Abstract 5034: Imact of KRAS mutation on clinical outcomes in pancreatic cancer patients who were treated with first-line gemcitabine-based chemotherapy
Authors: Park Joon Oh , Kim Seung Tae , Lim Do Hyoung , Lee Jeeyun , Jang Kee-Taek , Choi Yoon-La , Jang Hey-Lim , Park Se Hoon , Park Young Suk , Lim Ho Ho , Kang Won Ki 
Published: June 2012

Abstract
Background: Gemcitabine forms the backbone of chemotherapy and a recent study showed small but significant clinical benefits of erlotinib combined with gemcitabine in patients with pancreatic ductal adenocarcinoma. However, the high frequency of KRAS mutations in this population probably limits the benefits of an EGFR inhibitor, and this limitation seems to be similar to that observed in colon cancer and non-small cell lung cancer. We undertook this study to understand the clinical significance of KRAS mutation in pancreatic cancer patients who were treated with gemcitabine-based chemotherapy. Patients & Methods: We retrospectively studied 136 pancreatic cancer patients with available formalin-fixed paraffin-embedded tumor blocks from 2003 to 2009. KRAS mutations were analyzed by sequencing codons 12, 13 and 61. Results: In this study, 71 (52.2%) of the 136 pancreatic adenocarcinomas examined harbored a point mutation in codon 12 (N=70) and 61 (N =1) of KRAS. Observed point mutations at codon 12 in the order of frequency were: GGT-GAT (35G&gt;A; 41 of 71 patients, 57.7 %); GGT-GTT (35G&gt;T; 19 of 71 patients, 26.8%); GGT-CGT (34G&gt;C; 7 of 71 patients, 10.0%); and GGT-TGT (34G&gt;T; 3 of 71 patients, 4%). KRAS mutation was not associated with clinicopathological parameters such as age, sex, ECOG PS, smoking, tumor location, histologic differentiation, TNM staging, level of CA19-9 and first-line chemotherapy regimens. Patients with KRAS mutations showed a worse response and disease control rate (11.3 and 35.2%) than those with wild type KRAS (26.2 and 52.3%). KRAS mutation also adversely influenced survival of pancreatic cancer patients (mutant KRAS, 5.8 months [95% C.I. 5.1-6.5] vs. wild type KRAS, 8.0 months [95% C.I. 5.8-10.2]; p=0.001) Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology (p&lt;0.001; hazard ratio (HR) = 0.437, 95% C.I. 0.301∼0.634), locally advanced disease (p&lt;0.001; HR 0.417, 95% C.I. 0.255∼0.681), response to first-line chemotherapy (p=0.003; HR 0.482, 95% C.I. 0.297∼0.780) and wild type KRAS (p=0.001; HR 0.523, 95% C.I. 0.355∼0.70). Conclusions: Our results suggest that KRAS mutation may play an important role as a biomarker for response to erlotinib treatment and in determining prognosis in pancreatic cancer patients who were treated with gemcitabine-based chemotherapy. These findings should be further explored in preclinical and upcoming prospective clinical trials to potentially allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and provide a rationale for personalized medicine in pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5034. doi:10.1158/1538-7445.AM2011-5034