Abstract P1-11-01: ANZAC: A Randomised Neoadjuvant Biomarker Study Investigating the Anti-Tumour Activity of the Addition of Zoledronic Acid to Chemotherapy in Breast Cancer

Abstract

Background: Pre-clinical studies have demonstrated sequence-dependent synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (Z) in bone and soft tissue tumours. We have also reported that the addition of Z to neoadjuvant CT appears to improve pathological response in the surgical resection specimen. The ANZAC study aimed to investigate the short-term anti-tumour effects of neoadjuvant CT +/− Z in patients with invasive breast cancer, evaluating biological end-points including apoptosis, proliferation and angiogenesis. Methods: Forty patients were randomised to receive a single 4mg infusion of Z 24 hours after the first cycle of FE100C chemotherapy, as per the most effective schedule demonstrated pre-clinically, or CT alone (CT n=20, CT+Z n=20). Randomisation was stratified for tumour (T) stage, ER, HER2 status and menopausal status to minimise biological differences in the two treatment groups that may influence chemosensitivity. All patients had repeat breast core biopsy at Day 5 (D5) +/− Day 21 (D21). Apoptotic index (AI) and proliferation were measured on core biopsy specimens using TUNEL and Ki67 immunohistochemistry, counting a total of 2000 and 1000 tumour cells respectively. Serum VEGF was also measured at baseline prior to CT +/− Z, and on D5 and D21. Differences between the groups in change from baseline to subsequent timepoints were investigated using the Mann-Whitney U test. Results: Baseline clinico-pathological characteristics were well balanced between the two groups. For the different biological end-points, percentage change from baseline to D5 and from baseline to D21 are shown in Table 1. At D5, a greater reduction in serum VEGF occurred in patients treated with CT+Z compared to CT: median percentage change -23.8% (IQR -32.9, -15.8) vs. -8.4% (IQR -27.3, +8.9); p=0.02), but these effetcs were lost by D21. Cell turnover index fell at D5 in both groups (increased apoptosis and reduced proliferation) but recovered much more rapidly with CT+Z than CT alone by D21 to levels above baseline (p=0.006). Conclusions: No definite evidence of a direct anti-tumour effect of the addition of Z to CT was observed, but potentially relevant biological effects were seen in this small study. The clinical relevance of recovery of cell turnover by D21 with CT+Z is unclear. Studies with more frequent dosing of Z are warranted to exploit any potential anti-angiogenic effect of Z. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-01.

Direct antitumour activity of zoledronic acid: preclinical and clinical data

“…To build on the animal data, a neoadjuvant clinical trial in women with breast cancer (ANZAC, NCT00525759) randomised women to a standard chemotherapy regimen of 5-fl uorouracil, epirubicin and docetaxel plus or minus ZA administered as a one time dose the day after the fi rst cycle of chemotherapy. The correlative biomarkers examining apoptosis, proliferation and angiogenesis did not demonstrate frank evidence of an antitumour affect, although a single dose of ZA may not have been suffi cient to cause an appreciable change in the selected biomarkers [83].…”

“…Ottewell et al have observed that the administration of doxorubicin 24 h before ZA administration has sustained inhibition of tumour growth and prolonged survival in breast cancer [89]. There are clinical [83]. The neoadjuvant setting of studies like ANZAC provides a unique situation for assessing the impact of ZA on the primary tissue as seen in soft tissue and the ANZAC results highlight the importance of optimising the dose, interval and duration of ZA therapy.…”

Adjuvant therapy with bone-targeted agents

“…Significant differences in serum vascular endothelial growth factor (VEGF) levels at day 5 and rates of proliferation (Ki-67) at day 21 were seen between the two treatment groups. Further study is required to determine the clinical relevance of these observations [51 ].…”

Combined Therapies of Bone Disease with Bisphosphonates

“…AN-ZAC (Addition of Zoledronic Acid to Pre-operative Chemotherapy, NCT00525759), a randomized phase II feasibility study, aims to look at the short term biological changes in breast tumours following the addition of a single dose of zoledronic acid 24 hours after initial neo-adjuvant chemotherapy is administered to patients with invasive breast cancer [64]. As already described above, preclinical work has highlighted the potential benefit of administering zoledronic acid 24 hours after chemotherapy.…”