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Pancreatic Cancer (C25.9)

Modern understanding of pancreatic ductal adenocarcinoma (PDAC) centers on a convergent network of oncogenic signaling, stromal–immune crosstalk, and metabolic rewiring rather than a single dominant driver. Activating mutations in KRAS (present in ~90% of cases) initiate constitutive MAPK and PI3K–AKT signaling, while cooperating alterations in TP53, CDKN2A, and SMAD4 dismantle cell-cycle control, DNA damage response, and TGF-β–mediated growth restraint. Beyond tumor cell–intrinsic pathways, PDAC is defined by a dense desmoplastic stroma composed of cancer-associated fibroblasts, extracellular matrix (notably hyaluronan and collagen), and immunosuppressive myeloid populations that reinforce hypoxia, limit drug delivery, and blunt cytotoxic T-cell activity. Modifiable nodes therefore extend beyond KRAS itself to include downstream RAF–MEK–ERK signaling, PI3K–mTOR metabolism, autophagy dependence, DNA repair vulnerabilities (e.g., BRCA1/2-mutant homologous recombination deficiency targetable with PARP inhibition), stromal remodeling pathways (FAK, CXCR4, TGF-β), and innate immune checkpoints such as CD47 and CSF1R. Emerging strategies focus on allele-specific KRAS inhibitors (e.g., G12C and next-generation G12D agents), KRAS degraders, synthetic lethal combinations, precision immuno-oncology guided by tumor microenvironment profiling, and spatially resolved multi-omics to map temporo-dynamic pathway activation. The anticipated advancement is a shift from static histologic classification to adaptive, pathway-indexed treatment algorithms that integrate genomic, transcriptomic, and microenvironmental signatures to modulate the rhythm and context of signaling rather than merely suppress bulk tumor growth.

Causes

The etiology of pancreatic ductal adenocarcinoma (PDAC) reflects the interaction between inherited susceptibility, acquired somatic mutations, and chronic inflammatory–metabolic stressors that create a pro-oncogenic microenvironment. Germline variants in DNA repair genes such as BRCA1, BRCA2, PALB2, and mismatch repair genes increase lifetime risk by impairing genomic integrity, while somatic activating mutations in KRAS typically arise early within precursor lesions (PanINs), establishing constitutive proliferative signaling. Environmental and metabolic factors—including cigarette smoking (the strongest modifiable risk factor), long-standing type 2 diabetes, obesity, and chronic pancreatitis—promote sustained oxidative stress, cytokine signaling (e.g., IL-6/STAT3), and fibrogenic activation of pancreatic stellate cells. This inflammatory milieu enhances DNA damage, epigenetic remodeling, and selection for clones harboring TP53, CDKN2A, and SMAD4 loss. Notably, pancreatic cancer often emerges in the context of decades-long subclinical injury and stromal remodeling, suggesting that etiology is less a single carcinogenic event and more a progressive systems-level failure in genomic maintenance, immune surveillance, and metabolic homeostasis.

Pathophysiology

The pathophysiology of PDAC is defined by oncogenic KRAS-driven signaling embedded within a highly fibrotic, immunosuppressive microenvironment. Early PanIN lesions acquire constitutive MAPK (RAF–MEK–ERK) and PI3K–AKT–mTOR activation, promoting unchecked proliferation, metabolic reprogramming toward glycolysis and autophagy dependence, and resistance to apoptosis. Progressive loss of TP53, CDKN2A, and SMAD4 disrupts cell-cycle arrest, genomic surveillance, and TGF-β–mediated growth control, enabling genomic instability and clonal evolution. A hallmark feature is intense desmoplasia: activated pancreatic stellate cells and cancer-associated fibroblasts deposit collagen and hyaluronan, increasing interstitial pressure, compressing vasculature, and limiting drug penetration. Concurrently, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells establish immune exclusion, blunting effective cytotoxic T-cell infiltration. Hypoxia and nutrient scarcity further select for aggressive, therapy-resistant phenotypes through HIF-1α signaling and altered redox balance. Thus, PDAC pathophysiology reflects not only malignant epithelial transformation but a dynamically co-evolving stromal–immune ecosystem that reinforces tumor persistence and therapeutic resistance.

Clinical features

Pancreatic ductal adenocarcinoma typically presents insidiously and is often advanced at diagnosis due to the retroperitoneal location of the pancreas and early absence of specific symptoms. Tumors arising in the pancreatic head commonly produce painless obstructive jaundice from compression of the common bile duct, accompanied by dark urine, pale stools, pruritus, and sometimes a palpable, distended gallbladder (Courvoisier sign). Lesions in the body or tail more often manifest with vague epigastric or back pain, unintentional weight loss, early satiety, and progressive cachexia. New-onset diabetes or worsening glycemic control in older adults may precede diagnosis, reflecting tumor-induced metabolic dysregulation. Systemic features such as fatigue, anorexia, and thromboembolic events (e.g., migratory thrombophlebitis) reflect the pro-inflammatory and hypercoagulable state associated with advanced disease. Because early-stage disease is frequently asymptomatic, many patients present with locally advanced or metastatic involvement, including liver metastases, ascites, or supraclavicular lymphadenopathy.

