KRAS mutations and their correlation with survival of patients with advanced pancreatic cancer.

To the Editor: Herein, we describe our previously unpublished data that could strengthen the results presented within a recent original article written by Oliveira-Cunha et al and published in Pancreas. In this interesting article, the authors report the molecular analysis of epidermal growth factor receptor (EGFR) (exons 18, 19, 20, and 21) and KRAS (codons 12, 13, and 61) gene mutations in pancreatic cancer tissues taken from 100 patients, which included 43 ductal adenocarcinomas and 22 ampullary adenocarcinomas. They concluded that EGFR somatic mutations are rare in pancreatobiliary malignancies. They also concluded that KRAS mutations did not influence or correlate with patient survival, whatever the status of the tumor (ie, resectable or locally advanced/metastatic). We investigated the role of KRAS mutations, sampled by fine-needle aspiration using endoscopic ultrasound, for the differential diagnosis of pancreatic cancer. Codons 12 and 13 KRAS mutations were analyzed (restriction fragment length polymorphism and sequencing) in 129 patients (68 men, 61 women; mean [SD] age, 66.1 [16] years) with histologically proven pancreatic ductal adenocarcinoma (PDAC). The patients were categorized as either having locally advanced (n = 50) or metastatic tumors (n = 79). These 2 groups were comparable in terms of sex, age, and tumor localization. After histological confirmation of PDAC and analysis of KRAS mutations, the patients were routinely managed according to standard care and the French national guidelines for digestive cancers. Patients were then allocated to best supportive care (BSC) (n = 31) or to first-line gemcitabine-based chemotherapy (n = 98), either gemcitabine alone (76%) or gemcitabine plus other drugs such as oxaliplatin or erlotinib (24%). Secondor third-line chemotherapy protocols were given to, respectively, 17 and 5 patients. All patients were followed up monthly until death. After statistical analyses, no difference was found in terms of 1-year and overall median survival times when KRAS status was assessed between the 2 subgroups (locally advanced vs metastatic). Overall, survival rates of patients treated with chemotherapy or BSC were also not influenced by KRAS status (Table 1). Because the RAS-mediated signaling pathway links downstream growth factors, especially epidermal growth factor (EGF), studies conducted on colon and lung cancers show that KRAS mutations and EGFR expression can indicate a poor prognosis. However, because of the specific problems encountered with PDAC, these results are ambivalent for this disorder. Two recent studies have reported KRAS mutations in advanced PDAC, although no correlation was found between KRAS mutations and patient survival. Conversely, 3 other published studies (1 that included patients with resected PDAC and 2 that included mixed populations with resected and locally advanced/metastatic PDAC) suggest that the presence of KRAS mutations in tumor tissues has a significant adverse impact on median survival time. The purpose of this letter is not to provide a comprehensive meta-analysis but to report the major differences between these reports. Overall, (1) the number of patients ranged from 50 to 129; (2) the rate of KRAS mutations found in samples varied between 42% and 67% (which is less than generally reported); and (3) the populations included mixed populations of resected and nonresectable advanced and/or metastatic PDAC. Therefore, it is still difficult to conclude that the presence of KRAS mutations influences or does not influence the prognosis of advanced PDAC. To gain further insights and to obtain a definitive conclusion, investigations on a larger cohort of similar patients (to allow strong multivariate analysis) are needed. In addition, our results show that activation of KRAS intracellular pathways by mutations did not influence the results of the gemcitabine-based treatments. Two recent articles reported similar results for patients receiving first-line gemcitabine treatment. However, Kim et al demonstrated that wild-type KRAS status was a marker that could predict improved survival in advanced PDAC patients who had received erlotinib plus gemcitabine as a first-line treatment. Besides the possible (but not proven) role of KRAS mutation analysis to provide a prognosis for PDAC, we and others suggest that detection of KRAS gene mutations might be useful in supplementing histocytopathology when there is an inconclusive or indeterminate endoscopic ultrasoundYguided fine-needle aspiration biopsy. The presence of KRAS mutations is evocative of malignancy. Conversely, wild-type KRAS status could be evocative of a benign lesion, especially when there