut microbiota in patients with unresectable cholangiopancreatic cancer: SCRUM-Japan MONSTAR-SCREEN.

733 Background: MONSTAR-SCREEN prospectively assessed the gut microbiota of 2000 patients (pts) with advanced solid cancer at 31 Japanese institutions. Here, we report the interim analysis results of the correlation between gut microbiota and the efficacy of first-line chemotherapy in pts with unresectable pancreatic cancer (PC) and bile tract cancer (BTC). Methods: We analyzed unresectable 205 PC and 83 BTC pts with clinical data as data cut-off on April 30, 2021, and 16S ribosome analysis results of stool samples. Among PC pts, 133 and 40 were treated with GnP (gemcitabine (GEM) plus nab-paclitaxel) and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), respectively. Among BTC pts, 32 and 33 were treated with GC (GEM plus cisplatin) and GCS (GEM, cisplatin, plus S-1), respectively. Pts with an above-median overall survival (OS) were defined as long-term survivors (LTS), and those with below-median OS and OS events were defined as short-term survivors (STS). We compared the alpha diversity index (ADI) of LTS and STS, and identified potential microbial biomarkers of LTS, STS, responders, and non-responders to first-line chemotherapy according to RECIST version 1.1, by linear discriminant analysis effect size (LEfSe). In each cohort, the top three microbiota with linear discriminant analysis scores of ≥ 3.0 were considered significant. Results: The median OS of PC and BTC pts was 13.5 and 15.9 months, respectively. In PC pts, no significant difference was noted in the ADI between LTS (n=20) and STS (n=40). In BTC pts, the ADI of LTS (n=10) was significantly higher than that of STS (n=20) in the Shannon index. LEfSe analysis in PC pts revealed that Burkholderiales and Sutterellaceae were predominant in LTS, while Lactobacillaceae was, in STS. In PC pts, Brachyspiraceae and Erysipelotrichales were predominant in responders (n=67), while Enterococcaceae and Lactobacillaceae were, in non-responders (n=137). In BTC pts, Peptostreptococcaceae, Fusobacteriaceae, and Clostridiaceae in LTS; Cardiobacteriaceae, Prevotellaceae, and Actinobacteriota in responders (n=24); and Bacilli in non-responders (n=59) were overrepresented. Conclusions: This interim analysis identified potential biomarkers of the gut microbiota that may contribute to the prognosis and efficacy of chemotherapy in pts with unresectable PC and BTC. The results of this analysis will be validated in the primary analysis.

Outcomes of FOLFIRINOX and gemcitabine plus nab-paclitaxel in patients with early recurrent pancreatic cancer after adjuvant S-1: A propensity score–matching analysis.

707 Background: An oral fluoropyrimidine, S-1, is a standard adjuvant (adj) chemotherapy practice in Japan for patients (pts) with resected pancreatic cancer (PC). Patients experiencing recurrence after adj S-1 administration are treated with FOLFIRINOX (FFX), including intravenous fluoropyrimidine, or gemcitabine plus nab-paclitaxel (GN), which is commonly used as the first-line chemotherapy approach in pts with advanced PC. Some pts have good response to FFX with acceptable toxicity levels even though recurrence within 6 months (mo) after the last S-1 administration is attributed to PC refractory to fluoropyrimidine. To the best of our knowledge, there is no clinical study comparing FFX and GN in this particular population. Methods: This multi-center, retrospective study included pts with PC that had a recurrence-free interval (RFI) < 6 mo from the last adj S-1 administration and were treated with FFX or GN between December 2013 and 2018. The decision to administer FFX or GN was taken by the attending physicians. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response, and serious adverse events (SAE). The OS and PFS were calculated from the time of initiation of treatment with FFX or GN. To adjust confounding factors in the comparison of FFX with GN, propensity score-matching (PSM) analysis was performed. Potentially confounding factors were identified by univariate analysis for OS, and statistical significance was set at p < 0.1. Results: A total of 284 (FFX; 50, GN; 234) pts were enrolled from 32 institutions in Japan. Potential confounding factors comprised curability, pathological T/N, tumor differentiation status, reasons for the end of S-1 administration, chemotherapy regimen, performance status, serum albumin/C-reactive protein/carbohydrate antigen 19-9 levels, and presence or absence of liver metastasis before initiating the administration of FFX or GN. After PSM, 43 pts each in the FFX and GN groups were compared in pairs. The patient characteristics, excluding age, in the matched pair were well-balanced; the proportion of pts aged < 65 years in the FFX and GN groups was 61% and 30%, respectively. The median OS and PFS were longer in the GN group than in the FFX group; OS was 14.5 vs. 11.1 mo (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.38-0.97); PFS was 7.1 vs. 5.1 mo (HR, 0.65; 95% CI, 0.41-1.02). The objective response, disease control rates, and observed SAE in the GN and FFX groups were 20/19%, 80/66%, and 14/19% respectively. Seventy-two percent of the pts in the GN group received subsequent therapies of FFX/S-1/FOLFIRI/FOLFOX (28/12/9/5%); while 77% of the FFX group pts received subsequent therapies of GN/GEM (54/7%). Conclusions: Real world data suggests that GN may be recommended in PC pts with RFI < 6 mo from the last administration of adj S-1.

