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Absolute Quantitation of Circulating Tumor DNA in Pancreatic Ductal Adenocarcinoma
Naoto Hadano*1, Yoshiaki Murakami1, Kenichiro Uemura1, Yasushi Hashimoto1, Naru Kondo1, Naoya Nakagawa1, Taijiro Sueda1, Eiso Hiyama2
1Department of Surgery, Hiroshima University, Hiroshima, Japan; 2Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, Hiroshima, Japan
Purpose: The present study aimed to detect oncogenic v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in circulating tumor DNA (ctDNA) from plasma samples and to assess the clinical implications of KRAS-mutated ctDNA a useful surrogate biomarker in patients with pancreatic ductal adenocarcinoma (PDAC).
Experimental Design: Tumor specimens and plasma samples were collected from 105 patients who underwent pancreatic resection for PDAC at a single institution. KRAS-mutated ctDNA was detected using droplet digital polymerase chain reaction (ddPCR). The overall survival (OS) of patients in this study was analyzed according to the presence of ctDNA.
Results: Among the 105 resected PDACs evaluated in this study, KRAS mutations were detected in 86 (82%) and 33 (31%) of primary tumors and matched plasma samples, respectively. The median OS durations were 13.6 months for patients with KRAS-mutated ctDNA (ctDNA+) and 27.6 months for the other patients. The ctDNA+ patients had a significantly poorer prognosis with respect to OS (P < 0.0001).
Dicussion: PDAC is a fatal disease that is often diagnosed at an advanced stage, which leads to a poor prognosis. Hence, interest in the development of noninvasive biomarkers for early PDAC detection and prognostic prediction has grown rapidly. A recent study reaffirmed the importance of mutations in various genes (KRAS, TP53, and CDKN2A) characteristic of PDAC. Among these, activating mutations of KRAS are often considered the best-characterized tumor-related gene element for the following reasons. First, among all human malignancies, PDAC exhibit the highest frequency (75%-100%) of KRAS mutation. Second, in PDAC, the most frequent KRAS point mutations are located in codon 12, among two consecutive nucleotides. Third, alterations in this gene appear to occur at an early stage of pancreatic carcinogenesis. Therefore, KRAS mutation was selected as the most suitable potential biomarker in this study. We used droplet digital polymerase chain reaction (ddPCR), a next-generation system with a revolutionary approach to target DNA quantitation, to successfully detect rare mutant tumor-derived KRAS genes in plasma. We found that patients with PDAC who harbored KRAS-mutated circulating tumor DNA (ctDNA) had a significantly poorer prognosis. Accordingly, ctDNA detection may be a promising approach with respect to PDAC treatment.
Conclusions: The study findings implicate that the presence of ctDNA in plasma samples could be an important and powerful predictor of poor survival in patients with PDACs. Robust technologies such as ddPCR could therefore potentially contribute to the establishment of new therapeutic strategies for these patients.
 OS curves according to the presence of KRAS-mutated ctDNA. Significant differences in OS were observed according the categorization of patients into ctDNA+ and ctDNA − groups.
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