No abstract

Purpose Oesophageal squamous cell carcinoma (ESCC) has a poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy followed by irinotecan or taxane monotherapy, but resistance is common and new treatments are needed. Approximately 20% of ESCCs carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous trials show that while anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high EGFR expression, combining anti-EGFR therapies with platinum fluoropyrimidine chemotherapies is not effective, and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC. Methods The effects of EGFR CNG on fluoropyrimidine/platinum chemotherapy sensitivity in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed. Results EGFR CNG in gastroesophageal cancer patients was associated with improved overall survival following fluoropyrimidine/platinum chemotherapy. However, co-administration of gefitinib and oxaliplatin or cisplatin was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic. Conclusion Gefitinib/platinum co-administration demonstrated antagonism suggesting a possible explanation for the lack of benefit from addition of anti-EGFR therapies to fluoropyrimidine/platinum chemotherapy in trials. Gefitinib/docetaxel co-administration demonstrated synergy suggesting taxanes could be the most effective cytotoxic partner for anti-EGFR therapies in EGFR CNG-positive ESCC, but careful consideration of drug scheduling is required.

BACKGROUND Oesophageal squamous cell carcinoma (ESCC) has high mortality and poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy (PBC) followed by second-line irinotecan or taxane monotherapy, but resistance is common and new therapeutic approaches are needed. Approximately 20% of ESCC tumours carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous analysis of randomised clinical trials shows that anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high expression by Immunohistochemistry (IHC). However, responses are often of short duration indicating that combining anti-EGFR therapy with other agents is required to optimise the benefit from anti-EGFR therapies even in biomarker selected patients. Randomised clinical trials have not shown benefit from the addition of anti-EGFR therapies to platinum fluoropyrimidine chemotherapy and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC. METHODS The effects of EGFR CNG on sensitivity to PBC in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed. RESULTS EGFR CNG in gastroesophageal cancer patients was associated with better overall survival following platinum-based chemotherapy. Drug combination studies showed that co-administration of gefitinib and platinum-based cytotoxics was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic. CONCLUSIONS Gefitinib/docetaxel co-administration demonstrated synergy and taxanes are likely to provide the most effective cytotoxic chemotherapy partner for anti-EGFR therapies in EGFR CNG-positive advanced ESCC. Combination of gefitinib and platinum-based cytotoxics was antagonistic suggesting anti-EGFR therapies might reduce anti-cancer effects of chemotherapy which could provide a key explanation for the lack of benefit for the addition of anti-EGFR therapies to PBC in randomised clinical trials. Our data suggest that the combination of docetaxel with anti-EGFR therapies, with careful consideration of dosing schedules, should be evaluated in advanced EGFR CNG-positive and/or IHC high EGFR expressing ESCC.