Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Neovascularization, Pathologic

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Bone Density Conservation Agents

Docetaxel

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Zoledronic Acid

Diphosphonates

Patients will be treated every 3 weeks (+/- 2 days ) for 8 cycles in total. The 4 first cycles : Zometa 4 mg (in a 15 min. infusion) + doxorubicin (60 mg/m²) + cyclophosphamide (600 mg/m²). The 4 last cycles with Zometa 4 mg (in a 15 min. infusion) + docetaxel (100 mg/m²)

Patients will be treated every 3 weeks (+/- 2 days) for 8 cycles in total. The 4 first cycles : doxorubicin (60 mg/m²) combined with cyclophosphamide (600 mg/m²). The 4 last cycles with docetaxel (100 mg/m²)

4 mg (in a 15 min. infusion) every 3 weeks for a total of 8 injections

Zometa + Neoadjuvant therapy

4 injections of doxorubicin (60 mg/m²) combined with cyclophosphamide (600 mg/m²) every 3 weeks (+/- 2 days), followed by 4 injections of docetaxel (100 mg/m²) every 3 weeks (+/- 2 days)

Neoadjuvant therapy

Patrice Mathevet, Professor

Breast cancer is the leading female cancer by a very wide margin in France. Despite widespread breast cancer screening, many cases of breast cancer are discovered at a locally advanced stage. The tumoral consequences of a cancer size greater than 3 cm are: increased risk of metastasis and death and, most often, impossibility of performing breast-conserving surgery (a mastectomy is usually advisable in case of a first surgical procedure). It is increasingly recommended to treat locally advanced breast cancers with neoadjuvant chemotherapy. Very numerous studies have shown that by proceeding that way, the oncologic prognosis was not harmed and, on the contrary, it was possible to obtain sufficient tumor response to allow breast-conserving treatment in more than 60% of cases.

The use of zoledronic acid (Zometa) has an established place in the management of malignancies with a predilection for skeletal involvement (in particular metastasis). Although the main target of biphosphonates is the osteoclast, there is also preclinical data indicating that biphosphonates can have effects on cells other than osteoclasts, including tumor cells. Anti-tumor activity including inhibition of tumor cell growth and induction of tumor cell apoptosis, inhibition of tumor cell adhesion and invasion, and anti-angiogenic effects have been demonstrated. In addition several in vitro studies have shown that Zometa causes synergistic induction of breast cancer cell apoptosis when combined with clinically relevant concentrations of chemotherapy drugs such as paclitaxel and doxorubicin. Therefore testing of combinations of biphosphonates with these agents in breast cancer is of significant interest.

In the context of locally advanced breast cancers, the combination of a bisphosphonate with neoadjuvant chemotherapy appears to have an important potential: preventing possible bone metastases, but also possibly amplifying the efficacy of the chemotherapy's tumoricidal activity, both on the primary tumor and on potential metastatic localizations.

So it appears that, the use of bisphosphonates in a neoadjuvant situation presents a potentially favorable benefit-risk ratio. That is why we are proposing to perform a prospective randomized multicenter comparative study to evaluate 2 systemic neoadjuvant treatments, one with Zometa and the other without Zometa, in patients with locally advanced breast cancer. Zometa will be administered according to the usual administration procedure: one infusion every 3 weeks.

The therapeutic response will be evaluated by studying the different biological markers (circulating blood and bone marrow tumor cells, serum cell apoptosis and neoangiogenesis markers, bone resorption markers, etc.), but also by analyzing clinical, radiologic, and histologic response and by breast conservation rates. The impact of other factors that may affect therapeutic response will be taken into account: aggressivity of the tumor, presence or absence of tumor receptors, tumor stage, etc.

The purpose of the study is to show a marked benefit of treatment with Zometa in managing locally advanced breast cancers with synergistic action of the neoadjuvant chemotherapy and improvement in the laboratory parameters of tumor aggressivity. These markers will be used as surrogate markers of long term outcome.

Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancers

To assess the improvement obtained by adding Zometa treatment to neoadjuvant chemotherapy in patients with locally advanced breast cancer on concentrations of serum VEGF (neoangiogenesis marker and prognostic factor) before treatment and during surgery after neoadjuvant treatment (i.e., at about 8 months)

To assess the impact of each of the treatment arms on circulating tumor cells (CTC) present in the blood

To assess the impact of each of the treatment arms on serum markers of apoptosis,

assessment of the change in serum tumor markers by CEA, V-EGF and CA 15-3 assay

Assessment of renal failure and osteonecrosis of the jaw

To assess the impact of each of the strategies treatment arms on clinical, and radiological tumour response (maximum tumour diameter)

To assess the breast conservation rate for each of the strategies

To assess the changes in tissue biomarkers at day 90-105 (intermediate biopsy) in each of the strategies.

* measurement of IPP and ApppI (PBMCs), FPPS mRNA (PBMCs)
* FACS analysis of gamma-delta T cell subsets, measurement of IFNg, TNFa
* Measurement of gamma-delta T cells cytotoxic activity
* Injection of expanded gamma-delta T cells in NOD/SCID mice bearing patients' tumors and follow-up of animals (tumor size measurement, survival, IHC). Correlation with clinicopathological factors and clinical outcome of patients.
* RNA extraction of primary tumour biopsies before treatment and at the time of surgery for DNA microarray hybridization studies

Spots Global Cancer Trial Database for tumors markers