Tamoxifen Versus Anastrozole, Alone or in Combination With Zoledronic Acid

• - To compare overall and recurrence-free survival between tamoxifen and anastrozole
• - To compare bone loss reduction/prevention between zoledronic acid and no zoledronic acid

• For the assessment of the recurrence free survival (RFS) patients receiving tamoxifen will be compared to patients receiving anastrozole and patients receiving zoledronate will be compared to controls, respectively. [ Time Frame: 28.05.2008 ] [ Designated as safety issue: No ]
• For the assessment of the overall survival (OS) patients receiving tamoxifen will be compared to patients receiving anastrozole and patients receiving zoledronate will be compared to controls, respectively. [ Time Frame: 28.05.2008 ] [ Designated as safety issue: No ]
• The objective is to assess whether zoledronate added to standard adjuvant therapy can decrease or even prevent bone loss in patients treated with hormonal blockade combined with an anti-estrogen or aromatase inhibitor (AI). [ Time Frame: 28.05.2008 ] [ Designated as safety issue: No ]
• Adverse and severe adverse events will be listed for all therapy subgroups "anastrozole / zoledronate" (AZ), "anastrozole / zoledronate control" (AC), "tamoxifen / zoledronate" (TZ), "tamoxifen / zoledronate control" (TC). [ Time Frame: 28.05.2008 ] [ Designated as safety issue: Yes ]

• - To compare overall and recurrence-free survival between zoledronic acid and no zoledronic acid given with tamoxifen or anastrozole
• - To compare bone metastasis development with zoledronic acid vs no zoledronic acid

The primary objective is, first, the comparison of tamoxifen and anastrozole and, second, the comparison of zoledronate added to standard adjuvant therapy with controls according to disease-free survival (DFS) in premenopausal patients with non-metastatic breast cancer treated with tamoxifen or anastrozole. To assess whether zoledronate added to standard adjuvant therapy can decrease or even prevent bone loss in patients treated with hormonal blockade combined with an antiestrogen or aromatase inhibitor.

The trial is conducted as an open multi-center phase III study, in a two-factorial study design and according to GCP guidelines. Patients will be randomly assigned to a total of 4 study groups in a 1:1:1:1 assignment ratio. Several stratification criteria will be used in order to ensure balanced distribution of known risk factors.

A total of 1.803 patients will be enrolled in 4 arms. Patients will either be treated with anastrozole (1mg daily for 3 years) or tamoxifen (20mg daily for 3 years), and will additionally receive either zoledronate (8mg q4 weeks for 3 years) or no zoledronate (arm A: Nolvadex alone; arm B: Nolvadex plus zoledronate; arm C: Arimidex alone; arm D: Arimidex plus zoledronate).

Zoledronate will be administered by i.v. injection at a dose of 4 mg/month for the treatment period of 3 years. Five BMD measurements will be performed in a subgroup of patients (404 patients, enrolled in 3 centres).

• Drug: tamoxifen
  20 mg/d
  Other Name: Nolvadex
• Drug: anastrozole
  1 mg/d
  Other Name: Arimidex
• Drug: zoledronic acid
  4 mg q6m
  Other Name: Zoledronate, Zometa

• Active Comparator: AZ (Arimidex+Zoledronat)
  Study Drugs Arimidex (Anastrozole), Zometa (Zoledronate)
  Interventions:

  • Drug: anastrozole
  • Drug: zoledronic acid
• Active Comparator: TZ (Tamoxifen+Zoledronate)
  Study Drugs Nolvadex (Tamoxifen), Zometa (Zoledronate)
  Interventions:

  • Drug: tamoxifen
  • Drug: zoledronic acid
• Active Comparator: AC (Arimidex Control)
  Study Drug Arimidex (Anastrozole)
  Intervention: Drug: anastrozole
• Active Comparator: TC (Tamoxifen Control)
  Study Drug Nolvadex (Tamoxifen)
  Intervention: Drug: tamoxifen

• Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011 Jul;12(7):631-41. Epub 2011 Jun 5.
• Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radisic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rücklinger E, Greil R; ABCSG-12 Trial Investigators; Marth C. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009 Feb 12;360(7):679-91.
• Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kässmann H, Piswanger-Sölkner JC, Seifert M, Ploner F, Menzel C, Dubsky P, Fitzal F, Bjelic-Radisic V, Steger G, Greil R, Marth C, Kubista E, Samonigg H, Wohlmuth P, Mittlböck M, Jakesz R; Austrian Breast and Colorectal Cancer Study Group (ABCSG). Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol. 2008 Sep;9(9):840-9. Epub 2008 Aug 19.

Inclusion Criteria:

• Premenopausal, hormone receptor-positive patient
• Histologically verified (minimally) invasive breast cancer, local radical treatment
• 0-9 involved axillary lymph nodes (≥ 10 histologically examined nodes)
• Tumor stage: pT1b-3, yT0 or yT1a

Exclusion Criteria:

• T1a, T4d, yT4; M1
• Previous breast tumor irradiation
• Previous or concurrent chemotherapy (except for preoperative chemotherapy)
• Serum creatinine > 1.5 x UNL or creatinine clearance < 60 ml/min

• AstraZeneca
• Novartis Pharmaceuticals