Lack of Relationship Between Clinical Features and KRAS Mutations in Patients with Metastatic Colorectal Cancer.

BACKGROUND/AIM: We previously identified three clinical predictive factors of efficacy of cetuximab-irinotecan. Here, we analyzed the clinical characteristics of patients with metastatic colorectal cancer (CRC) in order to detect potent correlations with KRAS mutations. PATIENTS AND METHODS: We conducted a retrospective, multicenter study between 2008 and 2012. We included patients with metastatic colorectal adenocarcinomas, previously treated by irinotecan, and with an available KRAS mutation test. RESULTS: We included 299 patients. The median age was 60 years; the median number of metastatic sites was 2. One hundred and eight patients (36.1%) had a previous objective response to irinotecan. The median interval between diagnosis and irinotecan discontinuation was 1.94 years. A KRAS mutation was detected in 133 patients (44.5%). In univariate and multivariate analyses, none of the assessed factors was associated with the presence of a KRAS mutation. CONCLUSION: No easily clinically assessable parameter was significantly associated with KRAS mutations in patients with colorectal cancer.

E-selectin gene S128R polymorphism is associated with poor prognosis in patients with stage II or III colorectal cancer.

Some host-related factors may predict the risk of metastasis after surgery of colorectal cancer (CRC). The endothelial adhesion molecule E-selectin is implicated in the metastatic spread of CRC. We postulated that some polymorphisms within the E-selectin gene, especially the S128R polymorphism, may increase the risk of metastases by facilitating adhesion of tumour cells to the endothelium. We collected blood samples for DNA extraction from 264 patients treated for stage II or III CRC and from 310 healthy controls in order to assess three polymorphisms within the E-selectin gene (S128R, G98T and L554F) and one within the P-selectin gene (V640L). Genotypes were analysed by the allelic discrimination TaqMan real-time PCR assay. The S128R polymorphism was detected in 59 patients (22.3%) and was strictly correlated with the G98T polymorphism. In multivariate analysis, the S128R polymorphism was associated with shorter event-free survival (EFS) and overall survival (OS) in the whole population (EFS: P=.003, HR 1.82, 95% CI 1.23-2.70; OS: P<10(-4), HR 4.31, 95% CI 2.46-10.99), in patients with stage II CRC(EFS: P=.04, HR 1.92, 95% CI 1.02-3.60; OS: P=.02, HR 4.44, 95% CI 1.16-17.03), and in patients with stage III CRC (EFS: P=.04, HR 1.68, 95% CI 1.01-2.80; OS: P=.001, HR 4.04, 95% CI 1.73-9.46). L554F and V640L polymorphisms had no prognostic value. The S128R polymorphism is a constitutional factor associated with a higher risk of relapse and death in patients treated for CRC. This polymorphism detection may permit better selection of patients suitable for adjuvant therapy, especially among those with stage II disease.

Assessment of baseline clinical predictive factors of response to cetuximab-irinotecan in patients with irinotecan-refractory metastatic colorectal cancer.

OBJECTIVE: To identify easily available predictive factors of response to cetuximab-irinotecan in patients with irinotecan-refractory metastatic colorectal cancer. METHODS: Retrospective analysis of patients treated with cetuximab (400 mg/m(2) in week 1, 250 mg/m(2) in subsequent weeks) plus irinotecan (180 mg/m(2) every 2 weeks). We assessed demographic data, prior response to chemotherapy, number of metastatic sites, disease and metastatic disease durations, irinotecan-free interval and tumoral immunohistochemical epidermal growth factor receptor status. RESULTS: We analyzed 311 patients. Objective response rate under cetuximab-irinotecan was 26%. In univariate analysis, prior response to irinotecan, presence of only 1 metastatic site, disease duration, metastatic disease duration and irinotecan-free interval equal or above median (24, 18 and 1.8 months, respectively) were predictive of response to cetuximab-irinotecan. Multivariate analysis confirmed independent predictive value of prior response to irinotecan, number of metastatic sites and disease duration. CONCLUSION: Prior response to irinotecan, number of metastatic sites and disease duration may contribute to better select patients suitable for cetuximab-irinotecan therapy.

Protein and lipid analysis of detergent-resistant membranes isolated from bovine kidney.

Detergent-resistant membranes (DRM) were prepared from bovine kidney cortex. The criterion used to test their purification was the increase in the activity of a GPI membrane-anchored protein, the alkaline phosphatase. Its association with specific proteins and lipids was tested. Two successive Triton X-100 treatments followed by purification on sucrose gradient at 4 degrees C were necessary to obtain DRM with a maximum of alkaline phosphatase activity and a typical protein pattern. A third Triton treatment did not alter this DRM composition. Among the enriched protein, we identified, by mass spectrometry, a microsomal dipeptidase, which was GPI membrane-anchored. Protein-kinase activities, mainly serine-kinase, were enriched during the DRM purification. Using the typical FTIR olefinic =C-H bands of the acyl chains, a global decrease in the unsaturation level of DRM lipids was observed as compared with total membranes. Three main phospholipids were identified in DRM. Their fatty acid compositions were determined by gas chromatography and compared with those of total membranes. The most enriched saturated fatty acid was palmitic acid (+44% for phosphatidylethanolamine, +52% for phosphatidylcholine and +49% for sphingomyelin), agreeing with a selection of specific phospholipids among the saturated ones during the DRM purification.