EGFR gene copy number predicts response to anti‐EGFR treatment in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer

Anti‐EGFR antibodies are used for the treatment of RAS wild type metastatic colorectal cancer. We previously showed that EGFR gene copy number (GCN) predicts response to anti‐EGFR therapy in KRAS exon 2 wild type metastatic colorectal cancer. The aim of our study was to analyse the predictive role of EGFR GCN in RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. The material included 102 patients with KRAS exon 2 wild type metastatic colorectal cancer treated with anti‐EGFR ± cytotoxic therapy. Next generation sequencing was used for KRAS, NRAS, BRAF and PIK3CA gene mutation analyses. EGFR GCN was analysed by EGFR immunohistochemistry guided automated silver in situ hybridisation. Increased EGFR GCN (≥4.0) predicted a better response and prolonged progression free survival in anti‐EGFR treated RAS/BRAF/PIK3CA wild type patients (Log‐rank test, p = 0.0004). In contrast, survival of RAS/BRAF/PIK3CA wild type, EGFR GCN below 4.0 patients did not differ from patients with mutant RAS, BRAF or PIK3CA. Our study indicates that EGFR GCN predicts anti‐EGFR treatment efficacy in patients with RAS/BRAF/PIK3CA wt metastatic CRC. Tumours with EGFR GCN below 4.0 appear to be as refractory to anti‐EGFR treatment as tumours with mutation in any of the RAS/RAF/PIK3CA pathway genes. What's new? Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are an important therapeutic option for patients with RAS wild‐type metastatic colorectal cancer. However, the efficacy of anti‐EGFR therapy may be undermined by the presence of mutations in other EGFR pathway genes. According to this study, in order to better predict anti‐EGFR therapeutic response, the addition of EGFR gene copy number (GCN) analysis to the biomarker panel used today seems to be a promising approach. EGFR GCN of ≥ 4.0 predicted positive response and favourable survival in anti‐EGFR‐treated RAS/BRAF/PIK3CA wild‐type patients. No survival benefits were detected, however, when EGFR GCN was below 4.0.