Biomarker alterations with metronomic use of low-dose zoledronic acid for breast cancer patients with bone metastases and potential clinical significance

Zoledronic acid has direct and indirect antitumor effects. However, the optimal regimen for breast cancer patients remains to be determined. This study aimed to compare biomarker changes between a weekly low dose (metronomic arm) and a conventional dosage of zoledronic acid (conventional arm), and to explore correlations between biomarkers and progression-free survival (PFS). Sixty breast cancer patients with bone metastases were randomized to receive either zoledronic acid 1 mg IV weekly for 4 doses or a single dose of zoledronic acid 4 mg IV. Administration of other treatments was delayed for 1 month. Serial blood samples were collected on days 1, 15, 29, and at 3 months. Serum VEGF alteration was the primary endpoint. Compared to the conventional arm, the metronomic arm resulted in a significantly greater reduction in serum levels of VEGF and N-telopeptide of type I collagen (NTx) over time during the first month of treatment. Serum CA 15-3 level stabilized over time in the metronomic arm, but increased in the conventional arm. Independent prognostic factors for PFS included chemotherapy received (HR, 8.042; P = 0.000), estrogen receptor status (HR, 2.837; P = 0.020), VEGF levels at 3 months after intervention (HR, 2.026; P = 0.045), and baseline NTx (HR, 1.051; P = 0.001). Metronomic low-dose zoledronic acid is more effective than the conventional regimen and generates sustained reductions in circulating VEGF and NTx levels, as well as stabilization of serum CA 15-3 levels (ClinicalTrials.gov number, NCT00524849).