Primary tumor location predicts poor clinical outcome with cetuximab in RAS wild-type metastatic colorectal cancer

Abstract

BackgroundIn metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer.MethodsGenotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure.ResultsA total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death.ConclusionsIn RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer.

PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer

“…Contrary to the findings by several studies [24][25][26][27][28]37], the PREMIUM study did not find a significantly longer PFS among patients with a left-sided colon primary tumor (including rectal cancers) compared to another primary tumor location. We observed only a trend towards (p = 0.15) better PFS in patients with left-sided colon primary tumor location (in a univariate analysis).…”

Aloperine inhibits proliferation, migration and invasion and induces apoptosis by blocking the Ras signaling pathway in human breast cancer cells

“…At present, it is believed that the occurrence of human tumor is the result of multiple gene mutations that control the proliferation, differentiation and apoptosis of normal cells, and these mutations include the activation of the oncogenes and the inactivation of the anti-oncogenes. It has been found that mutation or activation of Ras gene and abnormal over-expression of Ras protein exist in about 30% human tumors ( 37 , 38 ). Therefore, research on the regulation of Ras signal transduction pathway plays an important role in the design of antitumor drugs targeting the cellular signal transduction pathway ( 39 ).…”

Colorectal Cancer: Genetic Abnormalities, Tumor Progression, Tumor Heterogeneity, Clonal Evolution and Tumor-Initiating Cells

“…A more recent meta-analysis of six trials comparing the therapeutic effect of chemotherapy plus EGFR antibody therapy, compared to chemotherapy alone, showed a significant benefit for chemotherapy plus EGFR therapy in patients with left-sided tumors, compared to no significant benefit for those with right-sided tumors [ 239 ]. In RAS-wild-type colon cancer treated with cetuximab as a salvage treatment, right-colon primary was associated with poorer survival outcomes that left colon and rectal cancer [ 240 ]. Taieb and coworkers performed a phase III randomized trial to determine the prognostic and predictive value of primary tumor location according to BRAF, RAS and MSI status in patients with stage III colon cancer receiving adjuvant treatment with FOLFOX, with or without cetuximab, in stage III colorectal patients categorized according to primary tumor site (proximal or distal).…”