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Title: The role of female hormones and oestrogen receptor status in influencing the anti-tumour effects of zoledronic acid in early breast cancer
Author: Wilson, Caroline
ISNI:       0000 0004 5357 9677
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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The AZURE trial was the first adjuvant breast cancer trial to report a novel interaction between the anti-tumour efficacy of zoledronic acid (ZOL) and menopausal status of patients. It showed a significant reduction in disease recurrence events in and outside of bone, in those clinically > 5 years postmenopausal, compared to an increase in non-bone recurrences in all others. Data from neoadjuvant studies had also shown an enhanced anti-tumour effect of ZOL in oestrogen receptor negative (ER-ve) tumours. Three main questions arose from these data and were the focus of this thesis; firstly how can postmenopausal status be accurately defined in patients?, secondly, which reproductive hormone is interacting with the drug?, and thirdly, what are the molecular mechanisms? Follicle stimulating hormone (FSH), oestradiol and inhibin A were evaluated from 806 patients recruited to AZURE. With all 3 hormones in postmenopausal range, ZOL treatment resulted in an improved invasive disease free survival compared to control (HR 0.809, 95%CI 0.537-1.22). No single hormone was predictive of an interaction with ZOL. A low pretreatment FSH and oestradiol were borderline significant for a shorter time to bone and distant recurrence respectively. Evaluation of serum, pre- and post neoadjuvant FEC100chemotherapy +/- ZOL in 40 patients recruited to the ANZAC trial, identified changes in the tumour suppressor activin (?) and tumour promoter follistatin (?) in postmenopausal patients and those with ER-ve primary tumours. The direct effect of ZOL on these proteins in breast cancer cell lines in vitro and in vivo, showed a reduction in follistatin secretion from ER-ve cell lines only, which was diminished in the presence of inhibin A. Moreover, ZOL and inhibin A altered levels of these proteins in the bone microenvironment, with a reduction in bone follistatin levels after ZOL only in ovariectomised mice. In addition, inhibin A decreased bone activin levels. These data suggest that pretreatment evaluation of reproductive hormones can assist in selection of postmenopausal patients for adjuvant ZOL, and breast cancer cells may preferentially home to premenopausal bone (low FSH), preferring distant non-bone sites in postmenopausal women (low oestradiol). ZOL has novel direct and indirect effects on activin and follistatin levels in the tumour and bone microenvironment that is influenced by ER status of tumor cells and presence of inhibin A.
Supervisor: Holen, Ingunn ; Coleman, Robert Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available