Trial of Perioperative Endocrine Therapy - Individualising Care

Study Overview
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Brief Summary
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To determine whether perioperative endocrine therapy with an aromatase inhibitor (AI) followed by standard adjuvant therapy improves outcome compared with standard adjuvant therapy alone in postmenopausal women with hormone receptor positive breast cancer. To determine whether the proliferation marker Ki67 as measured by immunohistochemistry (IHC) in the excised cancer around 2 weeks after starting AI therapy will predict for time to recurrence (TTR) in the individual patient more effectively than the pre-treatment Ki67 value. To determine whether molecular profiling 2 weeks after starting endocrine therapy predicts for long-term outcome in postmenopausal women with hormone receptor positive breast cancer better than at diagnosis.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Aromatase Inhibitors


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post menopausal women with core biopsy-proven hormone receptor positive invasive breast cancer. Postmenopausal is defined as a woman aged ≥50 years fulfilling any one of the following criteria: i) with amenorrhoea >12 months and an intact uterus; ii) has undergone a bilateral oophorectomy; iii) in women who have undergone a hysterectomy, then FSH levels within the postmenopausal range (utilising ranges from the testing laboratory facility) are required if the patient is aged <55 years; or iv) in women who have been on HRT within the last 12 months and therefore not amenorrhoeic, FSH levels within the postmenopausal range (utilising ranges from the testing laboratory facility) are required if the patient is aged <55 years. No evidence of metastatic spread by standard assessment according to local guidelines Standard adjuvant endocrine therapy indicated A palpable tumour of any size , or a tumour with an ultrasound size of at least 1.5cm WHO performance status of 0 or 1 Written informed consent to participate in the trial and to donation of tissue (fresh tissue and surplus tissue from diagnostic procedures) and blood samples. Exclusion Criteria: Locally advanced/inoperable breast cancer Evidence of metastatic disease Previous invasive breast cancer (surgically treated DCIS or LCIS allowed) Current bilateral breast cancer Multiple unilateral tumours with different ER/PgR/HER2 status, grade or type (e.g. ductal vs lobular) i.e. anything that suggests two or more different cancers. Multifocal disease with homogenous ER/PgR/HER2 status, grade and type is allowed if at least one lesion is palpable or at least 1.5cm on ultrasound; the largest lesion should be used for sample collection and CRF completion. Concurrent use (defined as use within 4 weeks prior to diagnostic tissue sample being taken) of HRT or any other oestrogen-containing medication (including vaginal oestrogens) Previous use of oestrogen implants at ANY time Prior endocrine therapy or chemotherapy for breast cancer Any invasive malignancy diagnosed within previous 5 years (other than basal cell carcinoma or cervical carcinoma in situ) Any severe co-incident medical disease, inability to give informed consent or unavailability for follow-up Treatment with an unlicensed or investigational drug within 4 weeks before randomisation Current, continuous, long term systemic steroid usage

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No Aromatase Inhibitor<br>No aromatase inhibitor given around the time of surgery | |
| Experimental: Aromatase Inhibitor<br>Aromatase Inhibitor given perioperatively for 4 weeks (two weeks before and two weeks after surgery) Choice of AI is according to centre policy and may be either anastrozole (1mg/day) or letrozole (2.5mg/day) | Drug: Aromatase Inhibitors<br>* Choice of AI is according to centre policy; any brand can be used<br>* Other names: Letrozole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to recurrence | Time to recurrence (TTR) is defined as time from randomisation to local, regional, or distant tumour recurrence or death from breast cancer without prior notification of relapse. Second primary cancers and intercurrent deaths will be treated as censoring events. Patients who are alive and disease free will be censored at the date last seen alive. | 5 years post-randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse free survival | Second primary cancers and deaths from non-breast cancer causes in the absence of breast cancer relapse will be treated as censoring events. | 5 years post-randomisation | 
| Time to local recurrence |  | 5 years post-randomisation | 
| Time to distant recurrence |  | 5 years post-randomisation | 
| Overall Survival |  | 5 years post-randomisation | 
| Breast cancer free survival |  | 5 years post-randomisation | 
| Proliferation rate (Ki67) | Comparison of the predictive value of Ki67 at surgery in the perioperative therapy and non perioperative therapy groups will be undertaken using Cox regression, comparing the estimates of the hazard ratios obtained in each treatment group. | At time of surgery (around 2 weeks post-randomisation) | 
| Gene expression profile |  | At time of surgery (around 2 weeks post-randomisation) |