The frequency of the LCS6 variant allele in a Norwegian cohort was similar in healthy controls, individuals with polyps, and CRC patients. These results do not support the LCS6 variant allele as a candidate risk factor for development of colorectal polyps or CRC. The frequency of the LCS6 variant allele varies across geographic populations, with European populations exhibiting the variant allele most frequently
[24, 31, 32, 39, 40]. The frequency of the LCS6 variant allele was 16% in 535 genotyped patients in the NORDIC-VII cohort, which is consistent with a recent study which analyzed 734 CRC cases from the Netherlands
. Interestingly, the frequency of the variant allele in mCRC patients in the NORDIC-VII cohort is significantly lower than in the CRC patients from the KAM cohort (P = 0.02). A possible explanation could be that the NORDIC-VII cohort consists of a more heterogeneous population from the Nordic countries compared to the KAM cohort, which consists of a homogenous Norwegian population. Another possible explanation could be that CRC patients with the LCS6 wild-type have a greater tendency to metastasize.
A recently published study found that early-stage CRC cases with the LCS6 variant had improved survival
. Another study reported that the LCS6 variant was associated with a reduced risk of mortality in late-stage CRC
. Numerically increased median PFS and OS were found in patients with the LCS6 variant allele when compared to LCS6 wild-type carriers, but the differences were not statistically significant at the 5% level and we cannot conclude that mCRC patients with the variant allele belong to a favorable prognostic group. Furthermore, the difference in treatment response of adding cetuximab was larger, albeit not statistically significant, in patients with the LCS6 variant. There was a non-significant trend of increased response rate for patients with the LCS6 variant allele when treated with 5-fluorouracil/oxaliplatin and cetuximab compared to 5-fluorouracil/oxaliplatin alone. The trend of numerically increased PFS, OS and response rate was also observed independent of KRAS mutation status and in KRAS and BRAF wild-type patients, but none of the findings proved statistically significant. Thus, any potential predictive effect of the LCS6 variant allele is likely to be too small to be demonstrated with the patient sample available from the NORDIC-VII study. The NORDIC-VII cohort has limitations for studies of biomarkers predictive of cetuximab effect, as cetuximab did not add significant benefit to the Nordic FLOX regimen. Also, the number of patients with the LCS6 variant allele is relatively small, and the analyses of LCS6 as a predictive marker thus have low power.
Zhang et al. demonstrated that of 67 KRAS wild-type mCRC patients, there was a higher response rate and a trend of longer PFS and OS in patients with LCS6 variant allele (N=12) compared to patients with LCS6 wild-type (N=55) when treated with cetuximab monotherapy
. Contrary, another study on 121 BRAF wild-type mCRC patients who underwent salvage cetuximab – irinotecan therapy, of which 58 were KRAS mutated, reported that patients with LCS6 variant allele (N=34) had shorter PFS and OS compared to LCS6 wild-type (N=87)
. Similar results were reported by Winder et al. who found mCRC patients with mutant KRAS and LCS6 variant allele to have shorter PFS when treated with irinotecan and cetuximab
. The conflicting results in these studies suggest that the chemotherapy backbone may play a role, and that the LCS6 variant allele have different predictive values in mCRC patients treated with cetuximab alone or in combination with 5-fluorouracil/oxaliplatin than in patients treated with cetuximab in combination with irinotecan
Ragusa et al. demonstrated that cetuximab treatment induced miRNA transcriptome changes in drug-sensitive and drug-resistant CRC cell lines
. The set of differentially expressed miRNAs in the two cell lines (one sensitive and the other resistant) was almost entirely not overlapping. These data suggest that different responses to cetuximab are associated with different sets of miRNAs and thereby different molecular signaling. Interestingly, 67% of the differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had previously been reported to be involved in the cetuximab pathway and CRC. Based on their results, they suggest downregulation of let-7b and let-7e and the upregulation of miR-17* to be associated with cetuximab resistance
. Although these miRNAs were generated from cell studies, they illustrate that miRNAs may be promising predictive markers of cetuximab response to be further studied in mCRC patients.
We have only investigated one miRNA binding site polymorphism in this study, representing a small piece in a large puzzle of polymorphisms in the miRNA pathway. Future research on miRNA pathway polymorphisms as potential prognostic and/or predictive markers in mCRC should ideally include an integrated approach using bioinformatical tools combined with biological data to get a comprehensive understanding of the role and functions of miRNA polymorphisms and cetuximab response.