Denosumab as an add-on Neoadjuvant Treatment (GeparX)
Denosumab as an add-on Neoadjuvant Treatment (GeparX)
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.
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.
Inclusion criteria:

 -  Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by
 core biopsy. Fine-needle aspiration from the breast lesion alone is not sufficient.
 Incisional biopsy or axillary clearance is not allowed. In case of bilateral cancer,
 the investigator has to decide prospectively which side will be evaluated for the
 primary endpoint.

 -  Tumor lesion in the breast with a palpable size of 2 cm or a sonographical size of 1
 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably
 by sonography. In case tumor isn't measurable by sonography, then MRI or mammography
 is sufficient. In case of inflammatory disease, the extent of inflammation can be used
 as measurable lesion.

 -  Patients must have stage cT1c - cT4a-d disease.

 -  In patients with multifocal or multicentric breast cancer, the largest lesion should
 be measured.

 -  Centrally confirmed ER-negative and PR-negative status. Central pathology includes
 also assessment of HER2, Ki-67, TIL and RANK status on core biopsy. ER/PR negative is
 defined as ≤1% stained cells and HER2-positive is defined as IHC 3+ or in-situ
 hybridization (ISH) and according to ASCO-CAP guidelines as of 2013. LPBC (lymphocyte
 predominant breast cancer) is defined as more than 50% stromal tumour infiltrating
 lymphocytes. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy
 has therefore to be sent to the GBG central pathology laboratory prior to
 randomization.

 Exclusion criteria:

 -  Patients with stages cT1a, cT1b, or any M1.

 -  Prior chemotherapy for any malignancy.

 -  Prior radiation therapy for breast cancer.

 -  History of disease with influence on bone metabolism, such as osteoporosis, Paget's
 disease of bone, primary hyperparathyroidism requiring treatment at the time of
 randomization or considered likely to become necessary within the subsequent six
 months.

 -  Use of bisphosphonates or denosumab within the past 1 year.

 -  Significant dental/oral disease, including prior history or current evidence of
 osteonecrosis/ osteomyelitis of the jaw, active dental or jaw condition which requires
 oral surgery, non-healed dental/oral surgery, planned invasive dental procedure for
 the course of the study.

 -  Previous malignant disease being disease-free for less than 5 years (except CIS of the
 cervix and non-melanomatous skin cancer).

 -  Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease,
 angina pectoris requiring antianginal medication, previous history of myocardial
 infarction, evidence of transmural infarction on ECG, uncontrolled or poorly
 controlled arterial hypertension (i.e. BP >140 / 90 mm Hg under treatment with two
 antihypertensive drugs), rhythm abnormalities requiring permanent treatment,
 clinically significant valvular heart disease.

 -  Currently active infection.

 -  Incomplete wound healing.

 -  Definite contraindications for the use of corticosteroids.