The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response – exploratory evidence for direct anti-tumor activity in breast cancer.
Authors: Winter MC , Thorpe HC , Burkinshaw R , Beevers SJ , Coleman RE 
Published: December 2010

Abstract
Abstract #5101
Background: Sequence-dependent synergistic anti-tumor effects of chemotherapy (CT) and zoledronic acid (Z) in bone and soft tissues have been demonstrated in pre-clinical studies. It has also recently been reported that the addition of zoledronic acid to adjuvant endocrine therapy significantly increases disease-free survival in pre-menopausal with hormone-receptor positive breast cancer, and these beneficial effects were not confined to bone(1). The AZURE trial recruited 3360 women with stage II/III breast cancer to determine whether treatment with zoledronic acid in addition to (neo)adjuvant therapy improves disease related outcomes. We have performed a retrospective exploratory evaluation of the subgroup of AZURE patients who received neoadjuvant CT to determine if the addition of Z to CT influences pathological response in the primary tumor.&#x2028; Methods: Eligible patients received neoadjuvant CT according to local practice and were randomised to receive Z 4mg i.v. (3-4 weekly for 6 months in the neoadjuvant period) in addition to CT, or no additional treatment. The primary surrogate endpoint for response was pathologically assessed residual invasive tumor size (RITS,mm) at surgery. Secondary endpoints included pathological complete response rate, number of positive axillary nodes and percentage of patients requiring mastectomy. Following independent central review of surgical pathology reports, outcome differences between the groups were assessed using multivariate analysis, adjusting for T stage, ER and PR status, CT type (anthracycline/taxane), treatment duration, and menopausal status.&#x2028; Results: 205 (6.1%) patients received neoadjuvant CT (104 CT, 101 CT+Z). Baseline characteristics and treatments were similar, and median number of CT cycles and treatment duration were the same in both groups. Z had no negative effect on chemotherapy dose delivery or serious adverse event reporting. Median RITS was 30mm (IQR 7.5-60) in the CT group and 20.5mm (IQR 7-38.5) in the CT+Z group. In a multivariate analysis (of 171 patients with complete data), zoledronic acid, ER status and treatment duration were independent significant factors for RITS. The adjusted mean RITS in CT and CT+Z groups were 42.4mm and 28.2mm respectively, giving a difference in means of 14.1mm (95%CI: 5.4mm to 22.9mm; p=0.002). The pathological complete response rate (breast and axilla) was 5.8% in the CT arm and 10.9% in the CT+Z arm (p=0.033). Median number of positive lymph nodes following chemotherapy was 3 (IQR 0-7) in the CT group and 2 (IQR 0-5) in the CT+Z group (p=0.629). The proportion of patients requiring mastectomy in the CT and CT+Z arms were 77.9% and 65.3% respectively.&#x2028; Conclusion: These data suggest a possible direct anti-tumor effect of Z in combination with neoadjuvant CT and warrants formal evaluation in prospective studies.&#x2028; 1. Gnant, M et al. J Clin Onc 26:2008 (May 20 suppl; abstr LBA4).
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5101.