Background
CRC, toxicity, cancer, tumours, mCRC
METASTATIC COLORECTAL CANCER, TUMOURS, CANCER, HER2 GENE AMPLIFICATION, ARREST
Monoclonal antibodies targeting EGFR, either when combined with conventional cytotoxic chemotherapy, or as single agents, produce significant survival prolongation in patients with RAS and BRAF wild type metastatic colorectal cancer (mCRC) [A factor limiting the efficacy of agents targeting the EGFR pathway is the compensatory upregulation of HER2 (Erb-B2) and HER3 (Erb-B3), which can activate bypass pathways and hence mediate resistance. It has been suggested primary or acquired resistance to antibodies targeting EGFR could either be due to HER2 gene amplification or heregulin up-regulation (a HER3 ligand), leading to persistent extracellular signal-regulated kinase signalling and resistance to cetuximab [Both oxaliplatin and irinotecan have shown synergistic activity with AZD8931 in a variety of preclinical models (AstraZeneca, unpublished data). In this trial AZD8931 was assessed in combination with FOLFIRI (irinotecan/5-FU) chemotherapy. This was based on results of Phase III studies in CRC, indicating that cetuximab confers a survival advantage with this regimen [There is extensive evidence that antibodies targeting EGFR have activity only in tumours expressing wild-type RAS [An important issue in determining the efficacy of EGFR inhibition in CRC has been the schedule used. Continuous treatment with TKIs such as gefitinib and erlotinib can result in G1 arrest, which may reduce the effectiveness of agents that are S phase specific such as irinotecan [The expression level of HER family members is unreliable as a predictive marker for targeted therapies in cancer [Förster resonance energy transfer (FRET) assays using fluorescence lifetime imaging microscopy (FLIM) have been developed to analyse the interaction between pairs of molecules [Previous work in our group has shown HER2:HER3 crosstalk was required for endogenous feedback HER3 phosphorylation upon cetuximab treatment in metastatic colorectal cancer cells, and co-treatment with cetuximab and lapatinib can limit this effect [This trial examined the toxicity and efficacy profile of pulsed AZD8931 in combination with chemotherapy in first-line treatment of RAS WT metastatic colorectal cancer patients and explored potential biomarkers that may predict response to therapy.