Denosumab as an add-on Neoadjuvant Treatment (GeparX)
- Conditions
- Inflammatory Breast CancerInvasive Ductal Breast CancerHER2 Positive Breast CancerTubular Breast Cancer Stage IIBreast Cancer Female NOSTubular Breast Cancer Stage IIIMucinous Breast Cancer Stage II
- Interventions
- Registration Number
- NCT02682693
- Lead Sponsor
- German Breast Group
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 780
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description nab-paclitaxel 2 of 3 weeks nab-Paclitaxel nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel. nab-Paclitaxel weekly nab-Paclitaxel nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel. nab-Paclitaxel weekly Carboplatin nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel. Denosumab Denosumab Denosumab every 4 weeks for 6 cycles. nab-Paclitaxel weekly Pertuzumab nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel. nab-Paclitaxel weekly Trastuzumab nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel. nab-paclitaxel 2 of 3 weeks Carboplatin nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel. nab-paclitaxel 2 of 3 weeks Trastuzumab nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel. EC every two weeks or every three weeks Cyclophosphamide Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. nab-paclitaxel 2 of 3 weeks Pertuzumab nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel. EC every two weeks or every three weeks Epirubicin Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. EC every two weeks or every three weeks Trastuzumab Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. EC every two weeks or every three weeks Pertuzumab Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab.
- Primary Outcome Measures
Name Time Method pcR rates of neoadjuvant treatment with or without denosumab in addition to nab-paclitaxel and EC. 24 weeks pcR (ypT0 ypN0) rates of nab-Paclitaxel weekly for 12 weeks or 2 of 3 weeks for 12 weeks 12 weeks
- Secondary Outcome Measures
Name Time Method To test for interaction of denosumab treatment with RANK expression. 24 weeks To assess the pCR rates per arm for both randomizations separately for TNBC and HR-/HER2+ tumors. 24 weeks
Trial Locations
- Locations (1)
Charité Campus Mitte
🇩🇪Berlin, Germany