Impact of KRAS Mutations on Clinical Outcomes in Pancreatic Cancer Patients Treated with First-line Gemcitabine-Based Chemotherapy

Abstract

Although erlotinib has become an important therapeutic option in addition to gemcitabine, the high frequency of KRAS mutations in pancreatic cancer probably limits the benefits. We retrospectively studied 136 pancreatic cancer patients with available formalin-fixed paraffin-embedded tumor blocks from 2003 to 2009 to understand the clinical significance of KRAS mutations in pancreatic cancer patients treated with gemcitabine-based chemotherapy. KRAS mutations were analyzed by sequencing codons 12, 13, and 61. In this study, 71 (52.2%) of the 136 pancreatic adenocarcinomas examined harbored a point mutation in codons 12 (n ¼ 70) and 61 (n ¼ 1) of KRAS. KRAS mutation was not associated with clinicopathologic parameters. Patients with KRAS mutations showed a worse response (11.3%) than those with wild-type KRAS (26.2%) and poor survival (mutant KRAS, 5.8 months vs. wild-type KRAS, 8.0 months; P ¼ 0.001). Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology (P < 0.001; HR ¼ 0.437, 95% CI: 0.301-0.634), locally advanced disease (P < 0.001; HR ¼ 0.417, 95% CI: 0.255-0.681), response to first-line chemotherapy (P ¼ 0.003; HR ¼ 0.482, 95% CI: 0.297-0.780), and wild-type KRAS (P ¼ 0.001; HR ¼ 0.523, 95% CI: 0.355-0.770). However, the observed survival advantage is derived from the subgroup of patients treated with gemcitabine/erlotinib (9.7 vs. 5.2 months; P ¼ 0.002), whereas no survival difference based on KRAS mutation status is obvious in the other subgroup of patients treated without erlotinib (7.0 vs. 7.0 months; P ¼ 0.121). These results need to be further explored in upcoming prospective studies to provide a rationale for personalized medicine in pancreatic cancer.

<b>Metabolic profiling of gemcitabine- and paclitaxel-treated immortalized human pancreatic cell lines with K-RAS</b>^{<b>G12D </b>}

“…6) indicates that there was no considerable difference between GEM-treated CRL-4037 and GEM-treated CRL-4039 K-RAS G12D samples except for guanosine and adenosine, which were reduced in GEM-treated CRL-4037 but not in GEM-treated CRL-4039. A previous study reported that subgroup patients with K-RAS mutations showed an adverse response and shorter survival compared to those with wild-type K-RAS (17). Though the relationship between GEM and the K-RAS G12D mutation is controversial, the difference between CRL-4037 and CRL-4039 in adenosine and guanosine highlights the significance of K-RAS G12D .…”

Study of Clinical Survival and Gene Expression in a Sample of Pancreatic Ductal Adenocarcinoma by Parsimony Phylogenetic Analysis

“…This in vitro finding highlights that K-ras inhibition cannot be clinically targeted in all the PDAC patients due to its significant variation between K-ras-driven tumor types, which is consistent with the latest K-ras studies. While some studies concluded the absence of correlation between K-ras and overall survival (Da Cunha Santos et al, 2010), others declared K-ras as a prognostic biomarker in pancreatic cancer (Chen et al, 2010;Lee et al, 2007;Ogura et al, 2013), which is also in contrast to another retrospective study suggesting K-ras as a predictive marker for erlotinib efficacy rather than a prognostic factor (Kim et al, 2011). Although K-ras has been one of the triggers in PDAC, drugs that target K-ras have not been effective to date.…”

The genetic classification of pancreatic neoplasia

“…The four most frequently involved genes in PDA play a role in IPMNs too. As mentioned, somatic KRAS mutations occur in a high proportion of IPMNs, with higher incidence in gastric and pancreatobiliary subtypes and the associated tubular adenocarcinomas [85][86][87][88]. Somatic TP53 mutations are almost exclusively found in areas of high-grade dysplasia or invasion, which indicates that this mutation is a relatively late event in carcinogenesis [88][89][90][91].…”