Abstract
BackgroundRecent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3′untranslated region (3′UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin) +/− cetuximab.MethodsThe feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314).ResultsLCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) (P = 0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P = 0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P = 0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16).ConclusionsThe LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1st line Nordic FLOX +/− cetuximab.
Highlights
Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 30untranslated region (30UTR) of KRAS and clinical outcome in metastatic colorectal cancer patients receiving cetuximab
In this work we have studied if the let-7 complementary site 6 (LCS6) variant allele was associated with clinical outcome in NORDICVII, a randomized phase III trial where Nordic FLOX was given with or without cetuximab as first-line treatment in metastatic colorectal cancer (mCRC) [10]
LCS6 status and KRAS mutation status were available from 471 patients, of which 183 (39%) were KRAS mutated
Summary
Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 30untranslated region (30UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The prognosis for patients with metastatic colorectal cancer (mCRC) included in clinical trials has increased from approximately 12 months with 5-fluorouracil monotherapy to 20–24 months with the addition of newer chemotherapeutic agents and targeted drugs [1]. In the recent NORDIC-VII study, we did not find an improved outcome of adding cetuximab to first-line oxaliplatin-based chemotherapy in KRAS wild-type patients [10]. It was recently reported that copy number aberrations (CNA) may provide additional information to mutation status and their use may potentially further improve the selection of mCRC patients for EGFR-targeted therapy [13]
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