Serum tumor DNA may predict pancreatic cancer patients at risk for poor outcomes

By Liz Meszaros, MDLinx
Published December 19, 2016

Key Takeaways

In patients with pancreatic adenocarcinoma, detection of circulating tumor DNA (ctDNA) via serum testing with specific next-generation sequencing (NGS) may not only be feasible, but could provide strong prognostic value regarding outcomes in these patients, according to research published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

By 2030, experts predict that pancreatic cancer will be the second leading cause of cancer-related death in the United States, outdone only by lung cancer. Because only 10% to 15% of patients with pancreatic adenocarcinoma have resectable disease at diagnosis, predictive and/or prognostic biomarkers have become urgently needed in these patients no matter what stage of disease they have.

Researchers conducted this prospective study to identify possible serum biomarkers in patients with pancreatic adenocarcinoma. They include 135 patients diagnosed with pancreatic adenocarcinoma, of whom 31 had resectable tumors, 36 had locally advanced disease (LA), and 68 had metastatic disease (M). From patient serum samples, they extracted DNA, and performed NGS analysis to detect low-allele frequency mutations. Plasma samples were also screened for several KRAS mutations, including the three most commonly found in patients with pancreatic adenocarcinoma via picoliter droplet-based digital PCR (dPCR).

In the 104 patients with advanced disease, researchers found that the presence of ctDNA was an independent prognostic biomarker that was correlated with disease stage and tumor grade differentiation, upon multivariate analysis. Among these patients, 50 had detectable ctDNA (LA: 17%, M: 65%).

In the 50 patients with detectable circulating tumor DNA (ctDNA), overall survival (OS) was shorter compared with patients with no detectable ctDNA (6.5 vs 19 months, respectively). After a median follow-up of 34.2 months, 76 patients died. Patients with advanced disease were grouped into tertiles according to the frequency of ctDNA mutations, and researchers observed significant dose-response relationship with OS, with those in the lowest tertile having an OS of 18.9 months, compared with 7.8 months in patients in the middle tertile, and 4.9 months for those in the highest.

Six of 31 patients with resectable disease had detectable ctDNA, and after a median follow-up of 33.3 months, 23 had disease recurrence, and 13 died. When compared with patients with no detectable ctDNA, these patients had a lower disease-free survival as well (4.6 vs 17.6 months, respectively), and OS was 19.3 vs 32.2 months).

Finally, researchers observed a strong correlation between NGS and droplet-based dPCR results in detecting KRAS.

 “Our study confirms, in one of the largest reported series, the feasibility of detecting ctDNA in patients with pancreatic adenocarcinoma using a specific next-generation sequencing (NGS) analysis method that allows us to screen a large number of genes,” said author Jean-Baptiste Bachet, MD, PhD, from the Gastroenterology and Digestive Oncology Department at Sorbonne University, and the Centre Universitaire des Saints-Pères, Paris, France. “Our study also confirms the strong prognostic value of the presence of ctDNA and of its level, when detected, in advanced pancreatic adenocarcinoma,” he added.

“Our results demonstrate the utility of circulating biomarkers in subclassifying cancers and managing treatment,” concluded Dr. Bachet. “We need to confirm these results in prospective clinical trials to better assess the predictive value of this biomarker in light of the dynamic biological changes that occur during treatment.”

This study was funded by the Fondation d’Aide et Recherche en Cancérologie Digestive, the Ministère de l’Enseignement Supérieur et de la Recherche, the Université Paris-Descartes, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Agence Nationale de la Recherche, the Institut Mérieux the SIRIC CARPEM, and a Fondation Servier fellowship.

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