EGFR polymorphism and KRAS mutational status as predictors of resistance to anti-EGFR therapy in advanced colorectal cancer (ACRC): A GEMCAD study

Abstract

4060 Background: Single nucleotide polymorphism (SNP) in codon R497K of EGFR by reducing EGFR activity has been associated to resistance to anti-EGFR monoclonal antibodies in ACRC (Carcereny, ASCO2008). Methods: We retrospectively investigated the role of EGFR R497K and KRAS mutational status in primary CRC or metastases, in predicting response rate (RR), progression free survival (PFS) and overall survival (OS) of cetuximab or panitumumab in second or third line therapy in patients (pts) with ACRC. EGFR R497K was detected by real-time PCR using the TaqMan technology and KRAS mutation status in codons 12/13 was determined by sequencing. CT scans were done every 6–8 weeks (w) until progressive disease. Results: A total of 117 pts with available tissue out of 168 pts treated with anti-EGFR therapy in 6 Spanish Institutions, were analysed for EGFR R497K and KRAS mutational status. There were no differences in RR (18.8 vs.16.8%), PFS (13.2 vs. 12 w) and OS (31 vs. 28 w) between the whole and the selected cohort. We found no significant differences on RR (9/59;15.2 vs. 9/52; 17.3%), PFS (13.5 vs. 13.2 w) and OS (33 vs. 26.8 w) according to EGFR R497K (GG vs. GA/AA). Pts with wild-type (WT) KRAS had better response (20.7% vs. 8.1%;p=0.07) and PFS (14.4 vs. 11.7 w; p=0.006) compared with mutant KRAS. Interestingly, a significant increment on RR (30 vs. 0%, p=0.003), PFS (14.4 vs. 7.4 w, p=0.002) and OS (34.1 vs. 20 w, p=0.03) was observed only in those patients with WT KRAS and >1x upper limit of normal (ULN) lactate dehydrogenase (LDH) levels compared with mutant KRAS, but these differences were not found in pts with WT KRAS and <1xULN levels of LDH: [RR (14 vs. 14%, p=NS), PFS (14.4 vs. 13.1 w, p=NS) and OS (31 vs. 31 w; p=NS)]. Conclusions: EGFR R497K is not a predictive marker of efficacy to EGFR-inhibitors. Our study suggest that pts with WT KRAS and >1xULN levels of LDH, have major benefit to anti-EGFR therapy in second-third line therapy. No significant financial relationships to disclose.