Success rates and clinicopathologic associations with experimental outcomes of a novel circulating tumor cell (CTC) technology in advanced colon cancer (CC) and pancreatic cancer (PC).

805 Background: Studying CTC cultures (cx) ex-vivo can provide valuable insights into cancer metastases (mets). However, current immunoaffinity- and size-based-methods used to isolate and expand these cells have low success rates for culturing CTCs (6-20%). Here, we report our experience using a novel technology developed at Georgetown for culturing CTCs from patients (pts) with metastatic (m) CC, mPC, and locally advanced PC (LAPC). Methods: 44 peripheral blood samples were prospectively collected from 35 pts with adenocarcinoma across 3 cohorts (18 samples from 15 mCC pts, 21 samples from 15 mPC pts, and 5 samples from 5 LAPC pts). Pts were previously treated, treatment-naïve, or actively undergoing treatment. FiColl-Paque-based separation of red blood cells was performed, plasma and buffy coat cells were resuspended in cx medium, and successfully grown CTC cxs were processed and injected subcutaneously (subQ) in the flanks of mice. A single predetermined sample from each pt was used in assessing the clinicopathologic associations with experiment outcomes and survival analyses. Results: CTC cxs were successfully grown from 81.8% (36/44) of all samples. Cxs grew from 72.2% (13/18) of mCC, 85.7% (18/21) of mPC, and 100% (5/5) of LAPC samples. At the time of analysis, 25 injected mice were evaluable for subQ tumor growth. 4 mice failed to grow tumor, 10 were still under monitoring, and 11 grew tumor, 9 of which also developed mets. These were mostly macro-mets and partially mirrored the met pattern seen in the matched pt. Across all cohorts, samples were predominantly collected from pts during systemic treatment (79.5%), during 2nd- (36.4%) and 1st-line treatment (20.5%), at a median of 15 (0-111) and 5 (1-20) months after diagnosis in mPC/mCC and LAPC pts, respectively, after scans with new/progressing disease (72.7%), and with a median of 3 (1-9) sites of disease on scans done within 2 months of collection . In all pts, no clinicopathologic or genomic factor predicted for cx growth. In the mCC subgroup, female sex (p=0.044), longer time from diagnosis to CTC collection (p=0.033), and presence of lung mets (p=0.022) were associated with cx growth. With cohorts combined, the median pt progression-free survival was 174 days (95% CI 97-220) and median overall survival was not reached. There was no statistically significant relationship between cx growth and pt survival. Conclusions: This novel platform demonstrated historically high rates of successful CTC cx and xenograft tumor growth using samples from advanced CC and PC pts. Studies to elucidate reasons for mice failing to grow tumor and others with matched tumor-CTC molecular analyses are ongoing to validate this promising technology to ultimately use to identify biomarkers for metastases, uncover novel therapeutic targets, and inform clinical decisions.

1307P Real-world impact of olaparib use in advanced pancreatic cancer (PC) patients (pts) harboring germline BRCA1/2 (gBRCA) mutations

gBRCA mutations are found in approximately 8% of Italian PC pts screened within 3 months from diagnosis. gBRCA PC pts display enhanced sensitivity to platinum-based chemotherapy (CHT) and PARP inhibitors, such as olaparib. In metastatic gBRCA PC pts, maintenance olaparib after platinum-based CHT doubled PFS and resulted in twice as many long-term (3-yr) survivors (34% versus 18%) in the randomized POLO trial. However, despite guideline recommendations, olaparib is currently not reimbursed in Italy in metastatic gBRCA PC pts, based on the absence of significant differences in median OS.

1305P Landscape and clinical significance of germline pathogenic variants (PV) in pancreatic cancer (PC)-predisposing genes in PC patients

International guidelines recommend multigene germline (MGP) testing for PC pts, although no surveillance program for high-risk individuals has been validated. The implementation of this recommendation is limited by the uncertainty around its clinical utility. Preliminary data from Italian PC pts showed a high prevalence of CDKN2A PV, regardless of familial status, and BRCA1/2 PVs only in pts<74 yo. Here, we provide a comprehensive analysis by MGP in unselected Italian PC pts.

Abstract 5775: Landscape of BRAF and RAF1 fusions identified by next-generation sequencing in a Chinese multi-cancer retrospective analysis

Abstract Background: The RAF family includes three members, ARAF, BRAF, and RAF1/CRAF. These kinases function downstream of RAS as part of the MAPK (RAF-MEK-ERK) signaling cascade. The BRAF gene is mutated in ∼7% of cancers, whereas ARAF and RAF1 mutations are rare. Gene fusions in BRAF or RAF1 fusions, which activate the MAPK pathway, can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. Here we focused on the prevalence of BRAF and RAF1 fusions in a multi-cancer cohort for patients (pts) whom might benefit from MEK/RAF inhibitors in clinical development. Methods: Genomic profiling was performed on samples from 29,102 lung cancer pts, 676 melanoma pts, 392 colorectal cancer pts, 1,463 gastric cancer pts, 1,014 sarcoma pts, 1,079 liver cancer pts, 215 gallbladder carcinoma pts, 297 ovarian cancer pts, 46 tongue cancer pts, 62 thymic carcinoma pts, 6 hemangioma pts, and 890 pancreatic cancer pts using next-generation sequencing (NGS), which covers all exons of BRAF and RAF1. The fusion patterns were analyzed. Results: A total of 5 RAF1 and 114 BRAF fusions were identified in approximately 0.34% (120/35,242) of the patients in this Chinese multi-cancer cohort. The positive rates of RAF1 fusions were 0.0034% (1/29,102) in lung cancer pts, 0.44% (3/676) in melanoma pts, and 0.10% (1/1,014) in sarcoma pts. The fusion partners of RAF1 were LYRM4 in lung cancer, LMCD1 and USP20 in melanoma, and FMR1 in sarcoma. RAF1 fusions involving the intact in-frame RAF1 kinase domain were LYRM4-RAF1, LMCD1-RAF1, and USP20-RAF1, which might be targeted with MEK/RAF inhibitors. The BRAF fusion-positive rates were 0.27% (80/29,102) in lung cancer pts, 1.18% (8/676) in melanoma pts, 2.81% (11/392) in colorectal cancer pts, 0.41% (6/1,463) in gastric cancer pts, 0.20% (2/1,014) in sarcoma pts, 0.19% (2/1,079) in liver cancer pts, 0.47% (1/215) in gallbladder carcinoma pts, 0.34% (1/297) in ovarian cancer pts, 2.17% (1/46) in tongue cancer pts, 1.61% (1/62) in thymic carcinoma pts, 16.67% (1/6) in hemangioma pts, and 0.11% (1/890) in pancreatic cancer pts. The most common 5’partners of BRAF were TRIM24 (4 cases) and SND1 (3 cases). Whereas the most common 3’partners of BRAF were BAIAP2L1 (5 cases) and TRIM24 (4 cases). Furthermore, 57 BRAF fusions contained intact BRAF kinase domain and nearly half of BRAF fusion-positive patients might be sensitive to MEK inhibitor. The most frequent location of the breakpoints occurred in intron 8 of the BRAF gene, followed by intron 7. However, the sensitivity of these fusions to MEK/RAF inhibitors in different cancers needs to be further studied. Conclusions: This study revealed the molecular features of BRAF and RAF1 rearrangements in Chinese cancer patients, which could help to identify therapeutic targets and personalize therapy management, leading to improved patient outcomes. Citation Format: Tao Li, Xin Zhang, Yanling Niu, Tonghui Ma. Landscape of BRAF and RAF1 fusions identified by next-generation sequencing in a Chinese multi-cancer retrospective analysis [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 5775.

Metabolomics in advanced pancreatic cancer (PC) patients (pts) achieving weight stability on enteral feeding for cachexia.

