Effect of Peri-operative anti-HER2 therapy On early breast cancer Study - Biological phase

Recruitment & Eligibility

Status: Completed

Sex: Female

Target Recruitment: 257

Inclusion Criteria

1. Women aged greater than or equal to 18 years old
2. HER2 (3+ on immunohistochemistry [IHC] or amplification proven by fluorescent in-situ hybridisation [FISH]) positive operable invasive breast cancer diagnosed by core biopsy
3. Planned surgery within one month of diagnosis
4. Serum creatinine and bilirubin less than 2 times the upper limits of normal for the institution, or creatinine clearance greater than 30 mg/dL (Marginally
abnormal test results should be repeated)
5. Eastern Cooperative Oncology Group (ECOG) performance status 0,1, or 2 (Karnofsky greater than or equal to 60%)
6. Non-pregnant and non-lactating with no intention of pregnancy during study treatment
7. Written informed consent obtained for trial and to donation of tissue and blood samples

Added 19/02/10:
8. Patients must be candidates for and willing to undergo adjuvant chemotherapy and trastuzumab post surgery

Exclusion Criteria

Current information as of 19/02/10:
1. HER2 negative cancers and those with unknown HER2 status
2. Inoperable breast cancer (T4 category) or suspicion of distant metastases
3. Diagnosis of inflammatory breast cancer
4. Clinical evidence of metastatic disease
5. Prior herceptin therapy within the last 3 months or local (radiotherapy) cancer treatments
6. Previous cancer at any other site that has been treated within the last 6 months (except previous basal cell carcinoma and cervical carcinoma in situ)
7. Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
8. Impaired gastro-intestinal function thought sufficient to reduce lapatinib absorption
9. Contra-indicated to receive adjuvant chemotherapy and/or trastuzumab (ECOG >2)
10. Known immediate or delayed hypersensitivity, reaction to drugs chemically related to trastuzumab or lapatinib
11. Other concomitant investigational agents or concurrent anti-cancer therapy
12. Regular use of systemic steroids or other agents that could influence study endpoints (inhaled steroids are allowed)
13. Any altered mental state that would preclude obtaining written informed consent
14. Patients who have clinically significant cardiac abnormalities or uncontrolled hypertension
15. Previous myocardial infarction, heart failure, or significant angina. Cardiac function should be assessed by physical examination, ECG, and baseline LVEF should be =55% as measured by echocardiography or MUGA.

Initial information at time of registration:
1. HER2 negative cancers and those with unknown HER2 status
2. Inoperable breast cancer (T4 category) or suspicion of distant metastases
3. Diagnosis of inflammatory breast cancer
4. Clinical evidence of metastatic disease
5. No prior systemic (i.e. chemotherapy) or local (radiotherapy) cancer treatments
6. Previous cancer at any other site (except previous basal cell carcinoma and cervical carcinoma in situ)
7. Abnormal renal function
8. Abnormal liver function tests
9. Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
10. Impaired gastro-intestinal function thought sufficient to reduce lapatinib absorption
11. Contra-indication to receive adjuvant chemotherapy and/or trastuzumab (ECOG greater than 2)
12. Known immediate or delayed hypersensitivity, reaction to drugs chemically related to trastuzumab or lapatinib
13. Other concomitant investigational agents or concurrent anti-cancer therapy. In addition all herbal (alternative) therapies are prohibited.
14. Regular use of systemic steroids or other agents that could influence study endpoints
15. Patient must not have clinically significant cardiac abnormalities or uncontrolled hypertension
16. No previous myocardial infarction, heart failure, or significant angina. Cardiac function should be assessed by physical examination, electrocardiogram (ECG), and baseline left ventricular ejection fraction (LVEF) should be greater than or equal to 50% as measured by echocardiography or multiple-gated acquisition (MUGA) scan.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
1. Increase in apoptosis: change in the tumour (morphological apoptosis and activated caspase 3) measured at diagnosis and at surgery<br>2. Fall in proliferation between diagnosis and surgery: change in proliferation measured by Ki67 immunohistochemical assessment (%) at diagnosis and at surgery

Secondary Outcome Measures

Name	Time	Method
1. Changes in the angiogenic serum markers vascular endothelial growth factor A (VEGF-A), VEGF-R1 and CD105, measured at diagnosis, surgery (plus also tumour CD31) and 28 days post-surgery<br>2. To establish if the expression of molecular markers (epidermal growth factor receptor [EGFR], Her-3, insulin-like growth factor 1 receptor [IGF1R], c-myc, Akt, p-ERK, pS6 Kinase, activated Src, or truncated p95HER-2 expression) predict increases in apoptosis or decreases in proliferation in response to therapy

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