title: Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study).
abstract: OBJECTIVE
  Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT).
  
  
  METHODS
  Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug.
  
  
  RESULTS
  This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted.
  
  
  BACKGROUND
  University Hospital Medical Information Network. UMIN000003261.
authors.affiliation: Department of Breast Surgery, Hirosaki Municipal Hospital, Aomori, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Breast and Thyroid Surgery, Kitasato University Hospital, Kanagawa, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tanino
authors.affiliation: Department of Breast and Endocrine Surgery, Gunma University Hospital, Gunma, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Horiguchi
authors.affiliation: Department of Breast and Endocrine Surgery, Toranomon Hospital, Tokyo, Japan.
authors.forename: Daishu
authors.initials: D
authors.lastname: Miura
authors.affiliation: Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Breast Oncology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Breast Surgery, Hyogo Cancer Center, Hyogo, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Takao
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Breast Oncology, Shinko Hospital, Hyogo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamagami
authors.affiliation: Department of Surgery, Konan Hospital, Hyogo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyashita
authors.affiliation: Department of Surgery, Hyogo Prefectural Nishinomiya Hospital, Hyogo, Japan.
authors.forename: Muneharu
authors.initials: M
authors.lastname: Konishi
authors.affiliation: Department of Medical Oncology, Yodogawa Christian Hospital, Osaka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shigeoka
authors.affiliation: Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Endocrine & Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Taguchi
authors.affiliation: Department of Breast Surgery, Kamiiida Daiichi General Hospital, Nagoya, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Medical Informatics, Niigata University Medical and Dental Hospital, Niigata.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Akazawa
authors.affiliation: Department of Breast Oncology, Kobe Kaisei Hospital, Hyogo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Kohno
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000627:therapeutic use; D004164:Diphosphonates / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D018734:Genes, erbB-2; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D015251:Epirubicin; D000077211:Zoledronic Acid; D003520:Cyclophosphamide; D005472:Fluorouracil