e16291 Background: We previously showed that enteral feeding was associated with weight stability and compositional changes in the gut microbiome with increased abundance of the gram-negative genera Veillonella over time. Here, we evaluated the potential of plasma metabolites as predictors of weight stability and high Veillonella abundance in enteral fed pts. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for standard chemotherapy. In preplanned exploratory analyses, serial blood samples were collected over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. Pts were stratified by weight stable (WS, defined as weight change &lt; 0.1 kg/baseline BMI-unit over 12 wks of enteral feeding) vs. weight unstable (WU) and high (HV) vs. low Veillonella (LV) abundance (defined by dichotomizing at the mean relative abundance in WS pts). Results: Of 31 cachectic pts enrolled into PANCAX-1, a total of 55 blood samples were collected from 28 pts for plasma metabolomics. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. Plasma metabolomics in 10 pts showed that WU pts (n = 4) had significantly decreased levels of essential amino acids (AAs, L-histidine, L-phenylalanine) and non-essential AAs (L-citrulline, L-tyrosine, all p &lt; 0.05) than WS pts (n = 6) at the end of 12 wks of enteral feeding. In 7 WS pts with complete serial sets of blood samples available, enteral feeding over 12 wks was associated with increases in markers of muscle mass (creatinine) but decreases in nucleotide precursors (all p &lt; 0.05) compared to baseline. Comparison of baseline metabolites between 6 WS pts with HV and 4 WU pts with LV showed that HV was associated with increases in the nucleotide dCDP and essential AA L-isoleucine but decreased TCA cycle metabolite alpha-ketoglutarate (all p &lt; 0.05). Decreases in lactic acid was observed at 12 wks of enteral feeding in HV pts when compared to baseline (p &lt; 0.05). Conclusions: Our findings are hypothesis-generating in that metabolites unique to weight stability and Veillonella abundance may inform future studies of anti-cachexia therapies involving enteral feeding or microbial modulation.

Analysis of ROS1 fusions in nonlung solid tumors.

e15124 Background: Somatic chromosomal fusions involving ROS1 produce chimeric proteins that drive tumorigenesis and progression. Currently, ROS1-directed tyrosine kinase inhibitors (TKIs) are effective treatments for advanced non-small cell lung cancer (NSCLC) patients (pts) with ROS1 fusions. Except for NSCLC, Glioblastoma and spitzoid neoplasms, ROS1 fusions have been rarely reported in other cancers. Therefore, clarifying the patterns and frequency of ROS1 fusions in multi-cancer may help pts benefit from ROS1 inhibit therapy. Methods: To characterize the ROS1-fusion patterns in Chinese pts, we retrospectively analyzed the next-generation sequencing (NGS) data of 11,740 pts from 2017 to 2021. Results: In this study, a total of 12 ROS1 fusions were identified in this Chinese nonlung solid tumors cohort (12/11,740). Among them, the ROS1-fusion positive rate is 0.037% in colonrectal cancer pts (2/5,467), 0.13% in stomach cancer pts (3/2,268), 0.11% in liver cancer pts (2/1,774), 0.19% in kidney cancer pts (1/540), 0.21% in pancreatic cancer pts (2/966) and 0.28% in sarcoma pts (2/725). Particularly, we observed the coexistence of CD80- ROS1 and Intergenic- ROS1 in the same kidney cancer pt. Among ROS1 fusions described in this cohort, the frequency of known partners was 16.67%, and the frequency of unreported partners was 83.33%. Compared with NSCLC (1%̃2%), the ROS1 fusions are less frequent in the nonlung solid tumors (≤0.3%), and fusion partners are mostly unreported, which means that the efficacy of ROS1 TKIs in these solid tumor pts may be different from that in lung cancer. Therefore, more attention and in-depth research are needed in ROS1 fusion positive nonlung solid tumors, which have a low incidence and few cases, so as to bring clinical benefits to more pts. Conclusions: Through NGS, we identified ROS1 fusion patterns in non-lung solid tumors, most of which fusion partners are unreported, expanding the range of ROS1 fusions documented in tumors and providing potential for ROS1 TKIs in multiple tumors.[Table: see text]

Plasma metabolomics to predict chemotherapy (CTX) response in advanced pancreatic cancer (PC) patients (pts) on enteral feeding for cachexia.

600 Background: We evaluated the potential of plasma metabolites as predictors of response to CTX in a prospective cohort of pts who received enteral feeding for cachexia and advanced PC. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for palliative CTX. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. As part of an exploratory analysis of the PANCAX-1 trial, serial blood samples were collected at 3 predefined timepoints over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. The mean AUC was used in pts with metabolites measured from &gt; 1 timepoint of collection. Pts were stratified by stable disease (SD), partial response (PR), or progressive disease (PD) as best overall response to standard CTX. Results: Of 31 pts with advanced PC prospectively enrolled for enteral feeding, there were 55 blood samples collected from 28 pts available for plasma metabolomics. 20/28 (71%) pts received first-line CTX, the majority of whom (90%) received gemcitabine-based CTX. There were 2 PRs (7%) and 10 with SD (36%) as best response to CTX. Overall, there were statistically significant differences in levels of intermediates involved in multiple metabolic pathways including glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and nucleoside synthesis in pts with PR/SD vs. PD to CTX (all p &lt; 0.05). When stratified by CTX regimen, PD to 5-fluorouracil-based CTX (e.g., FOLFIRINOX) was associated with decreased levels of essential amino acids (AAs, L-leucine, L-methionine, L-tryptophan) and non-essential AAs (L-arginine, L-serine, L-tyrosine, all p &lt; 0.05). For gemcitabine-based CTX (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis (pyruvate), TCA cycle (L-glutamate), nucleoside synthesis (xanthine), and bile acid metabolism (taurocholic acid, all p &lt; 0.05). Conclusions: We are the first to demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced PC pts on enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of response and warrant further study.

