Clinical trial NCT01367288: Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancers
Official title: Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Locally Advanced Breast Cancer
Ductal Histologic Type
Without Her 2 Overexpression
Keywords: locally advanced breast cancer
neoadjuvant chemotherapy
HER2-negative breast cancer
stage IIb breast cancer
stage IIIa breast cancer
Zoledronic acid
bisphosphonate
zometa
therapeutic response
VEGF serum
tumors markers
neoangiogenesis
apoptosis
proliferation
disseminated tumors cells
gamma-delta T cells activation
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2011-06-07
Enrollment: 53
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* Women 18 years of age or older
* Absence of contraindication to treatment with Zometa: creatinine clearance greater than 30 mL/min (with Cockroft or MDRD method).
* Breast cancer (TNM IIa, IIb, IIIa) larger than 2cm in maximal diameter able to benefit from neoadjuvant chemotherapy
* Ductal or lobular histological type of the breast tumor
* WHO performance status 0-2
* Patient who understands the french language
* Covered by, or having the right to Social Security
* Signed informed consent

Exclusion Criteria:

* Breast cancers of rare histological type (other than ductal and lobular)
* Noninvasive cancer
* Multifocal tumor (more than 2 tumoral lesions or 2 tumoral lesions distant more than 2cm each other)
* T4 breast tumor
* Presence of organ, bone, or skin metastases (in the initial staging workup)
* Patient with a history of breast cancer
* Other cancer currently in treatment (except carcinoma in situ).
* Severe systemic disease potentially interfering with follow-up.
* Contraindication to injected products: known allergy to bisphosphonates, zoledronic acid or excipients, severe renal failure (creatinine clearance \< 30 mL/min with Cockroft or MDRD method).
* Women who are pregnant (positive pregnancy test) or breast-feeding, or absence of contraception in a woman who is able to become pregnant.
* Patient with evolutionary dental problems, including dental infection or infection of the jaw,intrabuccal exposure of jawbone, and history or current diagnosis of osteonecrosis of the jaw,requiring a fast chirurgical care.
* Prior treatment with bisphosphonates (either IV or oral).
* History of severe bone disease (severe osteoporosis with multiple skeletal-related events).

Primary outcomes:
measure: Decrease in serum VEGF concentration treatment
timeFrame: 8 months
Secondary outcomes:
measure: Change in CTC
timeFrame: 8 months
measure: Change in serum markers of apoptosis
timeFrame: every 3 weeks during 8 months
measure: Change in serum tumor markers
timeFrame: every 3 weeks during 8 monthes
measure: Change in tumor markers of apoptosis and proliferation
timeFrame: before treatment, at 90-105 days and at surgical excision
measure: Change in circulating gamma-delta T-cell activation
timeFrame: every 3 weeks during 8 monthes
measure: Therapeutic complications
timeFrame: at each of the chemotherapy sessions and during the final surgery
measure: Assessment of tumor response
timeFrame: at the start of treatment, at day 90-105, after 4 neoadjuvant treatment sessions, after all 8 neoadjuvant chemotherapy sessions
measure: Assessment of histological tumor response
timeFrame: during the final surgery
measure: Breast conservation rate
timeFrame: during the final surgery
measure: Assessment of the intermediate tumor response
timeFrame: at day 90-105
measure: Assessment of the markers studied in the complementary study
timeFrame: at the end of the treatment
Other outcomes:
Locations:
city: BRON Cedex
country: France
facility: Hopital Femme Mère Enfant, Service de Gynécologie
Study officials:
affiliation: Hospices Civils de Lyon
name: Patrice Mathevet, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lelievre L, Clezardin P, Magaud L, Roche L, Tubiana-Mathieu N, Tigaud JD, Topart D, Raban N, Mouret-Reynier MA, Mathevet P. Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancer With Serum VEGF as Primary Endpoint: The NEOZOL Study. Clin Breast Cancer. 2018 Dec;18(6):e1311-e1321. doi: 10.1016/j.clbc.2018.07.005. Epub 2018 Jul 10.