Abstract A19: Fundamental significance of specific KRAS mutant types for prognosis of unresectable pancreatic cancer patients

Abstract

Abstract Introduction: The overall survival prognosis of patients in advanced unresectable stages of pancreatic ductal adenocarcinoma is poor, typically ranging from days to months from diagnosis. A prognostic marker would be useful in management of the disease guiding rational decisions between systemic or palliative therapy ensuring longest survival at an adequate quality of life. Due to its frequent occurrence in PDAC, prognostic value of KRAS mutation status has traditionally been studied. The results, however, were often contradictory. In the present work, we explore the role of individual KRAS mutant types in the assessment of prognosis. In addition, we explore KRAS mutation analysis from circulating tumor DNA (ctDNA) as a source material to eliminate biopsy-associated burden to the patient. Experimental: A total of 118 patients with PDAC clinically confirmed by EUS-FNAC were included in the study. DNA was extracted from FNA slides following a standard cytology evaluation to ensure adequacy (viability, quantity) and to mark tumor cell fraction. CtDNA was extracted from plasma samples of patients in Stage IV of the disease. KRAS mutations were detected by denaturing capillary electrophoresis (DCE) revealing minute presence of mutation specific hetero-duplexes. Kaplan-Meier survival curves were calculated for individual KRAS mutation types. Data Summary: KRAS mutation was detected in 90% of tissue (106/118) and in 39 % of plasma (16/41) samples. All mutations were localized at exon 2, codon 12 with Gly12Asp (GGT>GAT) as the most frequent at 45% (48/106) and 68% (11/16), followed by other types including Gly12Val (GGT>GTT) at 31% (33/106) and 13% (2/16), Gly12Arg (GGT>CGT) at 17% (18/106) and 6% (1/16), Gly12Cys (GGT/TGT) at 5% (5/106) and 0% (0/16) and Gly12Ser (GGT/AGT) at 1% (1/106) and 13% (2/16) in tissue and plasma samples respectively. Survival of patients with the Gly12Asp was less than a half when compared to all of the other mutation types combined (107 days vs. 218 days, P=0.002, long-rank test) in tissues. In plasma samples it was less than four times (27 days vs. 146 days, P=0,03). Conclusions: FNA-biopsy followed by cytology evaluation and molecular testing of KRAS is feasible in routine management of pancreatic cancer patients. Differentiation of specific KRAS mutation types (above all the crucial Gly12Asp) is imperative for assessment of prognosis in the rational therapy decision process. Supported by the IGA grant no. 13638 Citation Format: Lucie Benesova, Tereza Halkova, Barbora Belsanova, Bohus Bunganic, Eva Traboulsi, Miroslav Zavoral, Marek Minarik.{Authors}. Fundamental significance of specific KRAS mutant types for prognosis of unresectable pancreatic cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A19.