Plain English Summary
Background and study aims
The development of breast cancer is a complex process that results in different types of tumors requiring different treatments. Drug treatment before surgery can have a clinical benefit by reducing tumour growth. The aim of this study is to assess the effectiveness of four drugs in patients awaiting surgery for breast cancer: tamoxifen and raloxifene in premenopausal women, and exemestane and celecoxib in postmenopausal women.
Who can participate?
Women aged 18 or over with breast cancer who are awaiting surgery
What does the study involved?
A biopsy (sample) of the cancer and a blood sample are taken from all participants. Premenopausal women are randomly allocated to be treated with either low-dose tamoxifen or raloxifene or placebo (dummy drug), while postmenopausal women are randomly allocated to be treated with either exemestane or celecoxib or placebo. Tumor growth is assessed at the start of the study and after 6 weeks of drug treatment.
What are the possible benefits and risks of participating?
This study will provide important information for the development of breast cancer treatment. For the short period of treatment no serious adverse effects are expected. For the same reason a clinical benefit is not expected, although a small shrinkage of the tumor might be possible. The main aim is to slow down tumor growth.
Where is the study run from?
European Institute of Oncology (Italy)
When is the study starting and how long is it expected to run for?
February 2004 to March 2009
Who is funding the study?
European Institute of Oncology (Italy)
Who is the main contact?
Dr Bernardo Bonanni
Trial website
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
IEO S162/303
Study information
Scientific title
Pre-surgical effects of serms, anti-COX-2 and aromatase inhibitors in breast cancer patients: a phase II randomized controlled trial
Acronym
Study hypothesis
The primary objective of the trial is to assess antiproliferative activity of the different drugs compared with placebo.
Ethics approval
European Institute of Oncology Ethics Committee [Comitato Etico dell'Istituto Europeo di Oncologia], 02/10/2003, ref: CC/13/04
Study design
Presurgical randomized phase II single-centre trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Estrogen receptor positive breast cancer
Intervention
Breast cancer patients are randomized based on menopausal status to Raloxifene or Tamoxifen or placebo, to Exemestane or Celecoxib or placebo.
Subjects with histologically-confirmed ER positive primary breast cancer will be randomly assigned in a 2:2:1 ratio to receive treatment or matching placebo for a total period of 6 weeks prior to surgery. Specifically, 125 premenopausal women will be randomized to either low-dose tamoxifen (10 mg/week) or raloxifene 60 mg/day or placebo, while 125 postmenopausal women will be allocated to exemestane (25 mg/day) or celecoxib (800 mg/day) or placebo.
Raloxifene: Evista® 60 mg/tablet. Daily administration.
Tamoxifen: Nomafen® 10 mg/tablet. Weekly administration.
Exemestane (Aromasin®): 25 mg/tablet. Daily administration.
Celecoxib: (Celebrex®) 200 mg/tablet. Two tablets will be administered twice a day
Placebo formulation of size-matched tablets will be manufactured by an external pharmaceutical service.
At randomization each subject will receive 1 box with 8 weekly bottles of the drug and will be instructed to take 1 tablet per day. However, in order to maintain the blinding of a weekly dose of tamoxifen in the premenopausal group, each subject will receive also 8 blisters with 1 tablet each. She will be asked to take 2 tablets the first day of the week, 1 from the bottle and 1 from the blister, and then proceed with 1 tablet/day for the rest of the week. Blisters will contain placebo or tamoxifen accordingly.
A regards the post menopausal group, given the unnecessary use of 3 extra placebo tablets, double-blinding will be maintained for exemestane and placebo (1 tablet/day) only, while the celecoxib arm will be open (2 tablets twice a day).
Intervention type
Drug
Phase
Not Applicable
Drug names
Tamoxifen, raloxifene, exemestane, celecoxib
Primary outcome measure
The primary endpoint is the change (tru-cut biopsy at baseline, and surgical specimen at surgery) in the percentage of neoplastic cells expressing the proliferation antigen Ki-67.
Biopsy and surgical specimens are fixed in 10% neutral-buffered formalin for 6-8 hours before being embedded in paraffin. Sections (4-micron thick) are cut and stained with hematoxylin and eosin. Consecutive serial sections are used for immunohistochemical determinations. Expression Ki-67 will be determined by immunohistochemistry. Briefly, de-waxed tumor sections are pretreated with 3% hydrogen peroxide for 5 minutes to block endogenous peroxidase activity and then treated with a solution of 0.001 M EDTA (pH 8.0) at 99°C for 20 minutes to retrieve antigens. The tumor sections are then incubated with primary mouse monoclonal antibodies Ki-67 (clone Mib-1, 1:200 dilution).
