The LCS6 polymorphism in the binding site of let-7 microRNA to the KRAS 3'-untranslated region: its role in the efficacy of anti-EGFR-based therapy in metastatic colorectal cancer patients.

OBJECTIVE: Although KRAS mutation status has been identified as a strong predictor of response to anti-epidermal growth factor receptor (EGFR) therapies, not all wild-type patients respond. The lethal-7 (let-7) family of microRNAs regulates KRAS activity. A functional polymorphism (rs61764370) has been described in the let-7 complementary site (LCS6). We hypothesized a possible association between this KRAS let-7 LCS6 polymorphism and the response to anti-EGFR treatments in KRAS and BRAF wild-type metastatic colorectal cancer patients (mCRC).
MATERIALS AND METHODS: We studied the association of the KRAS let-7 LCS6 polymorphism with the response in 100 refractory mCRC patients treated with anti-EGFR antibodies. To assess the real effect of this polymorphism in relation to the treatment administered, we also studied this association in an independent cohort of patients treated exclusively with chemotherapy. The KRAS let-7 LCS6 polymorphism was genotyped using the BioMark system in blood and tumor DNA samples. The BRAF V600E mutation was analyzed in tumor samples.
RESULTS: The KRAS let-7 LCS6 G-allele showed a statistically significant association with nonresponse to anti-EGFR-based treatment: 31.9% of patients with the T/T genotype presented a complete or a partial response versus no patients with T/G or G/G genotypes (P=0.004). No statistically significant differences were observed in the patients who received chemotherapy only.
CONCLUSION: These data support the pharmacogenetic role of the KRAS let-7 LCS6 polymorphism in predicting the efficacy of anti-EGFR-based therapy in mCRC patients with the KRAS and the BRAF wild-type genotype.