1894 - Genomic characterisation of locally advanced pancreatic adenocarcinoma

Background

Locally advanced pancreatic adenocarcinoma (LAPC) is treated similarly to metastatic pancreatic cancer (MPC). It has previously been thought that SMAD4 is wildtype (WT) in LAPC. We describe results of whole genome (WGS) and RNA sequencing (RNAseq) of LAPC and MPC tumours.

Methods

Patients with LAPC and MPC were enrolled in the COMPASS clinical trial (NCT02750657). Clinical, demographic and survival data were collected. WGS and RNAseq was performed along with modified Moffitt classification (basal-like or classical).

Results

Patients with LAPC (n = 27) and MPC (n = 163) did not differ in terms of age, gender or smoking status. Patients with LAPC had lower BMI (p = 0.005) than those with MPC. More LAPC patients received FOLFIRINOX than those with MPC (p = 0.003). LAPC/MPC tumours had similar rates of KRAS, p53, CDKN2A and SMAD4 mutations and similar levels of ploidy, indels, neoantigens and single nucleotide variants. There was a slight increase in structural variants in MPC vs. LAPC (p = 0.05). No LAPC tumours were homologous recombination deficient (HRD) or KRAS WT, compared with 10 MPC (HRD) and 15 MPC (KRAS-WT). LAPC patients with SMAD4 mutations had higher baseline Ca19.9 than those with WT SMAD4 (p = 0.0048). All LAPC were Moffitt classical subtype on RNAseq, compared with 77% of MPC (p = 0.0049). LAPC patients had improved OS compared with MPC patients on univariate analysis (p = 0.04) but not on multivariate analysis. There was no difference in OS between LAPC and classical subtype MPC, or between LAPC patients with/without SMAD4 mutations.

Conclusions

Patients with LAPC have a similar molecular profile to those with MPC with similar rates of altered drivers including SMAD4. LAPC tumours are more likely to be Moffitt classical subtype and have similar OS to classical subtype MPC. LAPC patients with SMAD4 mutations had similar OS to those with WT SMAD4. These data suggest that patients with LAPC should be treated similarly to those with classical-subtype MPC.

Clinical trial identification

NCT02750657.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Government of Ontario, Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Foundation, Canadian Cancer Society Research Institute Grant (702316), Pancreatic Cancer Canada Foundation, Canadian Friends of the Hebrew University (Alex U. Soyka), Lebovic Chair in Hepatobiliary/Pancreatic Surgical Oncology.

Disclosure

All authors have declared no conflicts of interest.