Two open-label, single arm, non-randomized phase II studies of irinotecan for the treatment of metastatic breast cancer in patients with increased copy number of the topoisomerase I gene

Abstract

Background Treatment options in metastatic breast cancer are limited. New therapies preferable with predictive biomarkers are needed. The aim of these trials was to investigate if gene copy number of the topoisomerase 1 gene was predictive of response to the topoisomerase inhibitor irinotecan. Methods Two open-label, single-arm phase II studies including HER2 positive and negative patients were conducted. Patients were eligible for inclusion if the primary tumor or a metastatic lesion had increased expression of the topoisomerase 1 gene defined as a TOP1 gene copy number of ≥4 or a TOP1/CEN20 ratio of ≥2. Patients were treated with irinotecan +/− trastuzumab weekly for 4 weeks following 2 weeks break, until progression or unacceptable toxicities. Evaluation scans were performed every 6 weeks. Primary endpoint was clinical benefit rate defined as the fraction of patients with stable disease for ≥4 months. Results The pre-planned number of 18 patients in each trial was not reached, thus no formal statistical analysis could be performed. Nine patients with HER2 negative disease and three patients with HER2 positive disease were included. Three patients obtained a partial remission and two patients had SD. Conclusions The trials did not include the planned number of patients. No association between gene copy number of the topoisomerase 1 gene and response to irinotecan could be proved, however a clinical benefit was found in 5/12 patients and in 2/3 patients with HER2 positive disease. This could call for further investigation of the drug in the metastatic setting, especially in HER2 positive BC. Trial registration Eudract registration numbers 2012–002348-26 and 2012–002347-23 . Registration date August 20th 2012.

A Retrospective Analysis of the Effect of Irinotecan-Based Regimens in Patients With Metastatic Breast Cancer Previously Treated With Anthracyclines and Taxanes

“…Given the dose-limiting toxicity of irinotecan and its inactivity in a large proportion of patients, it is more desirable to identify a biomarker to predict irinotecan’s activity. Some researchers have explored whether the increased topoisomerase 1 gene copy number or UGT1A1 polymorphisms can predict the response of the topoisomerase inhibitor irinotecan ( 3 , 12 ). Due to the limited number of cases, no significant correlation has been found to be related to irinotecan’s response.…”

“…A few clinical trials have shown that irinotecan had modest systemic activity in some patients previously treated with anthracyclines and taxanes. The objective response rate (ORR) of patients with MBC who received irinotecan monotherapy was 5%–23%, while the ORR of patients with MBC who received a combination of irinotecan and various chemotherapy drugs ranged from 14%–64%, usually including patients who had been heavily pretreated ( 5 , 12 , 13 ). Irinotecan has not been regarded as a routine treatment option for patients with MBC, and the outcome of subsequent therapy with irinotecan in patients with MBC was not clear.…”