Matrix metalloproteinase-related gene polymorphisms to predict efficacy of regorafenib in patients with metastatic colorectal cancer.

Abstract

692 Background: Matrix metalloproteinases (MMPs) are proteolytic enzyme for extracellular matrix and involved in regulation of tumor environment including angiogenesis. MMP-2 and MMP-9 were reported to be prognostic marker of anti-angiogenic therapy. We tested whether genetic polymorphisms in the MMP family predict clinical outcomes in patients with refractory mCRC receiving regorafenib. Methods: 228 patients with mCRC receiving regorafenib were included in this pooled analysis combining two different cohorts from Italy and Japan (median age, 62 years; male, 51.5%; median follow-up time, 26.2 months; Italian/Japanese, 150/79). Six single nucleotide polymorphisms (SNPs) of five genes in MMPs ( MMP2, MMP9, MMP14, TIMP2, CD44) were analyzed by PCR-based direct sequencing. Correlations between candidate SNPs and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank test. Disease control was compared by Fisher’s exact test. Multivariable analyses were conducted using the Cox proportional hazard regression model. Results: In univariate analysis, patients carrying the G/G variant in MMP2 rs1477017 had a significantly shorter OS compared to those with any A allele (4.4 vs. 7.8 months, HR 1.85, 95%CI: 1.13-3.03, P= 0.011). The findings were confirmed in multivariable analysis (HR 1.84, 95%CI: 1.11-3.07, P= 0.019). Although the frequency of the T/T variant in MMP9 rs2274755 was considerably low, the T/T variant was associated with shorter PFS and OS compared to any G allele in univariate analysis (1.7 vs. 2.1 months, HR 2.53, 95%CI: 1.17-5.46, P= 0.011; 3.9 vs. 7.6 months, HR 2.51, 95%CI: 1.11-5.72, P= 0.021) and multivariable analysis (HR 3.04, P= 0.009; HR 5.20, P< 0.001). No significant interaction was shown between the SNPs and cohorts. Disease control was significantly infrequent in patients carrying the T/T variant in MMP9 rs2274755 ( P= 0.046). Conclusions: Our data suggest that MMPs network potentially mediates tumor angiogenesis responding to regorafenib. The MMP2 and MMP9 SNPs may predict efficacy of regorafenib in patients with refractory mCRC. However, this preliminary finding warrants further validation.