Pancreatic Adenocarcinoma (PAAD)

Overview

OncoTree code for pancreatic adenocarcinoma. In the corpus, PAAD is characterized by near-universal KRAS mutation with allele-specific biology, recurrent TP53 / CDKN2A / SMAD4 co-alterations, and clinical behavior strongly shaped by stage at resection.

Cohorts in the corpus

Recurrent alterations

  • Included in pan-cancer MSK-IMPACT pathway and metastasis analyses PMID:39506116.
  • Canonical driver frequencies in the resected MSK cohort (n=397 sequenced): KRAS 90%, TP53 71%, CDKN2A 24%, SMAD4 17%; no significant difference in these frequencies between early- and late-stage disease after multiple-testing correction PMID:39214094.
  • KRAS allele distribution: G12D 36.5%, G12V 32.5%, G12R 13.9%, other KRAS 8.1%, KRAS wildtype 9.1% PMID:39214094.
  • KRASG12R tumors carry a higher proportion of CDKN2A mutations than KRASG12D (40% vs 22.1%, p=0.046) PMID:39214094.
  • Whole-exome sequencing of 19 pancreatic cystic neoplasms (IPMNs, MCNs, SPNs) identified recurrent somatic mutations in VHL, RNF43, and GNAS, linking driver genes to specific PAAD subtypes PMID:22158988
  • Whole-exome sequencing of 142 ICGC pancreatic ductal adenocarcinoma tumors revealed KRAS, TP53, SMAD4, and CDKN2A as the most frequently mutated genes, plus novel axon-guidance pathway alterations PMID:23103869
  • The gemcitabine + saridegib (Smoothened inhibitor) co-clinical trial in PAAD was halted after interim analysis showed inferior survival in the experimental arm despite positive preclinical signal in Kras-driven GEM models; post-clinical mouse experiments suggested chronic Smoothened targeting induces a more aggressive phenotype, illustrating the risk of short preclinical dosing windows PMID:23999436.
  • Whole-exome sequencing of 109 microdissected PAAD (plus 11 PAASC, 4 PAAC) identified 24 SMGs; KRAS 92%, TP53 50%, SMAD4 19%, CDKN2A/B 36%; MYC amplification at 8q24.13 uniquely associates with poor overall survival (P=0.0013) and adenosquamous (PAASC) subtype; BRAF V600E (3%) is mutually exclusive with KRAS and vemurafenib-sensitive in a patient-derived cell line; codon-61 KRAS alleles confer favourable prognosis vs codon-12 (P=0.01999) PMID:25855536
  • Narrative review of nine prospective SBRT trials in locally advanced PAAD: 33 Gy/5-fraction regimen with gemcitabine (Herman et al., n=49) achieved 79% 1-year local control and 13.9-month median OS with only 2% acute and 6% late grade 3+ GI toxicity; SMAD4/DPC4 loss is a candidate biomarker for metastatic propensity and patient selection for local intensification; duodenal dose constraints (V15Gy <9 cc, V20Gy <3 cc, V33Gy <1 cc) are essential PMID:27826200.
  • In the MSK-IMPACT pan-cancer cohort, KRAS was mutated in 90% of PAAD — the highest rate of any principal tumor type — with G12 codon variants comprising 80% of all KRAS mutations; KRAS was classified as non-actionable under then-current OncoKB criteria (predating approval of KRAS G12C inhibitors). PMID:28481359
  • MC3 pan-cancer mutation-calling project (10,510 TCGA pairs) included PAAD; PAAD recovered only 33% of original PanCan12 MAF calls due to low tumor purity (median ABSOLUTE purity 39.7%), making it the most problematic cancer type for MC3 concordance PMID:29596782
  • Pan-cancer fusion study (9,624 TCGA samples) included PAAD; FGFR2 fusions were detected in PAAD and represent potential therapeutic targets; FGFR3 druggable target annotation spanned 15 cancer types including PAAD PMID:29617662
  • Pan-cancer aneuploidy study placed PAAD in the gastrointestinal arm-level cluster (co-gaining 8q, 13q, chromosome 20 alongside COAD, READ, STAD); leukocyte fraction was most strongly negatively correlated with aneuploidy in PAAD (Spearman ρ = −0.428) PMID:29622463

Subtypes

  • KRASG12R-mutant PDAC is a distinct clinical subset: enriched in stage I disease (23% vs 11% in stage II–III, p=0.022), more often node-negative (47% vs 26% for KRASG12D, p=0.019), with improved OS and decreased distant recurrence compared to KRASG12D; also associated with family history of pancreatic cancer (16.4% vs 4.2%, p=0.003) PMID:39214094.
  • Transcriptional programs diverge by KRAS allele: KRASG12D tumors show enhanced KRAS signaling and EMT; KRASG12R tumors show increased TNF/NF-κB signaling by both bulk RNA-seq and CosMx SMI spatial profiling PMID:39214094.

Therapeutic landscape

  • NLP-augmented integrated survival-prediction models outperformed stage- or genomics-only models PMID:39506116.
  • KRASG12R resected PDAC was enriched among patients who received neoadjuvant fluorouracil-based chemotherapy (most frequently FOLFIRINOX with irinotecan and oxaliplatin), consistent with higher response likelihood rather than borderline-resectable selection PMID:39214094.
  • Allele-specific transcriptional divergence (NF-κB vs KRAS/EMT) suggests divergent actionable dependencies across KRAS-mutant PDAC rather than a single pan-KRAS strategy PMID:39214094.
  • BRAF fusions detected in PAAD at low frequency: SND1 was the dominant 5’ fusion partner in PAAD BRAF fusions (56%); acinar cell carcinoma of the pancreas had >=5% BRAF fusion prevalence. PMID:38922339
  • PAAD comprised 10% of the 4,141-patient liquid biopsy VTE discovery cohort; ctDNA detection was associated with higher VTE rates across pan-cancer including PAAD. PMID:39147831
  • ROBIN METEOR center (U54 CA274318; Washington University) METEOR-CRATR MCT (NCT05975593) has enrolled 12 pancreatic cancer patients with 10 tumor samples (3 with serial biopsies). Preliminary data: SBRT altered cDC1 infiltration in human and murine pancreatic tumors and produced an impaired antigen-presenting-cell (APC) phenotype with altered cDC1/cDC2 ratios in draining lymph nodes; myeloid-derived immunosuppressive remodeling of the TME is the working mechanistic hypothesis. CBCT delta-radiomics and ctDNA analyses are underway. PMID:41941260

Sources

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This page was processed by crosslinker on 2026-05-14. - PMID:22158988

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This page was processed by crosslinker on 2026-05-14. - PMID:23999436

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This page was processed by crosslinker on 2026-05-14. - PMID:27826200

This page was processed by entity-page-writer on 2026-05-15. - PMID:29596782

This page was processed by wiki-cli on 2026-05-15. - PMID:29617662

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This page was processed by wiki-cli on 2026-05-15.