Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial

Abstract

Summary Background Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer. Methods Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II–III (≥T2 and/or ≥N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m²) plus docetaxel (75 mg/m²) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203. Findings Of the 120 patients initially enrolled, one withdrew after signing consent and one patient’s baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline, DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group. At 3 months, 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs (p=0·054). The most common grade 3–4 toxicities were infection (five of 60 patients in the zoledronic acid group and six of 59 in the control group) and thrombosis (five of 60 in the zoledronic acid and two of 59 in the control group). There was one documented case of osteonecrosis in the zoledronic acid group. Interpretation Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery. Our study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through effects on DTCs. Funding Novartis Pharmaceuticals and Pfi zer Inc.

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

“…Based on the rationale that ZA may interfere with stimulatory interactions between the bone microenvironment and tumor cells and on observations of direct antiproliferative effects against tumor cells (3)(4)(5), the drug was also evaluated for the treatment of primary and metastatic bone tumors. As expected, ZA demonstrated clinical antitumor activity in multiple myeloma (6) and osteosarcoma (7) and against (micro)metastatic bone and/or bone marrow disease in solid tumors (8,9). In preclinical studies in Ewing sarcoma, ZA was found to inhibit in vivo tumor growth both alone and in synergism with chemotherapies (4,5), and initial clinical reports suggest that ZA combined with chemotherapy may be effective in refractory disease (10).…”

“…ZA has attracted recent interest as a non-cytotoxic anticancer drug and is under clinical investigation for use in various diseases, including primary bone tumors (3,4,(7)(8)(9). 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.…”

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.…”

Parathyroid hormone-related protein expression, in combination with nodal status, predicts bone metastasis and prognosis of breast cancer patients

“…Bisphosphonate is able to protect against resorption of the bone by downregulating the function of osteoclasts (29), preventing cancer cell activation by reducing cytokine release from the bone marrow and resulting in protection against skeletal bone events (30). Recent studies have also demonstrated the possible impact of bisphosphonates in protecting against bone metastasis in breast cancer patients (31). Experimental evidence shows that humanized monoclonal antibody against PTHrP suppresses osteolytic bone metastasis of human breast cancer cells (32).…”