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Pancreatic Cancer: Clinical Standards, Unmet Needs and Future Directions

A Special Issue of Cancers (ISSN 2072-6694) belonging to the section "Clinical Research in Cancer".

Deadline for manuscript submissions: closed (30 June 2026) | Viewed by 11012

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Special Issue Information

Dear Colleagues,

Pancreatic cancer is a highly complex and heterogeneous disease, with the worst prognosis among leading cancer types. Late diagnosis, minimal residual disease (MRD) following surgical resections and resistance to current standard neoadjuvant and/or adjuvant chemotherapy are the causes of alarmingly high recurrence rates (80–90%).

To overcome these unmet challenges, breakthrough patient-centric research focuses on the development of prognostic and predictive biomarkers to eliminate MRD through meaningful therapy. Towards this direction, this Special Issue invites a wide spectrum of clinicians such as surgical and medical oncologists, as well as researchers aiming to develop comprehensive rational treatment with targeted therapy and immunotherapy. Considering the limitations of chemotherapy and targeted therapy, research interest concentrates on how to enhance the natural capacity of immune cells within the tumor microenvironment (TME). Harnessing multiomics technologies at bulk and particularly single-cell resolution, the goal of cancer immunotherapy, encompassing immune checkpoint inhibitors (ICIs), adoptive cellular therapy and mRNA vaccines, could be achieved over the next decade. Indeed, phase II/III trials are ongoing, evaluating the clinical utility of next-generation bispecific antibodies for dual checkpoint inhibition. Moreover, on the basis of the successful mRNA cancer vaccines in phase I clinical trials, a global randomized trial will take place soon. The development of tumor and liquid biopsy biomarkers can further improve the efficacy of these immunotherapies by enabling precision immunotherapy.

Prof. Dr. Dimitrios H. Roukos
Guest Editor

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Keywords

  • standard clinical management
  • surgery
  • neoadjuvant and/or adjuvant treatment
  • cancer immunotherapy
  • targeted therapy
  • detection and elimination of MRD

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Published Papers (4 papers)

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Research

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11 pages, 2063 KB  
Article
Postoperative Geriatric Nutritional Risk Index as a Determinant of Tolerance to S-1 Adjuvant Chemotherapy After Curative Surgery for Pancreatic Ductal Adenocarcinoma: A Cohort Study with External Validation
by Naotake Funamizu, Akimasa Sakamoto, Shozo Mori, Miku Iwata, Mikiya Shine, Chihiro Ito, Mio Uraoka, Yoshitomo Ueno, Kei Tamura, Yoshiaki Kamei, Yasutsugu Takada, Taku Aoki and Yuzo Umeda
Cancers 2025, 17(9), 1448; https://doi.org/10.3390/cancers17091448 - 26 Apr 2025
Cited by 3 | Viewed by 1246
Abstract
S-1 adjuvant chemotherapy (AC) is the standard treatment for pancreatic ductal adenocarcinoma (PDAC) after curative surgery in Japan. Our prior research suggested that a lower postoperative geriatric nutritional risk index (GNRI) predicts S-1 discontinuation due to adverse events (AEs). This study aimed to [...] Read more.
S-1 adjuvant chemotherapy (AC) is the standard treatment for pancreatic ductal adenocarcinoma (PDAC) after curative surgery in Japan. Our prior research suggested that a lower postoperative geriatric nutritional risk index (GNRI) predicts S-1 discontinuation due to adverse events (AEs). This study aimed to validate the GNRI as a predictor of S-1 non-completion using an independent cohort. Methods: This retrospective study analyzed 180 patients who underwent curative PDAC resection at Dokkyo Medical University from January 2010 to March 2023. Postoperative GNRI values were recorded as part of nutritional screening. Data on S-1 therapy completion and related clinical factors were analyzed statistically. Results: Patients were classified based on S-1 completion (N = 93) and non-completion (N = 48). GNRI values were significantly lower in the non-completion group. A GNRI threshold of 94.4, identified in a prior study, effectively distinguished patients at risk of discontinuation. Univariate analysis confirmed that a GNRI of ≥94.4 was a significant predictor of successful S-1 completion [hazard ratio (HR) for recurrence-free survival (RFS), 1.54; 95% confidence interval (CI) 1.04–2.28 and for overall survival (OS), 1.89; 95% CI 1.20–2.99]. Conclusions: This study validated previous findings, confirming that the postoperative GNRI reliably identifies patients at risk of S-1 non-completion due to AEs after PDAC surgery. The GNRI serves as a practical marker for optimizing patient care and enhancing AC efficacy. Full article
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Review

