The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer

Abstract

BACKGROUND:Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. METHODS: In total, 205 patients received neoadjuvant CT ± ZOL (CT þ ZOL, n ¼ 102; CT, n ¼ 103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n ¼ 195), outcome differences between groups were assessed adjusting for potential response modifiers. RESULTS: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT þ ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5 -20.4 mm; P ¼ 0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT þ ZOL group (P ¼ 0.146). There was no difference in axillary nodal involvement (P ¼ 0.6315). CONCLUSION: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.

Zoledronic acid negatively affects the expansion of in vitro activated human NK cells and their cytolytic interactions with Ewing sarcoma cells

“…Promising features of ZA include the observed anticancer synergies between bisphosphonates and cytotoxic chemotherapies (4,30), the favorable toxicity profile, and the proposed effect on the tumor-promoting bone/bone marrow microenvironment to prevent dissemination. However, drug therapy alone is unlikely to completely eliminate residual disease in patients with high-risk disseminated tumors.…”

Final 5‐year results of Z‐FAST trial

“…2,3,[13][14][15][16][17] Recently, preclinical and clinical data have also demonstrated anticancer effects of bisphosphonates in breast and other cancer types. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] The prevention and treatment of bone loss with upfront (initiated simultaneously with letrozole) versus delayed (initiated with a decrease in T score to <À2 or occurrence of clinical nontraumatic fracture) zoledronic acid in early breast cancer patients receiving letrozole was evaluated in 3 similarly designed, geographically diverse studies (Z-FAST; ZO-FAST; E-ZO-FAST) and in the similarly-designed N03CC study. 15 Interim (<36 months follow-up) results from the former 3 studies indicate that upfront rather than delayed-start zoledronic acid is significantly more effective in preventing bone loss.…”

Follow-Up Study of Survival of Patients with Advanced Cancer in a Hospice Setting

“…Lastly, palliative treatments are necessary for advanced cancer patients to prolong survival and improve life quality. For example, zoledronic acid in combination with chemotherapy can reduce skeleton related events in non-small cell lung cancer patients (Coleman et al, 2010). Percutaneous placement of metal stents to patients with malignant biliary obstruction were beneficial with regard to survival time (O'Brien et al, 1995).…”