Molecular characteristics of and mutations in pancreatic ductal adenocarcinoma.

INTRODUCTION

Poly-(ADP)-ribose polymerase (PARP) inhibitors are successfully used for treatment of mutated (mut) breast cancers and are under extensive evaluation for and mutated pancreatic ductal adenocarcinoma (PDAC). However, the optimal treatment regimen for -mutated PDCA has yet to be established. Moreover, limited data are available on the association of gene alterations with other comutations and immunological biomarkers.

MATERIAL AND METHODS

Tumour samples of 2818 patients with PDAC were analysed for 1/2 mutations and other genes by next-generation sequencing (NGS) (MiSeq on 47 genes, NextSeq on 592 genes). TMB was calculated based on somatic non-synonymous missense mutations. MSI-H/dMMR was evaluated by NGS, and PD-L1 expression was determined using immunohistochemistry.

RESULTS

In 4.2% (n=124) of all PDAC samples mutations have been detected. mutations were more commonly observed than mutations (3.1%(n=89) vs 1.1% [n=35], p<0.0001). mutation was associated with an older age (64 vs 61 years for wild-type (wt), p=0.002) and mutation was observed more frequently in female than in male patients. and mutations were associated with MSI-H/dMMR compared with wt (: 4.8% vs 1.2%, p=0.002; : 6.7% vs 1.3 %, p=0.18), PD-L1 expression of >1.0% (: 21.8% vs wt 11.2%, p<0.001, : 0.0% vs 12.4 %, p=0.38) and high TMB (: mean 8.7 vs 6.5 mut/MB, p<0.001; : 10.6 mut/Mb vs 6.6 mut/Mb, p=0.0007). Also, PD-L1 expression and TMB differed between and mutation and wt samples in MSS tumours (p<0.05). -mutated and -mutated PDACs were characterised by a different mutational profile than was observed in wt tumours.

CONCLUSIONS

and mutations were found in a significant subgroup of PDACs. These mutations were associated with a distinct molecular profile potentially predictive for response to immune-checkpoint inhibitor therapy. Therefore, these data provide a rationale to evaluate PARP inhibitors in combination with immune-checkpoint inhibitors in patients with -mutated PDAC.