Primary endpoints will be detected at baseline and after 6 weeks of treatment (at biopsy and at surgery)
Secondary outcome measures
Secondary endpoints: Change in ER and PgR expression and apoptosis as measured by Caspase-3. Change in markers of hemostasis and inflammation: fibrinogen, antithrombin III (AT III), plasminogen activator inhibitor-I (PAI-I), ultrasensitive C-reactive protein (US-CRP). Change in circulating hormones (estradiol, estrone, estrone-sulphate, and sex hormone binding globulin). DNA will be extracted from circulating lymphocytes and some genetic polymorphisms related to hormone and drug metabolism will be investigated.
Expression of ER, PgR, Her2/neu, and Caspase-3 will be determined by immunohistochemistry. The tumor sections are then incubated with primary mouse monoclonal antibodies to ER (clone 1D5, 1:100 dilution), PgR (clone 1A6, 1:800 dilution), or with rabbit polyclonal antibody to the Her2/neu protein (1:3200 dilution), and to Caspase-3 (clone CPP32).
Routine hematology and biochemistry assessments will be performed at the central laboratory of the institute.
IGF-I levels will be determined from plasma by a chemiluminescent immunometric assay; antithrombin-III will determined by a kinetic colorimetric method. Serum concentration of US-CRP, SHBG and IGFBP-3 will be measured by a two-site chemiluminescent enzyme immunometric assay. Serum C-telopeptide and osteocalcin will be determined with a electrochemiluminescent immunometric assay. Serum estradiol and estrone-sulphate will be determined by the use of commercially available ultrasensitive radioimmunoassay kits.
Genomic DNA will be extracted from frozen whole blood samples stabilized with EDTA by the use of a commercially available kit (QIAamp DNA Blood kit) purchased from Qiagen S.p.A, Milan, Italy).The evaluation of the CYP2D6 single nucleotide polymorphisms will be performed utilizing a semiautomated instrument (Light Cycler Roche) that allows more rapid assay procedures and guarantees a good product specificity. Specific primers and probes are labeled with fluorescent dyes and light emission monitored to detect genotyping.
Secondary endpoints will be detected at baseline and after 6 weeks of treatment (at biopsy and at surgery)
Overall trial start date
17/02/2004
Overall trial end date
31/03/2009
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Female, aged at least 18 years old, no upper age limit
2. Performance status = 0 (SWOG)
3. Histologically-confirmed ER+ primary breast cancer candidated for conservative surgery
4. Stage T1-2, N0-1, M0 or women with larger tumors who refuse chemo and/or endocrine therapy before surgery
5. No previous treatment for breast cancer
6. Provision of written informed consent
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
250 subjects
Participant exclusion criteria
1. Previous treatment for breast cancer including chemotherapy and endocrine therapy
2. Patients eligible to neoadjuvant chemo and/or endocrine therapy
3. Evidence of previous superficial or deep venous thrombosis or other thrombo-embolic events of relevance (pulmonary embolism, stroke, etc)
4. Current anti-coagulant therapy
5. Moderate to severe alteration in hematologic profile, hemostasis, renal and hepatic metabolism
6. Clinically active peptic ulcer or gastroenteric disease
7. Severe retinal disease
8. Severe endometriosis (grade III-IV) or other proliferative disorders of the endometrium
9. Clinically active neurologic or psychiatric disease
10. Other medical contraindications as judged by the investigator
11. Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or cervical cancer in situ
12. Pregnancy or current breast feeding (women of child-bearing potential must have a negative pregnancy test within 7 days before the start of study treatment)
Recruitment start date
17/02/2004
Recruitment end date
31/03/2009
Locations
Countries of recruitment
Italy
Trial participating centre
European Institute of Oncology
Milano
20141
Italy
Sponsor information
Organisation
European Institute of Oncology [Fondazione Istituto Europeo di Oncologia (FIEO)] (Italy)
Sponsor details
Via Ramusio
1
Milano
20141
Italy
Sponsor type
Research organisation
Website
Funders
Funder type
Research organisation
Funder name
European Institute of Oncology Foundation [FIEO] (Italy)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list