title: Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial.
abstract: 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 (> or = T2 and/or > 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/m(2)) plus docetaxel (75 mg/m(2)) 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Novartis Pharmaceuticals and Pfizer Inc.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA. aftr@wustl.edu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Aft
authors.forename: Michael
authors.initials: M
authors.lastname: Naughton
authors.forename: Kathryn
authors.initials: K
authors.lastname: Trinkaus
authors.forename: Mark
authors.initials: M
authors.lastname: Watson
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ylagan
authors.forename: Mariana
authors.initials: M
authors.lastname: Chavez-MacGregor
authors.forename: Jing
authors.initials: J
authors.lastname: Zhai
authors.forename: Sacha
authors.initials: S
authors.lastname: Kuo
authors.forename: William
authors.initials: W
authors.lastname: Shannon
authors.forename: Kathryn
authors.initials: K
authors.lastname: Diemer
authors.forename: Virginia
authors.initials: V
authors.lastname: Herrmann
authors.forename: Jill
authors.initials: J
authors.lastname: Dietz
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Matthew
authors.initials: M
authors.lastname: Ellis
authors.forename: Peter
authors.initials: P
authors.lastname: Weiss
authors.forename: Timothy
authors.initials: T
authors.lastname: Eberlein
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ma
authors.forename: Paula M
authors.initials: PM
authors.lastname: Fracasso
authors.forename: Imran
authors.initials: I
authors.lastname: Zoberi
authors.forename: Marie
authors.initials: M
authors.lastname: Taylor
authors.forename: William
authors.initials: W
authors.lastname: Gillanders
authors.forename: Timothy
authors.initials: T
authors.lastname: Pluard
authors.forename: Joanne
authors.initials: J
authors.lastname: Mortimer
authors.forename: Katherine
authors.initials: K
authors.lastname: Weilbaecher
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009360:Neoplastic Cells, Circulating / Q000187:drug effects*; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid