Hormone Receptor Positive Malignant Neoplasm of Breast
Conditions
Keywords
neoadjuvant endocrine therapy, metformin, postmenopausal breast cancer
Brief summary
Preoperative letrozole versus letrozole with metformin in postmenopausal Estrogen receptor positive breast cancer patients Phase II multicenter 1:1 randomized clinical trial Total 208 patients Primary endpoint Clinical response rate Secondary endpoint Pathologic complete response rate Breast conserving surgery rate Percent mammographic density change Ki67(%) change after 4week medication of 2nd core needle biopsy Toxicity profile of neoadjuvant letrozole, metformin
Detailed description
To identify the anti-tumor effect of metformin with preoperatively given letrozole in postmenopausal estrogen receptor positive breast cancer patients
Interventions
DRUGMetformin
Metformin HCl 500mg(morning/evening) PO daily x 1week Metformin HCl 1000mg(morning)and 500mg(evening)PO daily x 1week Metformin HCl 1000mg(morning/evening) PO daily x 22weeks
DRUGPlacebo
Letrozole 2.5mg PO daily + Placebo 1 tablet PO 2/day x 1week Letrozole 2.5mg PO daily + Placebo 2 tablet+ 1 tablet PO x 1 week Letrozole 2.5mg PO daily + Placebo 2 tablet PO 2/day x 22 weeks
Sponsors
Seoul National University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Estrogen receptor positive breast cancer * Clinically measurable tumor size(stage II/III) * No evidence of distant metastasis * Postmenopause women 'Age≥60yr' OR 'previous bilateral oophorectomy' OR 'FSH\>30 with no bleeding history within 1yr' * ECOG 0-2 * Adequate hepatorenal, bone marrow function 'serum Cr\<1.4mg/dL' AND 'Bilirubin\< upper limit of normal x 1.5 AND 'AST/ALT \< upper limit of normal x 1.8 AND 'ALP \< upper limit of normal x 1.8 AND 'Hemoglobin \>10 g/dL' AND 'ANC \>1,500/mm3' AND 'Platelet \>100,000/mm3' * Spontaneous signed into the written informed consent
Exclusion criteria
* Who does not meet the above inclusion criteria * History of other carcinoma * Uncontrolled infection * History of psychiatric, epileptic disease * Male breast cancer * Diabetes 'HbA1c≥6.5' OR 'FBS≥126mg/dL' * Hypersensitivity or intolerance to metformin * Risk of metformin associated lactic acidosis 'Congestive heart disease of NYHA Class llll/IV' OR 'History of other acidosis' OR 'Alcohol intake more than either 3 bottles beer OR 1 bottle Soju' * During medication of metformin, sulfonylureas, thiazolidinediones, insulin * Diffuse microcalcification in mammogram * Multiple OR bilateral OR inflammatory breast cancer * Chemotherapy or endocrine therapy within 2yr due to history of breast cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical response rate | 24week(after completing medication, preoperatively) | Comparing with RECIST 1.1 From baseline to 24week(after completing medication, preoperatively) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic complete response rate | Postoperation(within 26weeks after starting medication) | In case that under postoperative biopsy, residual breast cancer cell is not present in primary lesion and lymph node. |
| Changes of Ki67(%) | Baseline-4week(second core needle biopsy) | IHC is performed for formalin-fixed paraffin embedded tissue at the central laboratory. Ki67 is recorded as % and percentage reduction of baseline and Ki67 expressed cell on day28 are compared. |
| Breast conservation rate | Baseline-postoperation(within 26weeks after starting medication) | Before pre-operative anti hormone therapy, the patients are classified into following three types 1. Candidate for BCS 2. Marginal for breast conservation surgery 3. Candidate for mastectomy only 4. Inoperable by standard mastectomy Classification of each type shall be determined by each researcher of each institution subjectively. For future separate objective analysis, central institution will collect image file of mammography of each patient. Type of operation being actually performed in each type is compared. (BCS vs mastectomy) |
| Breast density change | Baseline-24week(after completing medication, preoperatively) | Percent mammographic density (%) of cranial-caudal view of opposite breast is measured/compared based on continued variable by using validated computer-assisted thresholding program called Cumulus software (University Toronto, Toronto, Ontario, Canada). |
| Toxicity profile of letrozole and metformin | throughout the study | based on NCI-CTCAE version 4.0 |
Countries
South Korea
Outcome results
None listed