Cancer Commons’ virtual tumor board program: A patient-centric advisory panel and real-world data registry.

527 Background: We initiated a nationwide Virtual Tumor Board (VTB) program for pancreatic cancer (PC) patients (pts). The VTB consists of oncology experts and serves as an advisory panel by providing information on treatment (Tx) options based on a comprehensive review of patients’ oncologic history. Personalized Tx options and their rationales are provided and outcomes tracked in a prospective registry (XCELSIOR). Methods: PC pts who participated in XCELSIOR shared access to their full medical records, which were collected, processed, and abstracted. The panel reviewed cases asynchronously through an interactive platform followed by a VTB which was held weekly through videoconferencing. Tx options were summarized into a written report and provided to patients and their physicians. Outcomes and quality of life are tracked longitudinally through an IRB-approved 21CFR11 compliant observational registry (XCELSIOR). Results: From 9/2020 to 8/2021, the VTB reviewed 79 unique cases; 56% were male; median age at diagnosis was 66 (50-87). At the time of VTB, 68 (87%) had metastatic disease and 8 (10%) had locally advanced disease. Median prior therapy lines was 2 (0-9), with 26 (35%), 24 (32%), 6 (8%), and 19 (25%) pts having received 1, 2, 3 and 4+ lines of therapy, respectively. Median time from diagnosis for pts presenting after 1, 2, and 3+ lines of prior Tx was 9.5, 11, and 17.5 months, respectively. First-line Tx was FOLFIRINOX in 40 (53%) pts and gemcitabine/nab-paclitaxel in 22 (29%) pts. At the time of VTB, 32 (37%) of patients had stable disease, 23 (26%) had disease progression, 18 (21%) had recently started a new Tx, 7 (8%) were responding to Tx, 3 (3%) had stable disease on imaging but rising CA 19-9, and 4 (4%) were others. Prior to VTB, 69 (87%) pts had molecular profiling results available. Collectively the VTB provided 375 Tx and diagnostic (NGS, imaging, etc.) options with a median of 4 (1-12) options per patient. As of 9/8/2021, 87 VTB reports were provided. Of 25 instances of ‘no Tx decision’, 10 (40%) are deceased, 10 (40%) are stable, and 5 (10%) had other reasons. Of the 25 people who started a subsequent Tx, 14 (56%) were identified by the VTB. These included 9 (64%) FDA-approved, 3 (21%) off-label, and 2 (14%) on-trial Tx. Tx not identified by the VTB included 3 (33%) FDA-approved, 2 (22%) off-label, 2 (22%) on-trial, and 2 (22%) local Tx. Conclusions: We present our experience of utilizing a platform for patients to receive a virtual tumor board review and utilize an IRB-approved registry as a learning system. Early data indicate successes in identifying treatment and clinical trial opportunities. Future steps include streamlining communication with primary oncologists and enhancing access to treatments. NCT03793088.

Early-onset pancreatic cancer: Defining contemporary presentation, treatment, and outcomes in the under 50 age group using real-world data.

533 Background: The incidence of pancreatic cancer is increasing in younger patients (pts). Early onset pancreatic cancer (EOPC) is reportedly diagnosed at a later stage, potentially compromising outcomes compared to later onset pts (LOPC). With recent gains in staging and neo/adjuvant regimens, we sought to elaborate on the characteristics of EOPC and LOPC in a contemporary real-world cohort. Methods: The PURPLE registry, a prospectively collected multi-site data set on consecutive pancreatic cancer pts was interrogated. Patient, tumor, treatment and outcome data were extracted for EOPC vs LOPC. EOPC were those diagnosed prior to age 50 and LOPC after age 50. Resectability status was per MDT consensus. Results: Of 1534 pts, 93 (6%) were EOPC (51% male) and 1442 (94%) LOPC (51% male). EOPC had better ECOG performance status (0-1: 95% vs 81%, Relative Risk [RR] 1.2, p &lt; 0.001) and Charlson Comorbidity Index Score (0-2: 98% vs 28%, RR 3.5, p &lt; 0.001). Primary tumor site (head/body/tail: 66%/11%/20% for EOPC and 68%/17%/14% for LOPC), and staging (resectable/borderline resectable/locally advanced/metastatic: 29%/16%/14%/41% for EOPC vs 28%/9%/21%/41% for LOPC) did not differ. 25 (93%) of EOPC and 320 (79%) LOPC resectable pts underwent resection (p = 0.13). 12 (80%) EOPC and 36 (26%) LOPC borderline resectable pts underwent resection (RR 3.0, p &lt; 0.001). Resection margin status (R0 vs R1 vs R2) did not differ. Resected EOPC more frequently received neoadjuvant therapy (30% vs 9%, RR 3.2, p = 0.001). EOPC were more likely to receive palliative chemotherapy in the advanced/metastatic setting (77% vs 49%, RR 1.6, p &lt; 0.001), and were more likely to receive first line (1L) FOLFIRINOX than gemcitabine-nab-paclitaxel (36% vs 18%, RR 2, p = 0.019). Median overall survival (OS) was superior for EOPC (24 vs 12 months, Hazard Ratio [HR] 0.55, p &lt; 0.001). For resectable pts, relapse free survival (RFS) did not differ but OS was superior for EOPC (undefined vs 27.7 months, HR 0.26, p = 0.004). In borderline resectable pts, RFS was similar and OS only numerically superior for EOPC (31.2 vs 17.7 months, p = 0.20). For locally advanced disease, 1L progression free survival (PFS1) was similar and OS was superior for EOPC (27.8 vs 11 months, HR 0.40, p = 0.008). There was no difference in PFS1/OS for metastatic pts. Conclusions: EOPC are fitter, with similar stage at diagnosis as LOPC. EOPC are more likely to receive neoadjuvant chemotherapy and undergo resection when presenting with borderline resectable disease. EOPC receive more treatment and have superior OS, with RFS/PFS1 not statistically different to LOPC.

Phase II study of SHR-1701 combined with famitinib in the treatment of advanced pancreatic cancer or biliary tract cancer.

568 Background: Pancreatic cancer (PC) and biliary tract cancer (BTC) are highly malignant cancers with limited treatment (tx) options. SHR-1701 is a novel bifunctional anti-PD-L1/TGF-βRII agent. Famitinib is a multitargeted tyrosine kinase inhibitor (TKI). Many studies have proved the mutually enhanced effect of anti-angiogenesis and ICI therapy in multiple tumours. Herein, we reported the safety and efficacy of SHR-1701 in combination with famitinib in advanced PC and BTC patients (pts) who have failed previous standard tx. Methods: This is an ongoing single-site, exploratory phase II study. PC or BTC pts who have failed ≥1 prior therapy would be enrolled into PC or BTC cohort, and received SHR-1701 plus famitinib until disease progression or unacceptable toxicity. SHR1701 would be intravenously given at a fixed dose of 30mg/kg q3w. Famitinib was initially given at a dose of 20mg/d. Dose reduction of famitinib to 15mg was allowed if it was intolerable. The primary endpoint was objective response rate (ORR) as per RECIST v1.1. Simon’s two-stage minimax design was used in this trial. For each cohort, if ≥2 responses are observed among 15 patients in stage I, the study will proceed to full accrual. Results: Up to 15 Sep 2021, 15 pts and 9 pts were enrolled in PC and BTC cohorts respectively. The baseline data are shown in the table. Of 15 evaluable pts in PC cohort, one had complete response, one had partial response (PR), 6 pts had stable disease (SD). The ORR and DCR were 13% and 53%, respectively. The first stage of PC cohort had a sufficient response rate to meet full enrollment. Among 8 evaluable pts in BTC cohort, one had PR (tumor shrinkage &gt; 80%), 4 had SD. The ORR and DCR were 13% and 63%, respectively. 22 pts (92%) experienced treatment-related adverse events (TRAEs). The most frequently reported TRAEs (any grade) were proteinuria (58%), hypertension (42%), and blood urine present (42%). The incidence of Grade 3 TRAEs was 33%, among which the most common ones were hypertension (8%), and bilirubin conjugated increased (8%). No grade 4/5 TRAEs were reported. Conclusions: SHR-1701 plus famitinib showed encouraging activity with manageable safety in pts with advanced PC or BTC. Enrollment is ongoing and updated data will be presented. Clinical trial information: ChiCTR2000037927.[Table: see text]

Abstract 867: Incidence of molecular alterations in KRAS and other known cancer genes in patients with pancreatic cancer assessed with a commercial genomic profiling panel compared to TCGA results

