Denosumab as an add-on Neoadjuvant Treatment (GeparX)
Condition: Breast Cancer Female NOS; Tubular Breast Cancer Stage II; Mucinous Breast Cancer Stage II; Invasive Ductal Breast Cancer; HER2 Positive Breast Cancer; Inflammatory Breast Cancer; Tubular Breast Cancer Stage III
MeSH terms: Breast Neoplasms; Inflammatory Breast Neoplasms; Carcinoma, Ductal, Breast
Study type: Interventional
Phase: Phase 2

Summary: 
      Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and
      inhibits metastatic progression in multiple mouse models.

      In a retrospective analysis it could be demonstrated that elevated expression of RANK was
      found in 14.5% of patients overall, with a significant predominance in patients with
      hormone-receptor-negative disease. Expression of RANK was associated with a higher
      pathological complete response rate but with a shorter disease-free and overall survival. The
      ABCSG-18 study showed that adjuvant denosumab reduces clinical fractures, improves bone
      health, and can be administered without added toxicity.

      It appears therefore reasonable to test denosumab, a clinically available antibody against
      RANKL in patients with hormone-receptor-negative primary breast cancer as an adjunct to
      neoadjuvant chemotherapy for its ability to increase pCR rate and improve outcome in relation
      to the expression of RANK.
    

Detailed description: 
      RANK ligand (RANKL), a key factor for bone remodeling and metastasis, is crucial for the
      development of mouse mammary glands during pregnancy. RANKL functions as a major paracrine
      effector of the mitogenic action of progesterone in mouse and human mammary epithelium via
      its receptor RANK and has a role in ovarian hormone-dependent expansion and regenerative
      potential of mammary stem cells. Pharmacologic inhibition of RANKL attenuates the development
      of mammary carcinoma and inhibits metastatic progression in multiple mouse models.

      In a retrospective analysis of 601 patients treated in the GeparTrio study with chemotherapy
      (TAC) it could be demonstrated that elevated expression of RANK (immunohistochemical score >
      8.5 using the N-1H8 antibody by Amgen) was found in 14.5% of patients overall, with a
      significant predominance in patients with hormone-receptor-negative disease (33.7% vs 6.4%
      tumors positive for RANK). Expression of RANK was associated with a higher pathological
      complete response rate (pCR) (23.0% vs 12.6%) but with a shorter disease-free and overall
      survival. The ABCSG-18 study showed that adjuvant denosumab reduces clinical fractures,
      improves bone health, and can be administered without added toxicity. Moreover denosumab
      improves disease-free survival in postmenopausal woman with hormone receptor positive breast
      cancer.

      It appears therefore reasonable to test denosumab, a clinically available antibody against
      RANKL in patients with hormone-receptor-negative primary breast cancer as an adjunct to
      neoadjuvant chemotherapy for its ability to increase pCR rate and improve outcome in relation
      to the expression of RANK.
    

Intervention name(s): Denosumab; nab-Paclitaxel; Epirubicin; Cyclophosphamide; Carboplatin; Trastuzumab; Pertuzumab
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Denosumab 120 mg every 4 weeks for 6 cycles; nab-paclitaxel 125 mg/m² weekly for 12 weeks or at day 1,8 q22 for 4 cycles (12 weeks); Epirubicin 90 mg/m² every 2 or 3 weeks for 4 times; Cyclophosphamide 600 mg/m² every 2 or 3 weeks for 4 times; Carboplatin AUC 2 weekly in parallel to nab-Paclitaxel; Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all chemotherapy cycles; Pertuzumab 420 (840) mg every 3 weeks simultaneously to all chemotherapy cycles
Other intervention name(s): Human monoclonal IgG2 antibody; Abraxane; Farmorubicin; Endoxan; Diamminplatin(II)-cyclobutan-1,1-dicarboxylat; Herceptin; Perjeta
Intervention MeSH terms: Denosumab; Paclitaxel; Cyclophosphamide; Carboplatin; Trastuzumab; Epirubicin; Pertuzumab
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment