Association of a germ-line variant in the K-ras 3’ untranslated region with response and progression-free survival in patients with mCRC treated with single-agent cetuximab (IMCL-0144) or in combination with cetuximab (EPIC) independent of K-ras mutation status

作者：Thomas Winder, W. Zhang, Anthony B. El-Khoueiry, Daniel X. Yang, A. Pohl, Georg Lurje, Eric K. Rowinsky, Shirin Khambata‐Ford, Christiane Langer, M. Awad, Heinz‐Josef Lenz · 发表于：Journal of Clinical Oncology · 年份：2009 · DOI：10.1200/jco.2009.27.15_suppl.4061 · 被引用次数：6 · 研究领域：Lung Cancer Treatments and Mutations、Cancer Genomics and Diagnostics、Colorectal Cancer Treatments and Studies

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 sign...