Clinicalomics: Investigators from Sorbonne University in Paris have now assessed the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma, a significant advance in a hard-to-diagnose disease that is expected to become the second leading cause of cancer death in the U.S. by 2030. There remain several challenges to conducting translational research on pancreatic cancer, including the difficulty in obtaining tumor samples from patients, since most studies have been limited to patients with the resectable disease until now. However, only 10% to 15% of patients with pancreatic adenocarcinoma have resectable disease at diagnosis—making identification of robust prognostic or predictive biomarkers critical for all patients with pancreatic adenocarcinoma, whatever the stage of the disease.
For the current study, the French investigators initiated their
research 5 years ago to collect blood samples from patients with
pancreatic adenocarcinoma, with the goal of identifying blood-based
biomarkers to overcome the challenge of limited availability of tumor
samples for research purposes.
The Sorbonne team analyzed blood samples from 135 patients with
pancreatic adenocarcinoma—31 had resectable tumors, 36 had locally
advanced disease (LA), and 68 had metastatic disease (M). They extracted
DNA from the plasma samples and used a specific next-generation
sequencing (NGS) analysis method to detect low allele-frequency
mutations. They also screened all plasma samples for the three most
frequent KRAS mutations in pancreatic adenocarcinoma, besides several
other mutations, by droplet-based digital PCR (dPCR).
The findings from this study were published recently in Clinical
Cancer Research in an article entitled “Plasma Circulating Tumor DNA in
Pancreatic Cancer Patients Is a Prognostic Marker.”
"Our study confirms, in one of the largest reported series, the
feasibility of detecting ctDNA in patients with pancreatic
adenocarcinoma using a specific NGS analysis method that allows us to
screen a large number of genes," explained senior study investigator
Jean-Baptiste Bachet, M.D., Ph.D., physician in the gastroenterology and
digestive oncology department at Sorbonne University and the Centre
Universitaire des Saints-Pères. "Our study also confirms the strong
prognostic value of the presence of ctDNA and its level, when detected,
in advanced pancreatic adenocarcinoma."
In multivariate analysis, the presence of ctDNA was an independent
prognostic biomarker in patients with advanced disease, and it also
correlated with the stage of the disease and the grade of tumor
differentiation. Out of the 104 patients with advanced disease, 50 had
detectable ctDNA (LA, 17%; M, 65%). After a median follow-up of 34.2
months, 76 died. Overall survival (OS) was 19 months in patients with no
detectable ctDNA, versus 6.5 months in those with ctDNA.
Additionally, when patients with advanced disease were grouped into
tertiles based on the frequency of mutations in the ctDNA, there was a
significant dose–response relationship with OS: 18.9 months for those in
the lowest tertile, 7.8 months for those in the middle, and 4.9 months
for those in the highest tertile.
Of the 31 patients with resectable disease, six had detectable ctDNA.
After a median follow-up of 33.3 months, 23 had disease recurrence, and
13 of them died. Disease-free survival was 17.6 months in patients with
no detectable ctDNA, versus 4.6 months in those with ctDNA; OS was 32.2
months versus 19.3 months.
Interestingly, the research team found a strong correlation between
the results obtained with NGS and droplet-based digital (ddPCR) to study
KRAS, confirming that their NGS strategy is pertinent.
"Our results demonstrate the utility of circulating biomarkers in
subclassifying cancers and managing treatment," Dr. Bachet concluded.
"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."