title: Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer--a randomized biomarker pilot study.
abstract: OBJECTIVE
  To investigate the short-term biologic effects of neoadjuvant chemotherapy +/- zoledronic acid (ZOL) in invasive breast cancer.
  
  
  METHODS
  Forty patients were randomized to receive a single 4 mg infusion of ZOL 24 hours after the first cycle of FE100C chemotherapy, or chemotherapy alone. Randomization was stratified for tumor stage, ER, HER2, and menopausal status. All patients had repeat breast core biopsy at day 5 (D5) ± day 21 (D21). Effects on apoptotic index, proliferation (Ki67), growth index, surrogate serum markers of angiogenesis (VEGF), and serum reproductive hormones within the TGFβ family (activin-A, TGFβ1, inhibin-A, and follistatin) were evaluated and compared.
  
  
  RESULTS
  Baseline clinicopathologic characteristics were well balanced. Cell growth index (increased apoptosis and reduced proliferation) fell at D5 in both groups but recovered more rapidly with chemotherapy + ZOL compared with chemotherapy alone by D21 (P = 0.006). At D5, a greater reduction in serum VEGF occurred with chemotherapy + ZOL compared with chemotherapy: median percentage change -23.8% [interquartile range (IQR): -32.9 to -15.8] versus -8.4% (IQR: -27.3 to +8.9; P = 0.02), but these effects were lost by D21. Postmenopausal women showed a decrease in follistatin levels from baseline in the chemotherapy + ZOL group at D5 and D21, compared with chemotherapy alone (P(interaction) = 0.051).
  
  
  CONCLUSIONS
  In this pilot study, short-term changes in biomarkers suggest potentially relevant interactions between tumor biology, chemotherapy, modification of the bone microenvironment, and the endocrine status of the host. Larger studies with more frequent dosing of zoledronic acid are needed to assess these complex interactions more thoroughly.
authors.affiliation: Academic Unit of Clinical Oncology, CR-UK/YCR Sheffield Cancer Research Centre, Weston Park Hospital, Sheffield, United Kingdom. m.c.winter@sheffield.ac.uk
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Winter
authors.forename: Caroline
authors.initials: C
authors.lastname: Wilson
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Syddall
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.forename: Alyson
authors.initials: A
authors.lastname: Evans
authors.forename: Christine E
authors.initials: CE
authors.lastname: Ingram
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Jolley
authors.forename: Matthew Q
authors.initials: MQ
authors.lastname: Hatton
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Freeman
authors.forename: Stefano
authors.initials: S
authors.lastname: Mori
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage; D004164:Diphosphonates / Q000008:administration & dosage; D000077143:Docetaxel; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D038681:Follistatin / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007265:Inhibins / Q000097:blood; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D010865:Pilot Projects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000097:blood; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D000077211:Zoledronic Acid
chemical_list: D003520:Cyclophosphamide; D004164:Diphosphonates; D000077143:Docetaxel; D015251:Epirubicin; D005472:Fluorouracil; D038681:Follistatin; D007093:Imidazoles; D007265:Inhibins; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D043823:Taxoids; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D000077211:Zoledronic Acid