Abstract Background: The Cancer Genome Atlas (TCGA) characterizes somatic mutations of pancreatic cancer (PC) patients (pts) using whole-exome sequencing (WES, mean coverage 405x) of fresh frozen tumor tissues and matched blood samples. In addition, it includes a confirmation of the key genomic findings by a targeted sequencing panel (~644x) and microfluidic PCR-based sequencing (~30,000x). For the vast majority of patients who do not undergo resection, however genomic characterization of formalin-fixed, paraffin-embedded (FFPE) biopsy samples is the only available assessment. In order to assess this NGS testing process at Baylor College of Medicine, we sought to confirm that routinely collected diagnostic FFPE specimens could be used for sequencing without compromising the detection rates of key gene alterations in PC pts. Methods: Matched tumor and normal specimens (peripheral blood or saliva) from 59 Baylor College of Medicine PC pts were sequenced using Tempus|xT (Tempus Labs, Chicago, IL), a 648-gene DNA sequencing panel (avg. depth of 500x) integrated with whole-transcriptome RNA sequencing. Retrospective analysis of detection rates of all clinically reported pathogenic mutations was performed using LENS, a proprietary application that allows interrogation of large de-identified molecular and clinical datasets. Results: The tumor cellularity of the 59 FFPE samples as assessed by board-certified pathologists ranged from 10% to 80%. Approximately 88% (52/59) of these samples had detectable KRAS alterations, relative to 93% identified in the TCGA database. KRAS G12D, G12V, and G12R were the most frequent findings (29/59, 11/59, and 8/59, respectively). The average KRAS variant allele fraction (VAF) was 16.87% (range 1.7%- 42.2%). Alterations in CDKN2A were detected with a noticeably higher incidence as compared to the TCGA database, 37.2% (22/59) vs 17.4%, respectively. Conversely, TP53 and SMAD4 had similar detection incidence between the two platforms. In addition, 13.5% (8/59) of PC pts had a somatic or germline mutation in the homologous recombination (HR) pathway, with 4 pts having a BRCA2 alteration (6.7%). Finally, one patient was tumor mutational burden (TMB)-High and microsatellite instability (MSI)-High, both of which are tumor-agnostic indications for checkpoint inhibition. Conclusions: An analysis of PC FFPE tissues using the Tempus|xT panel at a clinical depth of 500x revealed a detection rate of KRAS, TP53, and SMAD4 alterations comparable to the TCGA database. Citation Format: Alexander D. Le, Bing Zhang, Kim C. Worley, David Wheeler, Benjamin L. Musher, Heidi Dowst, Amy Wood, Jeff Schaeffer, Nick Olsen, Lorenzo Grego, Matt Sonnleitner, William E. Fisher. Incidence of molecular alterations in KRAS and other known cancer genes in patients with pancreatic cancer assessed with a commercial genomic profiling panel compared to TCGA results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 867.

Abstract 603: Viable circulating tumor cells predict occult metastatic disease and prognosis, and aberrant expression of PD-L1 on viable CTC in pancreatic cancer