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34 pages, 1065 KB  
Review
From Standard of Care to mRNA Cancer Vaccines and Spatial Architecture-Based Precision Therapy in PDAC: Challenges and Expectations
by Elena X. Stea, Nikolaos Kydonakis and Dimitrios H. Roukos
Cancers 2026, 18(11), 1824; https://doi.org/10.3390/cancers18111824 - 2 Jun 2026
Viewed by 1052
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most complex and aggressive disease with the worst rates of unresectable or metastatic disease at diagnosis, resistance to systemic therapy, and case fatality rate (CFR) among leading cancers. In non-metastatic disease, neoadjuvant treatment with modern chemotherapeutic regimens [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is the most complex and aggressive disease with the worst rates of unresectable or metastatic disease at diagnosis, resistance to systemic therapy, and case fatality rate (CFR) among leading cancers. In non-metastatic disease, neoadjuvant treatment with modern chemotherapeutic regimens followed by surgical resection and/or adjuvant mFOLFIRINOX has significantly improved oncological outcomes. However, recurrence rates remain alarmingly high, while immune checkpoint inhibitors (ICIs) or molecularly targeted therapy have not yet demonstrated clinical benefits. Comprehensive genomic profiling through NGS-based approved assays such as TruSight Oncology 500 (TSO500) could guide targeted therapy. Rapidly evolving mRNA cancer vaccines and circulating tumor DNA (ctDNA)-based prediction of minimal residual disease (MRD) and recurrence risk hold great promise towards the realization of rational combination therapy to improve recurrence-free survival (RFS) and overall survival (OS). More recently, single-cell multiomics (SC MO), spatial proteomics and transcriptomics (SPT), artificial intelligence (AI), and systems biology have revolutionized cancer research, enabling holistic tumor microenvironment (TME) analysis. In this comprehensive review, we describe the latest advances and unmet needs in the standard of care of PDAC. Moreover, we discuss the expectations of ongoing randomized clinical trials of adjuvant mRNA vaccine-based therapy and ctDNA MRD testing as prognostic biomarkers, towards personalized treatment to improve RFS and OS in a medium-term perspective. With a longer perspective, we explore how harnessing SC MO, SPT, AI, and systems biology can reveal the 3D spatial organization of interacting cancer, immune, and stromal cells. Multi-dimensional TME-, TSO500- and ctDNA-based framework of dynamic biomarkers are of paramount importance to achieve an optimal patient-specific perioperative multimodal treatment combining precision immunotherapy, targeted drugs, and modern chemotherapy, translated into future practice-changing clinical trials, that could eliminate MRD towards recurrence prevention. Full article
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19 pages, 740 KB  
Review
Personalizing Treatment for Pancreatic Ductal Adenocarcinoma: The Emerging Role of Minimal Residual Disease in Perioperative Decision-Making
by Charalampos Theocharopoulos, Nikolaos Machairas, Ioannis A. Ziogas, Benedetto Mungo, Marco Del Chiaro, Georgios K. Glantzounis, Richard Schulick and Georgios C. Sotiropoulos
Cancers 2026, 18(1), 94; https://doi.org/10.3390/cancers18010094 - 27 Dec 2025
Cited by 4 | Viewed by 1873
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor long-term survival despite advances in surgical techniques, systemic therapies, and perioperative management. High rates of systemic recurrence following curative-intent resection suggest that many patients harbor minimal residual disease (MRD), microscopic tumor burden [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor long-term survival despite advances in surgical techniques, systemic therapies, and perioperative management. High rates of systemic recurrence following curative-intent resection suggest that many patients harbor minimal residual disease (MRD), microscopic tumor burden that persists postoperatively and remains undetectable by conventional diagnostic tools. Recent advances in liquid biopsy technologies, particularly circulating tumor DNA (ctDNA) analysis, alongside detailed characterization of the PDAC mutational landscape, offer a promising non-invasive approach for MRD detection. Emerging evidence indicates that MRD status can serve as a sensitive prognostic biomarker, identify patients at high risk of relapse, and guide personalized perioperative therapy, including optimization of adjuvant treatment. This review summarizes current knowledge on the biology and detection of MRD in PDAC, its implications for perioperative risk stratification and treatment decision-making, and discusses future directions for integrating MRD assessment into clinical practice to enable more precise, individualized patient management. Full article
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47 pages, 1236 KB  
Review
Cancer Vaccination and Immune-Based Approaches in Pancreatic Cancer
by Matthew Bloom, Ali Raza Shaikh, Zhengyang Sun, Babar Bashir and Adam E. Snook
Cancers 2025, 17(14), 2356; https://doi.org/10.3390/cancers17142356 - 15 Jul 2025
Cited by 5 | Viewed by 5632
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high recurrence rates even after curative resection and adjuvant chemotherapy. Although immunotherapeutic approaches, such as immune checkpoint blockade (ICB), have revolutionized the treatment of some solid tumor malignancies, this has not been the case [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high recurrence rates even after curative resection and adjuvant chemotherapy. Although immunotherapeutic approaches, such as immune checkpoint blockade (ICB), have revolutionized the treatment of some solid tumor malignancies, this has not been the case for PDAC. Several characteristics of PDAC, including its distinctive desmoplastic tumor microenvironment (TME), intratumor heterogeneity, and poor antigenicity and immune cell infiltration, contribute to its dismal immunotherapeutic landscape. Cancer vaccines offer one approach to overcoming these barriers, particularly in the resectable or borderline resectable settings, where tumor burden is low and immunosuppression is less pronounced. Various vaccination platforms have been tested in the clinical setting, from off-the-shelf peptide-based vaccines (e.g., AMPLFIFY-201 study, where over 80% of participants exhibited T-cell and biomarker responses) to personalized neoantigen mRNA vaccine approaches (e.g., autogene cevumeran, with significant responders experiencing longer median recurrence-free survival (RFS)). The key considerations for enhancing the efficacy of vaccination include combinations with chemotherapy, radiotherapy, and/or ICBs, as well as selecting appropriate immunomodulators or adjuvants. Recent results suggest that with continued mechanistic advancement and novel therapeutic development, cancer vaccines may finally be poised for clinical success in PDAC. Full article
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