In the third part of this series on pancreatic cancer, we’ll take a look at recent developments in identifying subtypes of pancreatic cancer and its potential impact on the lives of pancreatic cancer patients.
Twenty-one years ago, we had identified some of the histologically distinct types of pancreatic cancer. These neoplastic tissue types included: PanINs (pancreatic inter-epithelial neoplasms), IPMN (intraductal papillary mucinous neoplasms, MCN (mucinous cystic neoplasms). Wu et al established cancer-associated genes in the cyst fluids of IPMNs, and discovered that IPMNs harbored GNA and KRAS mutations.
In 2016, Andrew Biankin of the Wolfson Wohl Cancer Research Center in Glasgow, identified 4 distinct subtypes of pancreatic cancer in his paper “Genomic analyses identify molecular subtypes of pancreatic cancer”. These subtypes included:
- Squamous – enriched for TP53 & KDM6A mutations, upregulation of the TP63
∂N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis - Pancreatic progenitor – differentially expressed genes involved in early pancreatic development including (FOXA2/3, PDX1, and MNX1)
- Immunogenic – contained upregulated immune networks including pathways involved in acquired immune suppression
- Aberrantly differentiated endocrine exocrine (ADEX) – displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2)
With these subtypes, the hope is that clinicians can segment patient populations into groups that respond better to specific, targeted therapies. Already we’ve seen that patients with BRCA2 mutations are more likely to respond to PARP inhibitors, and researchers are currently investigating if patients in the Immunogenic subtype are more likely to respond to the latest immunotherapies.
Just recently, the Precision-Panc organization announced the first of three PRIMUS (Pancreatic cancer Individualized Multi-arm Umbrella Study) trials. PRIMUS-001 is an adaptive Phase II/III study with an integrated biomarker evaluation in patients with metastatic disease. PRIMUS-002 will aim to define biomarkers of therapeutic responsiveness in the neoadjuvant setting and is set to open in 2018. PRIMUS-003, supported by AstraZeneca, is using an immunotherapy approach and is also currently recruiting patients with metastatic disease.