A synonymous EGFR polymorphism predicting responsiveness to anti-EGFR therapy in metastatic colorectal cancer patients

Abstract

Genetic factors are known to affect the efficiency of therapy with monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) in patients with metastatic colorectal cancer (mCRC). At present, the only accepted molecular marker predictive of the response to anti-EGFR mAbs is the somatic mutation of KRAS and NRAS as a marker of resistance to anti-EGFR. However, only a fraction of KRAS wild-type patients benefit from that treatment. In this study, we show that the EGFR gene polymorphism rs1050171 defines, independently of RAS mutational status, a sub-population of 11 % of patients with a better clinical outcome after anti-EGFR treatment. Median PFS for patients with the GG genotype was 10.17 months compared to 5.37 of those with AG + AA genotypes. Taken together, our findings could be used to better define CRC populations responding to anti-EGFR therapy. Further studies in larger independent cohorts are necessary to validate the present observation that a synonymous polymorphism in EGFR gene impacts on clinical responsiveness.

Synonymous EGFR variant p.Q787Q is neither prognostic nor predictive in patients with lung adenocarcinoma

“…Although we did not observe association of p.Q787Q with clinicopathological or treatment parameters, we assessed possible modes of function as previously described by Bonin et al (Bonin et al, 2015). For the proposed mechanism of changed codon usage, we found that the original CAG codon is used more often than the CAA resulting from the polymorphism (73% vs. 27%; Codon usage database).…”

“…Contrasting the data by Koh et al (2016), Bonin et al (Bonin et al, 2015) observed improved overall survival in CRC patients homozygous for p.Q787Q. This study retrospectively analyzed a colon cancer cohort comprising controls treated with chemotherapy (n 5 65) and a cohort treated with the anti-EGFR antibodies cetuximab or panitumumab (n 5 98).…”

“…This study retrospectively analyzed a colon cancer cohort comprising controls treated with chemotherapy (n 5 65) and a cohort treated with the anti-EGFR antibodies cetuximab or panitumumab (n 5 98). Additionally, Bonin et al (2015) employed Sanger sequencing, which is less sensitive than our methodology, especially with samples of low tumor content (Endris et al, 2013;Warth et al, 2012) and might contribute to different study results. Although this effect was observed in patients with colon cancer independent of RAS status who were treated with anti-EGFR antibodies, both a different biology and different treatment modalities likely account for the differences between our study and the data reported by Bonin et al (2015).…”

“…Interestingly, a recent study by Bonin et al reported, the synonymous variant of EGFR p.Q787Q (rs1050171) to predict response to anti-EGFR antibody therapy in colorectal cancer independent of RAS mutation status (Bonin et al, 2015). Progression free survival for patients who harbored the homozygous (GG) polymorphism was almost doubled compared to these with the heterozygous (AG) or homozygous (AA) polymorphism.…”

Q787Q EGFR Polymorphism as a Prognostic Factor for Lung Squamous Cell Carcinoma

“…EGFR genetic polymorphisms have been investigated for carcinogenesis in various tumors including colon cancer [11], gastric cancer [12], head and neck squamous cell carcinoma [13], biliary tract cancer [14], and cervical cancer [15]. Furthermore, EGFR genetic polymorphisms have shown a predictive value for the risk of breast cancer [16].…”