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.
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