Diagnosis

Diagnosis of pancreatic ductal adenocarcinoma begins with high clinical suspicion in patients presenting with painless jaundice, unexplained weight loss, new-onset diabetes, or persistent epigastric/back pain. Multiphasic contrast-enhanced CT of the pancreas is the first-line imaging modality for detection, vascular involvement assessment, and staging. Endoscopic ultrasound (EUS) with fine-needle aspiration or biopsy provides tissue confirmation and enables molecular profiling. In patients with biliary obstruction, ERCP may be performed for ductal visualization and stent placement but is not primarily diagnostic. Serum CA 19-9 is commonly elevated and useful for disease monitoring, though it lacks sensitivity and specificity for screening and may be falsely negative in Lewis antigen–negative individuals. Comprehensive staging incorporates cross-sectional imaging of the chest and abdomen to evaluate metastatic spread. Increasingly, diagnostic workflows include germline testing (e.g., BRCA1/2, PALB2, mismatch repair genes) and somatic tumor sequencing to identify actionable alterations, reflecting a shift toward pathway-informed, precision-directed management.

Mechanism of action videos

Biological pathways

  • Cell Cycle, Mitotic
  • VEGF signaling pathway
  • TGF-beta signaling pathway
  • T cell modulation and desmoplasia in pancreatic cancer
  • Pancreatic cancer subtypes
  • Pancreatic cancer
  • Activation of NMDA receptors and postsynaptic events
  • Polymerase switching
  • PI3K-Akt signaling pathway
  • NRP1-triggered signaling in pancreatic cancer
  • Metabolic reprogramming in pancreatic cancer
  • MAPK signaling pathway
  • Loss of Function of TGFBR1 in Cancer
  • Loss of Function of SMAD4 in Cancer
  • ERBB2 Regulates Cell Motility
  • JAK-STAT signaling pathway
  • Interactions of natural killer cells in pancreatic cancer
  • Immune infiltration in pancreatic cancer
  • Cell interactions in pancreatic cancer microenvironment
  • Cell cycle
  • Apoptosis
  • Post NMDA receptor activation events
  • HDR through Homologous Recombination (HRR)
  • Leading Strand Synthesis
  • Removal of the Flap Intermediate
  • Processive synthesis on the lagging strand
  • DNA Double-Strand Break Repair
  • Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane
  • Transport of connexons to the plasma membrane
  • DNA replication initiation
  • Diseases of signal transduction by growth factor receptors and second messengers
  • HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
  • Homology Directed Repair
  • Polymerase switching on the C-strand of the telomere
  • Activation of AMPK downstream of NMDARs
  • RHO GTPases activate IQGAPs
  • Synthesis of DNA
  • DNA strand elongation
  • Sealing of the nuclear envelope (NE) by ESCRT-III
  • PCNA-Dependent Long Patch Base Excision Repair