Abstract [Introduction] CTCs as liquid biopsy are an emerging minimally invasive tool for cancer diagnosis, surveillance, and treatment. We tested novel methods for viable CTCs (v-CTC) isolation in the patients (pts) with pancreatic cancer (PC), and investigated the clinical potential of v-CTCs in prognosis. Furthermore, we analyzed the PD-L1(L1) expression in primary PC tumors, metastatic lymph nodes (LN) and v-CTCs. [Pts and Methods] 7.5 ml of venous blood was collected prospectively from 39 PC pts, either upfront surgery (Up group) or pre-treatment, consisted of Gem:800 mg/m2; and S-1:80 mg/m2 given concurrently with IMRT to 60 Gy (NACRT:N group). To detect v-CTCs, we employed a telomerase-specific replication-selective adenovirous expressing GFP. For Up group, samples were obtained before/after resection. For N group, samples were obtained before/after NACRT and after resection. To distinguish between leucocyte and cells with either epithelial or mesenchymal origin, cells were stained by anti-CD45, anti-Cytokeratin and anti-Vimentin Abs. GFP-positive and CD45-negative cells were counted as v-CTC. To assess L1 expression in PC tissues (PC tumors and LN) and v-CTCs, L1 IHC kit (22C3, for tissues) and anti-human L1 mAb (MIH1,for CTCs) were employed. [Results] Up group: 24 pts aged 53~85 years (male/female=12/12) were enrolled. 24 pts underwent curative resection. No v-CTCs were detected in 6 pts at both before and after resection, and 5 of 6 pts survived without recurrence. V-CTCs were identified in 18 of 24 pts, and 13 of 18 pts developed liver metastasis. Marked decrease of CTC counts were seen after resection in 10 of 18 pts, but 9 pts developed recurrence. N group: 15 PC pts aged 44~77 years (male/female=4/11) were enrolled. 15 pts underwent curative resection. No v-CTCs were detected in 5 pts, and all 5 pts survived without recurrence. V-CTCs was identified in 10 of 15 pts, and only 3 out of 10 pts developed disease recurrence. Marked increase in CTC counts was observed after NACRT in 5 of 6 CTC-positive pts before NACRT, and 3 of 5 pts developed liver metastasis and died. RT may induce tumor cell dissemination into the blood circulation for CTC-positive pts. PD-L1 expression: L1 expression were assessed for 21 pts (Up group:18, N group: 3). For PC tumors, L1 molecules were expressed in 12 pts and expression level of these pts were all low (57%, ≥50% [high]=0 pts, 1-49% [low]=12 pts {10%=6, 20%=4, 40%=2}, &amp;lt;1% [negative]=9 pts). For metastatic LNs, metastatic LNs were observed in 14 pts and L1-positive expression in these LNs were detected in only 4 pts (28%, all low expression). On the contrary, the majority of detected v-CTCs clearly expressed L1 molecule (92 CTCs out of 103 detected CTCs were L1-positive=89 %). [Conclusions] Viable CTC detection appears as a promising prognostic marker. Immunotherapy with anti-PD-1/PD-L1 Abs may effectively target v-CTCs to evade recurrence. Citation Format: Masahiro Tanemura, Kenta Furukawa, Manabu Mikamori, Yusuke Matsuura, Kenichi Matsumoto, Tadafumi Asaoka, Yasuo Urata. Viable circulating tumor cells predict occult metastatic disease and prognosis, and aberrant expression of PD-L1 on viable CTC in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 603.

Development of DNA methylation markers for predicting the prognosis of pancreatic cancer.

e16216 Background: Pancreatic cancer is an extremely malignant tumor that is associated with low survival rates. Currently, TNM staging, serum CA19–9, CA125 and CEA are used to assess the risk level and estimate prognosis. However, it is still a challenge to predict survival of pancreatic cancer patients (pts) with due to the impact of wide variability of outcomes and genetic heterogeneity. In our study, we aimed to develop a model based on multiple prognostic-related methylation markers and clinical parameters to predict the overall survival (OS) of pancreatic cancer pts. Methods: A total of 50 pts with early-stage resectable pancreatic cancer were included in this study. Preoperative blood, tumor and tumor-distant normal tissue samples were obtained from the pts. Methylation levels from all samples were profiled using targeted bisulfite sequencing using bespoke pancreatic cancer methylation panel covering 80,672 CpG sites, spanning 1.05 mega bases of the human genome. To improve the linkage of methylation sites, we further analyzed the methylation profile as methylation blocks. Results: A total of 1162 tumor-specific methylation blocks, including 737 hypermethylated and 425 hypomethylated blocks were found to be differentially methylated in tumor tissues as compared to tumor-distant normal tissues (P &lt; 0.05). Genes in hypermethylated blocks were significantly enriched in neuroactive ligand−receptor interaction and ca+ signaling pathways, whereas those in hypomethylated blocks were focused in E. coli infection and leukocyte transendothelial migration pathways. All these involved pathways are pancreatic cancer related. Moreover, 7 differentially methylated blocks were identified to significantly associate with OS, including 5 hyper- and 2 hypomethylated blocks. Therefore, we constructed a model based on prognostic-related blocks to predict OS of pancreatic cancer pts. A risk score was derived for each patient based on the model. Pts in the high-risk (HR) group (median risk score as cutoff) showed significantly poorer OS than those in the low-risk (LR) group in survival analysis (p = 0.0016, HR = 0.30). When clinical parameters were also considered, the risk score was found to be the only independent prognostic parameter (p &lt; 0.001) by Cox regression analysis. The prognostic effect of the risk score remained significant in patient groups separated by CA125 levels (p &lt; 0.01). In pre-operative blood samples, risk score was also significantly associated with OS (p = 0.031). Pts in the LR group showed significantly longer OS than those in the HR group. Conclusions: Our data revealed distinct methylation patterns between tumor tissues and tumor-distant normal tissues, suggesting tumor-specific methylation patterns could potentially be developed as diagnostic biomarkers. Importantly, our study also identified 7 blocks-based risk score that could potentially be used as prognostic markers for pancreatic cancer.