EGFR, HER2 and Kras as predictive factors for cetuximab sensitivity in colorectal cancer

Abstract

4021 Background: In colorectal cancer, biological mechanisms underlying response or resistance to cetuximab, a monoclonal antibody against the extracellular domain of the EGFR are not defined. Small retrospective studies suggested that EGFR increased gene copy number measured by fluorescence in situ hybridization (FISH) or presence of KRAS mutations were associated with cetuximab response or resistance, respectively. This study aimed to identify biological predictors for sensitivity/resistance to cetuximab treatment in colorectal cancer. We also compared biomarker results in primary tumors and corresponding metastases. Methods: We analyzed EGFR (IHC, FISH), HER2 (FISH), and KRAS (mutation) in paraffin embedded tumor blocks from 85 colorectal cancer patients treated with cetuximab. For FISH analyses, a positive result was defined according to criteria described in breast (Wolff et al. J Clin Oncol 2007), lung (Cappuzzo et al. JNCI 2005) and colorectal cancer (Moroni et al. Lancet Oncology 2005). EGFR, HER2 and PIK3CA mutation analyses are ongoing. Results: EGFR FISH positive patients (N=41), defined as ratio EGFR/nucleus =3, had a significantly higher RR (29.3% versus 6.8%, p=0.007) and TTP (6.6 versus 3.7 months, p=0.053) than EGFR FISH negative (N=44). No difference for clinical endpoints was observed using other scoring systems. EGFR expression assessed by IHC was not associated with any clinical end-point. Increased HER2 gene copy number was associated with shorter TTP (p=0.09) and survival (p=0.03). Compared to patients with wild type KRAS (N=49), KRAS mutation carriers (N=32) had a significantly lower RR (6.3% versus 26.5%, p= 0.02), shorter TTP (3.7 versus 6.3 months, p=0.07) and shorter survival (8.3 versus 10.8 months, p=0.2). In 22 patients with available primary and metastatic tumor tissue, there was no difference between these sites for EGFR FISH, HER2 FISH and KRAS results. Conclusions: This study, the largest biomarker analysis in colorectal cancer patients treated with cetuximab, shows a significant benefit in response and TTP for EGFR FISH positive patients. KRAS mutation analysis identifies a group of patients with the lowest chance to benefit from the therapy. Increased HER2 gene copy number predicts early escape from cetuximab therapy. No significant financial relationships to disclose.