Background: EGFR signaling blockade increases CCL5 expression, which attracts with tumor-infiltrating leukocytes regulating either the host-derived anti-tumor immunity or tumor progression. We tested whether genetic polymorphisms in the CCL5/CCR5 axis could predict efficacy of cetuximab (CET)-based first-line treatment in metastatic colorectal cancer (mCRC) patients (pts). Methods: Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC in the FIRE-3 study: an evaluation cohort of 244 pts receiving CET plus FOLFIRI (median age 64 yrs; median follow-up 34.1 mos); and a control cohort of 247 pts receiving bevacizumab plus FOLFIRI (median age 65 yrs; median follow-up 39.4 mos); Single nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analyzed by PCR-based direct sequencing. Results: Pts in the evaluation cohort with any CCL5 rs2280789 G allele had shorter OS compared to those with the A/A variant (19.9 vs. 33.4 mos, HR 1.56, 95%CI: 1.05–2.30, P= 0.024), which was confirmed in multivariable analysis (HR 1.64, P= 0.015). Pts carrying any CCR5 rs1799988 T allele had a trend lower response rate than those with the C/C variant (68 vs. 81%, P= 0.078). Statistically significant differences in efficacy were shown between the groups consisting SNPs and tumor location (Table). The findings were not confirmed in the control cohort. Conclusions: Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC pts receiving CET-based first-line treatment depending on tumor location.

^a left, ^b right