KRAS gene mutation quantification in the resection or venous margins of pancreatic ductal adenocarcinoma is not predictive of disease recurrence

Samuel Amintas,Etienne Buscail,Alexandre Chauvet,Laurence Chiche,Sandrine Dabernat,Christophe Laurent,Marion Marty,Geneviève Belleannée,Benjamin Fernandez

doi:10.1038/s41598-022-07004-x

Abstract

Pancreatic ductal adenocarcinoma (PDAC) patients eligible for curative surgery undergo unpredictable disease relapse. Even patients with a good pathological response after neoadjuvant treatment (NAT) remain susceptible to recurrent PDAC. Molecular analysis of R0 margins may identify patients with a worse prognosis. The molecular status of mutant KRAS (exon 2, codon 12/13) was analysed retrospectively by digital droplet PCR in tumour areas, venous and resection margins of resected tumours, either undergoing up-front surgery (UFS) or after NAT with a good pathological response. Expectedly, tumour tissues or remnants from patients who underwent NAT presented lower KRAS mutant allele frequencies (MAF) than patients eligible for UFS. Similarly, ypT1 tumour MAFs were greater than the ypT0 tumour remnant MAFs in the NAT group. Mutant KRAS status in margins did not distinguish NAT subgroups. It was not predictive of shorter recurrence-free or overall survival within or between groups. KRAS-double negativity in both venous and resection margins did not identify patients with a better prognosis, regardless of the groups. The cohorts ‘sizes were small due to limited numbers of patients meeting the inclusion criteria, but KRAS-positivity or MAFs in resection and venous margins did not carry prognostic value. Comparison of margins from good versus bad responders receiving NAT may provide better clinical value.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) patients eligible for curative surgery undergo unpredictable disease relapse
This study aimed to investigate the presence of KRAS mutations by ultra-sensitive droplet digital PCR in the resection and venous margins of R0 resected tumour samples, identifying rare microscopically undetectable tumour cells in tissue areas, declared healthy by the pathologist
In the neoadjuvant therapy (NAT) group, double pathological and margin positivity did not identify patients with shorter Recurrence-free survival (RFS) (Fig. 4G, n = 12, p = 0.25) or Overall survival (OS) (Fig. 4H, p = 0.48), as compared to single positives. These results show that the detection of molecular residual disease in the resection or venous margins of up-front surgery (UFS) or NAT PDAC patients does not carry prognostic value

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) patients eligible for curative surgery undergo unpredictable disease relapse. The molecular status of mutant KRAS (exon 2, codon 12/13) was analysed retrospectively by digital droplet PCR in tumour areas, venous and resection margins of resected tumours, either undergoing up-front surgery (UFS) or after NAT with a good pathological response. Mutant KRAS status in margins did not distinguish NAT subgroups It was not predictive of shorter recurrence-free or overall survival within or between groups. KRAS-double negativity in both venous and resection margins did not identify patients with a better prognosis, regardless of the groups. The cohorts ‘sizes were small due to limited numbers of patients meeting the inclusion criteria, but KRAS-positivity or MAFs in resection and venous margins did not carry prognostic value. The second population is brought to the surgery by neoadjuvant therapy (NAT) of borderline and locally advanced diseases. In the resected population, tumour material is available and may provide valuable molecular information that can relate to prognosis

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