Abstract
Mutations in KRAS oncogene are recognized biomarkers that predict lack of response to anti- epidermal growth factor receptor (EGFR) antibody therapies. However, some patients with KRAS wild-type tumors still do not respond, so other downstream mutations in BRAF, PIK3CA and NRAS should be investigated. Herein we used direct sequencing to analyze mutation status for 676 patients in KRAS (codons 12, 13 and 61), BRAF (exon 11 and exon 15), PIK3CA (exon 9 and exon 20) and NRAS (codons12, 13 and 61). Clinicopathological characteristics associations were analyzed together with overall survival (OS) of metastatic colorectal cancer patients (mCRC). We found 35.9% (242/674) tumors harbored a KRAS mutation, 6.96% (47/675) harbored a BRAF mutation, 9.9% (62/625) harbored a PIK3CA mutation and 4.19% (26/621) harbored a NRAS mutation. KRAS mutation coexisted with BRAF, PIK3CA and NRAS mutation, PIK3CA exon9 mutation appeared more frequently in KRAS mutant tumors (P = 0.027) while NRAS mutation almost existed in KRAS wild-types (P<0.001). Female patients and older group harbored a higher KRAS mutation (P = 0.018 and P = 0.031, respectively); BRAF (V600E) mutation showed a higher frequency in colon cancer and poor differentiation tumors (P = 0.020 and P = 0.030, respectively); proximal tumors appeared a higher PIK3CA mutation (P<0.001) and distant metastatic tumors shared a higher NRAS mutation (P = 0.010). However, in this study no significant result was found between OS and gene mutation in mCRC group. To our knowledge, the first large-scale retrospective study on comprehensive genetic profile which associated with anti-EGFR MoAbs treatment selection in East Asian CRC population, appeared a specific genotype distribution picture, and the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients.
Highlights
Colorectal cancer (CRC) still causes majority of mortality in the world [1]
Previous clinical trials have indicated that patients who carry KRAS mutations in codons 12 and 13 are nonresponsive to the epidermal growth factor receptor (EGFR)-targeted therapy [4,5,6,7], and the wildtype status seems a response condition, some wild-type patients still fail to respond to anti-EGFR monoclonal antibody therapy [8], and the mechanism remains unclear
KRAS mutation appeared more frequently in female than male (41.3% vs 32.3%, P = 0.02), and patients older than 60 years showed a higher rate of KRAS mutation (39.9% vs 32.0%, P = 0.03)
Summary
Colorectal cancer (CRC) still causes majority of mortality in the world [1]. In mCRC tumors, exceedingly poor prognosis was observed. The monoclonal antibody (MoAb) targeted on epidermal growth factor receptor (EGFR), has been implemented in clinical practice, and emerged as an effective single agent or chemotherapy adjuvant approach for mCRC treatment [2]. These MoAbs blocks the downstream intracellular signaling of EGFR, which includes two main signaling pathways, RAS-RAF-MAPK axis, which mainly involved in cell proliferation, and the phosphatidylinositol 3-kinase (PI3K)-PTEN-AKT, key mediators of survival, and motility-invasion [3]. It is possible that mutations in the downstream effectors of the EGFR signaling pathway, such as BRAF, PIK3CA and NRAS, may induce a negative effect on the response in anti-EGFR targeted treatment [9,10,11]
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