title: Biomarker alterations with metronomic use of low-dose zoledronic acid for breast cancer patients with bone metastases and potential clinical significance.
abstract: 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).
authors.affiliation: Department of Medical Oncology, Fudan University Cancer Hospital, Shanghai, 200032, China.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xu
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.forename: Joseph
authors.initials: J
authors.lastname: Ragaz
authors.forename: Haiyi
authors.initials: H
authors.lastname: Guo
authors.forename: Jiong
authors.initials: J
authors.lastname: Wu
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Shao
authors.forename: Ji
authors.initials: J
authors.lastname: Zhu
authors.forename: Xiaomao
authors.initials: X
authors.lastname: Guo
authors.forename: Jiayi
authors.initials: J
authors.lastname: Chen
authors.forename: Beiling
authors.initials: B
authors.lastname: Zhu
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Wang
authors.forename: Xichun
authors.initials: X
authors.lastname: Hu
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002681:China; D024042:Collagen Type I / Q000097:blood; D004164:Diphosphonates / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D018396:Mucin-1 / Q000097:blood; D010455:Peptides / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D007093:Imidazoles; D018396:Mucin-1; D010455:Peptides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C052929:collagen type I trimeric cross-linked peptide; D000077211:Zoledronic Acid