Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer

Marzia Del Re,Enrico Vasile,Mario Miccoli,Caterina Vivaldi,Eleonora Rofi,Lorenzo Fornaro,Alfredo Falcone,Paolo Davide D’Arienzo,Chiara Caparello,Romano Danesi

doi:10.1038/s41598-017-08297-z

Abstract

Pancreatic cancer (PDAC) is still lacking of reliable markers to monitor tumor response. CA 19-9 is the only biomarker approved, despite it has several limitations in sensitivity and specificity. Since mutations of KRAS occur in more than 90% of tumors, its detection in circulating free tumor DNA (cftDNA) could represent a biomarker to monitor chemotherapy response. Twenty-seven advanced PDAC patients given first-line 5-fluorouracil, irinotecan and oxaliplatin or gemcitabine and nab-paclitaxel were enrolled. Three ml of plasma were collected: 1) before starting chemotherapy (baseline); 2) at day 15 of treatment; and 3) at each clinical follow-up. cftDNA was extracted and analysed for KRAS mutations (mutKRAS) by digital droplet PCR. Nineteen patients displayed a mutKRAS in baseline plasma samples. There was a statistically significant difference in progression-free survival (PFS) and overall survival (OS) in patients with increase vs. stability/reduction of cftDNA in the sample collected at day 15 (median PFS 2.5 vs 7.5 months, p = 0.03; median OS 6.5 vs 11.5 months, p = 0.009). The results of this study demonstrate that cftDNA mutKRAS changes are associated with tumor response to chemotherapy and support the evidence that mutKRAS in plasma may be used as a new marker for monitoring treatment outcome and disease progression in PDAC.

Highlights

Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related deaths in Western countries and only 10–20% of patients are diagnosed with a resectable disease[1]
The present study provides the evidence that the change of mutKRAS circulating free tumor DNA (cftDNA) levels between baseline vs. day 15 is an early predictor of clinical outcome
To the best of our knowledge, the present study shows for the first time that cftDNA mutKRAS variation is an early marker of response to treatment in PDAC

Summary

Introduction

Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related deaths in Western countries and only 10–20% of patients are diagnosed with a resectable disease[1]. Since pancreatic tumor tissue is surrounded by a dense fibrotic stroma, the evaluation of tumor response to therapy is challenging and imaging techniques do not always provide an accurate estimate, despite the significant costs[4, 5] For this reason, the monitoring of these tumors by blood markers is a valuable alternative and is based on the evaluation of the Carbohydrate Antigen 19-9 (CA 19-9) levels, the standard serum marker for pancreatic cancer. CA 19-9 has been approved to monitor tumor response, it has several limitations including: (1) low sensitivity and specificity (estimated to be around 79% and 82%, respectively); (2) occurrence of unspecific changes in serum samples; (3) poor accuracy in the identification of small tumors[6, 7] These issues limit the utility of CA 19-9 as a biomarker and highlight the need for new biomarkers to complement the imaging in order to obtain a more effective monitoring of these patients and improve the clinical outcome. Looking at the specific type of mutation, the presence of KRAS p.G12V seems to be associated with a decrease in survival of pancreatic cancer patients[13]

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