Clinical trials

  • A Phase 1/2 Open-label Multicenter Study to Assess the Safety, Pharmacokinetics, and Anti-tumor Activity of GTAEXS617 in Patients With Advanced Solid Tumors
  • A Phase 1a/1b Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of BBO-11818 in Subjects With Advanced KRAS Mutant Cancers
  • A Pilot Study of Biologically Optimized Infusion Schedule of Gemcitabine and Nab-Paclitaxel in Metastatic Pancreatic Adenocarcinoma
  • An Open-Label, Phase 1/2 Dose Escalation, Dose Expansion and Cohort Expansion Study Evaluating the Safety, PK and Clinical Activity of FMC-376 in Participants With KRAS G12C Mutated Locally Advanced Unresectable or Metastatic Solid Tumors
  • A Phase I/II Open-label Dose Escalation and Dose Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of AZD4360 in Adult Participants With Advanced Solid Tumours
  • A Phase 1b Trial of M3814 (Peposertib) in Combination With Lutetium 177 Dotatate for Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
  • A Modular Phase I/IIa, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Ascending Doses of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies (CERTIS1)
  • APOLLO: A Randomized Phase II Double-Blind Study of Olaparib Versus Placebo Following Curative Intent Therapy in Patients With Resected Pancreatic Cancer and a Pathogenic BRCA1, BRCA2 or PALB2 Mutation
  • A Phase II, Open-Label, Multicenter, Randomized Study of the Efficacy and Safety of Adjuvant Autogene Cevumeran Plus Atezolizumab and mFOLFIRINOX Versus mFOLFIRINOX Alone in Patients With Resected Pancreatic Ductal Adenocarcinoma
  • DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors
  • A Phase II, Open-label, Multi-centre Study to Evaluate Safety, Tolerability, Efficacy, PK, and Immunogenicity of AZD0901 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Tumours Expressing Claudin 18.2 (CLARITY-PanTumour01)
  • SBRT Tumorjev in Zasevkov v Jetrih in Tumorjev Trebušne Slinavke
  • A Phase I Study of Anetumab Ravtansine in Combination With Either Anti-PD-1 Antibody, or Anti-CTLA4 and Anti-PD-1 Antibodies or Anti-PD-1 Antibody and Gemcitabine in Mesothelin-Positive Advanced Pancreatic Adenocarcinoma
  • The Analysis of End-stage Renal Disease for Outcomes in Pancreatic Surgery
  • A Phase Ib Dose Escalation/Dose Expansion Study of PTM-101 as an Adjunct to Neoadjuvant Therapy for Treatment Naïve, Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma (PDAC)
  • A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 193 in Combination With Other Therapies in Subjects With Advanced Gastrointestinal, Biliary Tract, or Pancreatic Cancers With Homozygous MTAP-deletion
  • A Phase 1 Study of Olaparib in Combination With Durvalumab (MEDI4736) and Concurrent Radiation Therapy Following First-Line Chemotherapy in Locally Advanced Unresectable Pancreatic Cancer
  • A Phase 1B/2 Pan-Tumor, Open-Label Study To Evaluate The Efficacy And Safety Of Ifinatamab Deruxtecan (I-DXd) In Subjects With Recurrent Or Metastatic Solid Tumors (IDeate-PanTumor02)
  • A Phase 1/2 Study of M3814 (Peposertib) in Combination With Hypofractionated Radiotherapy for the Treatment of Locally Advanced Pancreatic Adenocarcinoma
  • Randomized Phase II Clinical Trial of Olaparib + Pembrolizumab vs. Olaparib Alone as Maintenance Therapy in Metastatic Pancreatic Cancer Patients With Germline BRCA1 or BRCA2 Mutations
  • Phase Ib/II Study of ZEN003694 and Entinostat in Advanced and Refractory Solid Tumors
  • Research of the Application of Pancreatic Cancer Screening Artificial Intelligence Model 'PANDAPro': A Single-Center,Realworld Clinical Trial
  • A Phase 1/1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 410 Alone and in Combination With Other Agents in Participants With KRAS Altered Advanced or Metastatic Solid Tumors
  • A Pharmacodynamics-Driven Trial of Talazoparib, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Aberrations in Genes Involved in DNA Damage Response
  • The Vanguard Study: Testing a New Way to Screen for Cancer
  • Molecular Analysis for Therapy Choice (MATCH)
  • EXCEED - A Pan-European Post-Authorisation Safety Study: Risk of Pancreatic Cancer Among Type 2 Diabetes Patients Who Initiated Exenatide as Compared With Those Who Initiated Other Non-Glucagon-Like Peptide 1 Receptor Agonists Based Glucose Lowering Drugs
  • A Phase I Clinical Trial of CA-4948 in Combination With Gemcitabine and Nab-Paclitaxel in Metastatic or Unresectable Pancreatic Ductal Carcinoma
  • Efficacy Of Combination Chemotherapy And Ablative Radiotherapy (SBRT) In The First-Line Treatment Of Locally Advanced Inoperable Pancreatic Cancer
  • A Phase I Dose Escalation-Expansion Trial of Sunitinib Malate Plus Lutetium Lu 177 Dotatate (Lutathera) in Somatostatin Receptor Positive Pancreatic Neuroendocrine Tumors
  • A Phase 1b Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of a Heterologous Prime Boost Vaccination (ATP150/ATP152/ATP162, VSV-GP154) and Ezabenlimab (BI 754091) in Patients With Pancreatic Ductal Adenocarcinoma.
  • Study on Therapeutic Effect of Combination of Anti-PD-1 Antibody and Chemotherapy in Locally Advanced or Borderline Resectable Pancreatic Cancer Patients: A Randomized Clinical Trial
  • Pancreas Disease and High Risk Registry
  • Evaluation of Resection Techniques for Pancreatic Tumors
  • HIPANC-002 - Observational Performance Study of Transcriptome-Based OncoTreat/OncoTarget Testing With Patient-Derived Organoids in Metastatic Pancreatic Cancer
  • A Phase 1 Trial Investigating LY4101174, an Antibody-Drug Conjugate Targeting Nectin-4, in Participants With Recurrent, Advanced or Metastatic Solid Tumors
  • A Prospective Observational Study of First-Line Systemic Therapy Combined With Celiac Plexus Blockade in Patients With Advanced Biliopancreatic Malignancies and Cancer-Related Pain
  • INTEGRATIVE "MULTI-OMICS" AND FUNCTIONAL PLATFORM FOR THE COMPLETE DIAGNOSTIC CHARACTERIZATION OF TUMORS: THE ITALIAN TUMOR CHEMOGENOMIC PROFILER (IT-TCP)
  • A Phase 1, Open-Label, Dose-Escalation and Expansion Study of AGX101, a TM4SF1 Directed Antibody Drug Conjugate in Patients With Unresectable, Locally Advanced, or Metastatic Solid Tumors
  • A Randomized, Phase 2/3 Study Comparing BMS-986504 in Combination With Nab-paclitaxel and Gemcitabine Versus Placebo in Combination With Nab-paclitaxel and Gemcitabine in Participants With Untreated Metastatic Pancreatic Ductal Adenocarcinoma Harboring Homozygous MTAP Deletion

Therapeutic area: Oncology