Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08-10 trial

Giuseppe Gullo; Alex J Eustace; Alexandra Canonici; Denis M Collins; Michael J Kennedy; Liam Grogan; Oscar Breathhnach; John McCaffrey; Maccon Keane; Michael J Martin; Rajnish Gupta; Gregory Leonard; Miriam O'Connor; Paula M Calvert; Paul Donnellan; Janice Walshe; Enda McDermott; Kathleen Scott; Andres Hernando; Imelda Parker; David W Murray; Alice C O'Farrell; Ashwini Maratha; Patrick Dicker; Mairin Rafferty; Verena Murphy; Norma O'Donovan; William M Gallagher; Bonnie Ky; Dimitrios Tryfonopoulos; Brian Moulton; Annette T Byrne; John Crown

doi:10.1177/1758835919864236

Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08-10 trial

Ther Adv Med Oncol. 2019 Jul 24:11:1758835919864236. doi: 10.1177/1758835919864236. eCollection 2019.

Authors

Giuseppe Gullo¹, Alex J Eustace², Alexandra Canonici², Denis M Collins², Michael J Kennedy³, Liam Grogan⁴, Oscar Breathhnach⁴, John McCaffrey⁵, Maccon Keane⁶, Michael J Martin⁷, Rajnish Gupta⁸, Gregory Leonard⁶, Miriam O'Connor⁹, Paula M Calvert⁹, Paul Donnellan⁶, Janice Walshe¹⁰, Enda McDermott¹⁰, Kathleen Scott¹¹, Andres Hernando¹¹, Imelda Parker¹¹, David W Murray¹², Alice C O'Farrell¹², Ashwini Maratha¹³, Patrick Dicker¹⁴, Mairin Rafferty¹³, Verena Murphy¹¹, Norma O'Donovan², William M Gallagher¹³, Bonnie Ky¹⁵, Dimitrios Tryfonopoulos¹⁰, Brian Moulton¹⁶, Annette T Byrne¹², John Crown¹⁰

Affiliations

¹ Cancer Trials Ireland (formerly All-Ireland Clinical Oncology Research Group), Dublin Ireland.
² Molecular Therapeutics for Cancer in Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
³ Department of Medical Oncology, St James Hospital, Dublin, Ireland.
⁴ Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland.
⁵ Department of Medical Oncology, Mater Hospital, Dublin, Ireland.
⁶ Department of Medical Oncology, University Hospital Galway, Galway, Ireland.
⁷ Department of Medical Oncology, Sligo University Hospital, Sligo, Ireland.
⁸ Department of Medical Oncology, University Hospital Limerick, Limerick, Ireland.
⁹ Department of Medical Oncology, University Hospital Waterford, Waterford, Ireland.
¹⁰ Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.
¹¹ Cancer Trials Ireland (formerly All Ireland Co-operative Oncology Research Group), DCU Alpha, Dublin, Ireland.
¹² Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
¹³ Oncomark Ltd, University College Dublin, Dublin, Ireland.
¹⁴ Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
¹⁵ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁶ Clinical Oncology Development Europe, Dublin, Ireland.

Abstract

Background: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients.

Methods: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m²). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF).

Results: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1-72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12-54) months in TN patients versus 38 (22-71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity.

Conclusions: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further.

Trial registration: ClinicalTrials.gov Identifier: NCT00911716.

Keywords: bevacizumab; breast cancer; cardiotoxicity biomarker; docetaxel/cyclophosphamide.

Associated data

ClinicalTrials.gov/NCT00911716