Discussion
cancers, CRC, breast cancer, toxicity, tumours, arrest, human cancers
METASTATIC COLORECTAL CANCER, CANCERS, BREAST CANCER, TUMOURS, DNA DAMAGE, ARREST
This study showed that the administration of pulse high-dose AZD8931 160 mg bd was well tolerated being associated with a relatively low toxicity profile. However, the best overall response rate among the patients treated with AZD8931 160 mg bd was 25% (all PRs) and therefore it was not shown to be improved when compared to the assumed historical control rate of 35%.Preclinical studies show that EGFR inhibition enhances responses to DNA-interactive chemotherapies by a variety of mechanisms including inhibition of DNA repair [A potentially important factor in the lack of success in these combinations may be the cell cycle effects of TKI treatment of cancers. Gefitinib induces a cell cycle arrest in G1 phase with chronic administration and this may inhibit the effects of agents which act preferentially in S phase such as irinotecan. For example, in a preclinical study in breast cancer of the effects of gefitinib, short-term administration was associated with enhanced DNA damage when combined with DNA-interactive chemotherapies, whereas chronic exposure of cells for 48 h resulted in G1 arrest and diminished efficacy of the combination [From the limited and preliminary data in this study, there is no evidence that AZD8931 improves the rate of response when compared with historical control data. However, these preliminary data suggest that giving AZD8931 in combination with FOLFIRI is feasible and tolerable. In the FOCUS4-D study of metastatic colorectal cancer, patients with tumours that were stable or responding to cytotoxic chemotherapy received single agent AZD8931 40 mg bd continuously, and there was no PFS benefit of AZD8931 compared with placebo [Although there have been many studies investigating inhibition of EGFR in CRC little is known regarding the dynamics of the EGFR pathway in human cancers. We have previously demonstrated that the combined use of HER2-HER3 dimer imaging (applied to FFPE pathological specimens) and conventional mutation analyses can identify in a predictive manner the small subclass of metastatic CRC patients (15%) who will have better prognosis following chemotherapy/cetuximab treatment [In this study, we observed both increase and decrease of HER 2-3 dimer formation in patients after treatment with AZD8931, correlating to findings in cell line data. Our group have previously reported in breast cancer HER2-3 dimer quantification in formalin-fixed paraffin-embedded (FFPE) tumours predicted metastatic relapse post-surgery that was independent of HER2 expression [In the literature, there is a presumption that pan-HER tyrosine kinase inhibitors reduce the formation of homologous/heterodimer of HER receptors [