부산대학교 도서관

4061 Background: Recent studies have found K-ras mutation status predicts response to EGFR inhibitors in mCRC. An in vitro study demonstrated let-7 microRNA family can regulate RAS expression by binding to the 3'UTR of RAS gene. Chin et al found a SNP in a let-7 microRNA complementary site (LCS) in the K-ras 3' UTR increases cancer risk in NSCLC. We tested the hypothesis whether this SNP may be associated with clinical outcome in 130 mCRC patients enrolled in IMCL-0144 trial and in 186 pts enrolled in EPIC trial independent of K-Ras mutation status in the tumor.Methods: K-ras lcs 6 SNP was tested in 130 mCRC patients enrolled in IMC-0144 phase II clinical trial (single agent cetuximab) and in 186 mCRC patients enrolled in a second line phase III trial of cetuximab plus irinotecan versus irinotecan alone (EPIC). Genomic DNA was extracted from dissected formalin fixed paraffin embedded tumor tissue and K-ras mutation status and the polymorphism were analyzed using direct sequencing and PCR-RFLP technique.Results: The G harboring allele frequency in K-ras lcs6 was 8% in IMC-0144 and 11% in EPIC. K-ras lcs6 polymorphism was significantly associated with tumor response in patients with wild type K-ras in IMC-0144. The 12 pts harboring a G allele (TG+GG) had a 42% partial response (PR) rate compared to 55 pts with TT genotype with only 9% PR.(p=0.02, Fisher's-exact test). However, pts with TT genotype enrolled in EPIC treated with CPT-11 and cetuximab with mutant K-ras had a significantly better PFS of 12 weeks (95% CI 6.4-18) compared to those harboring the a G allele with median PFS of 6.4 weeks (95% 5.7-7) (p=0.037. log-rank test). There was no association between this polymorphism and clinical outcome in patients with wild type K-ras enrolled in EPIC. In a multivariate analysis the polymorphism remained independently associated with PFS in EPIC.Conclusions: Our data suggest for the first time that the functional germline polymorphism in K-ras lcs6 may be a potential predictive marker in mCRC patients treated with cetuximab-based chemotherapy independent of K-ras mutation status. This finding warranted further confirmative clinical trials. [Table: see text].