0:KRASmutation and loss of phosphatase and tensin (PTEN); 1: Either noKRASmutation or normal PTEN expression; 2: NoKRASmutation and normal PTEN expression. to cetuximab was found in 22 patients withKRASmutation and in 39 patients withoutKRASmutation, with a response rate of 4.5% and 46.1% respectively (P= 0.001), a shorter median progression-free survival (PFS) time of 14 1.3 wk and 32 2.5 wk respectively (P< 0.001), a median overall survival (OS) time of 11 1.2 mo and 19 1.8 mo respectively (P< 0.001), as well as in 24 patients with negative PTEN expression and in 37 patients with positive PTEN expression respectively (P< 0.001), with a responsive rate of 4.2% and 48.6% respectively, a shorter median PFS survival time of 17 2.0 wk and 28 1.9 wk respectively (P= 0.07), and a median OS time of 11 1.3 mo and 18 1.9 mo respectively (P= 0.004). Combined KRAS mutation and PTEN expression analysis showed that this PFS and OS time of patients with two favorable prognostic factors were longer than S63845 those of patients with one favorable prognostic factor or no favorable prognostic factor (P< 0.001). CONCLUSION:KRASmutation and PTEN protein expression are significantly correlated with the response rate and survival time of Chinese mCRC patients treated with cetuximab. Keywords:Cetuximab, Metastatic colorectal cancer,KRASmutation, Phosphatase and tensin protein expression == INTRODUCTION == The incidence of colorectal cancer (CRC) has been increasing in the past decades and CRC is the third-leading cause of cancer-related deaths in China. During the past few years, several new biological brokers have been evaluated in metastatic colorectal cancer (mCRC) with a remarkable anti-mCRC activity. Epidermal growth factor receptor (EGFR), one of the most promising targets, can activate the proliferation and prolong the survival time of cancer cells through the Ras/Raf/mitogen-activated protein kinase (MEK)/EPH receptor B2 (ERK) pathway or the phosphoinositide-3-kinase (PI3K)/PTEN/AKT pathway[1]. Cetuximab (Erbitux, Merck KgaA, Darmstadt, Germany), a chimeric mouse/human antibody against the extracellular domain name of EGFR, has a single-agent activity in mCRC refractory to irinotecan, oxaliplatin and fluoropyrimidines, and restores chemosensitivity in irinotecan-refractory mCRC patients[2-4]. However, only a small number of patients can benefit from cetuximab. The response rate to the combined cetuximab and irinotecan is about 23%[2]. Immunohistochemical studies showed that EGFR protein expression in CRC patients is not a useful predictor for the response to cetuximab[5,6]. Recent reports are available around the EGFR pathways, such asKRAS/BRAF/MAPKs, and on their potential correlation with cetuximab activity.KRASsomatic mutation occurs in approximately 40% of CRC patients. The unfavorable predictive value ofKRASmutation Rabbit polyclonal to FADD has been confirmed in CRYSTAL S63845 study of first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without cetuximab, demonstrating that only the patients withKRASwild-type mutations benefit from cetuximab treatment[7-9]. Increasing interest in anti-EGFR therapy has been focused on another EGFR pathway, and PI3K/AKT/PTEN. PTEN encodes phosphatase with phosphatidylinositol-3, 4, 5-triphosphate (PIP-3) produced by the activity of PI3K as its major substrate. Loss of PTEN function S63845 increases PIP-3 concentration, and subsequent AKT hyperphosphorylation stimulates the proliferation of cancer cells[10]. It was reported that PTEN protein expression andKRASmutation can S63845 predict the outcome of mCRC patients treated with cetuximab plus irinotecan, and unfavorable PTEN expression in mCRC patients can predict the resistance to cetuximab plus irinotecan. Combined PTEN expression andKRASmutational analysis can help to identify a subgroup of mCRC patients who have a greater chance of benefiting from EGFR inhibition[11]. KRASand PTEN are the important molecular determinants of the EGFR downstream signal pathway and play an important role in anti-EGFR therapy in Western countries. However, little is known.