Abstract
ᅟThe overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2A gene amplification in their tumor cells.BackgroundEpirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6 % of these tumors had TOP2A copy gain and 2.0 % had loss of TOP2A when compared to adjacent normal tissue. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5 % had a ratio ≥ 1.5 consistent with gene amplification and 2.6 % had a ratio ≤ 0.8 suggesting gene deletions. Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in mCRC patients, who are refractory to treatment with oxaliplatin.Methods/DesignThe study is an open label, single arm, phase II study, investigating the efficacy of epirubicin in patients with oxaliplatin refractory mCRC and with a cancer cell TOP2A/CEN-17 ratio ≥ 1.5. TOP2A gene amplification measured by fluorescence in situ hybridization. A total of 25 evaluable patients (15 + 10 in two steps) will be included (Simon’s two-stage minimax design). Every nine weeks, response is measured by computed tomography imaging and evaluated according to RECIST 1.1. The primary end-point of the study is progression-free survival.Trial registrationEudract no. 2013-001648-79.
Highlights
Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene
Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in metastatic colorectal cancer (mCRC) patients, who are refractory to treatment with oxaliplatin
In a study of the frequency of TOP2A gene aberrations in Colorectal cancer (CRC) tissue, we found that a total of 10.5 % of the patients had a TOP2A/ CEN-17 ratio ≥ 1.5, which is compatible with TOP2A amplification [23]
Summary
Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5 % had a ratio ≥ 1.5 consistent with gene amplification and 2.6 % had a ratio ≤ 0.8 suggesting gene deletions Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in mCRC patients, who are refractory to treatment with oxaliplatin. With an expected relatively low response rate, such drugs should only be used together with companion diagnostics allowing for a pre-treatment selection of patients with the highest likelihood of obtaining benefit from the treatment This third approach is called biomarker guided repurposing and is the foundation for the present protocol, where we investigate whether epirubicin has a beneficial effect in oxaliplatin resistant mCRC patients with TOP2A gene amplification
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