Letrozole in Preventing Cancer in Postmenopausal Women Who Have Received 4-6 Years of Hormone Therapy for Hormone Receptor-Positive, Lymph Node-Positive, Early-Stage Breast Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Estrogen can cause the growth of breast cancer cells. Letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known which regimen of letrozole is more effective in postmenopausal women who have received hormone therapy for early-stage breast cancer. PURPOSE: This randomized phase III trial is comparing two different regimens of letrozole in preventing cancer in postmenopausal women who have received 4-6 years of hormone therapy for hormone receptor-positive, lymph node-positive, early-stage breast cancer.

Detailed Description
-----------------
OBJECTIVES: Primary Compare the disease-free survival (DFS) of postmenopausal women treated with continuous letrozole for 5 years vs intermittent letrozole over a 5-year period. Secondary Compare overall survival of patients treated with these two regimens. Compare distant DFS of these patients. Compare breast cancer-free interval of these patients. Compare sites of first DFS failure in these patients. Compare second (nonbreast) malignancies in these patients. Compare deaths without prior cancer events in these patients. Compare adverse events resulting from these two regimens. OUTLINE: This is a multicenter study. Patients are stratified according to treatment center and type of prior endocrine therapy (selective estrogen receptor modulators [SERMs] alone vs aromatase inhibitors [AIs] alone vs both SERMs and AIs each for at least 1 month). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral letrozole daily for 5 years. Arm II: Patients receive oral letrozole daily for the first 9 months of years 1 through 4, followed by 12 months in year 5. After completion of study therapy, patients are followed annually.

Official Title
-----------------
SOLE, Study of Letrozole Extension, A Phase III Trial Evaluating the Role of Continuous Letrozole Versus Intermittent Letrozole Following 4 to 6 Years of Prior Adjuvant Endocrine Therapy for Postmenopausal Women With Hormone-Receptor Positive, Node Positive Early Stage Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Letrozole
* Drug: Letrozole


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Confirmed diagnosis of prior operable, noninflammatory breast cancer meeting the following criteria: Steroid hormone receptor-positive tumors (estrogen receptor and/or progesterone receptor), determined by immunohistochemistry, after primary surgery and before commencement of prior endocrine therapy Prior local treatment including surgery with or without radiotherapy for primary breast cancer with no known clinical residual loco-regional disease Following primary surgery, eligible patients must have had evidence of lymph node involvement either in the axillary or internal mammary nodes, but not supraclavicular nodes Clinically disease-free Must have completed 4-6 years of prior adjuvant selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or a sequential combination of both When calculating 4-6 years, neoadjuvant endocrine therapy should not be included No evidence of recurrent disease or distant metastatic disease No prior bilateral breast cancer PATIENT CHARACTERISTICS: Female Must be postmenopausal by any of the following criteria: Patients of any age who have had a bilateral oophorectomy (including radiation castration AND amenorrheic for > 3 months) Patients 56 years old or older with any evidence of ovarian function must have biochemical evidence of definite postmenopausal status (defined as estradiol, luteinizing hormone [LH], and follicle-stimulating hormone [FSH] in the postmenopausal range) Patients 55 years old or younger must have biochemical evidence of definite postmenopausal status (defined as estradiol, LH, and FSH in the postmenopausal range) Patients who have received prior luteinizing-hormone releasing-hormone (LHRH) analogues within the last year are eligible if they have definite evidence of postmenopausal status as defined above Clinically adequate hepatic function No bone fracture due to osteoporosis at any time during the 4-6 years of prior therapy No prior or current malignancy except adequately treated basal cell or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, or contra- or ipsilateral in situ breast carcinoma No other nonmalignant systemic diseases (cardiovascular, renal, lung, etc.) that would prevent prolonged follow-up No psychiatric, addictive, or any other disorder that compromises compliance with protocol requirements PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 12 months since prior and no other concurrent endocrine SERM/AI therapy Any type of prior adjuvant therapy allowed including, but not limited to, any of the following: Neoadjuvant chemotherapy Neoadjuvant endocrine therapy Adjuvant chemotherapy Trastuzumab (Herceptin®) Ovarian ablation Gonadotropin releasing hormone analogues Lapatinib ditosylate No concurrent hormone-replacement therapy, bisphosphonates (except for treatment of bone loss), or any other investigational agent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Continuous letrozole<br>Continuous letrozole: 5 years continuously (2.5 mg Letrozole daily) | Drug: Letrozole<br>* Film-coated tablet, oral use, 2.5 mg Letrozole daily for 5 years continuously<br>|
| Experimental: Intermittent letrozole<br>Intermittent letrozole: 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -> 36 mo) plus 1 x 12 mo in yr 5 -> 48 months | Drug: Letrozole<br>* Film-coated tablet, oral use, 2.5 mg daily, 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -> 36 mo) plus 1 x 12 mo in yr 5 -> 48 months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival (DFS) | Duration of time from randomization to the first indication of the following events: invasive recurrence at local (including recurrence restricted to the breast after breast conserving treatment), regional or distant sites; a new invasive cancer in the contralateral breast; any second (non-breast) invasive malignancy; or a death without prior cancer event. Appearance of DCIS or LCIS either in the ipsilateral or in the contralateral breast was not be considered as an event for DFS. In the absence of an event, DFS was censored at the date of last follow-up visit. | 5-year estimates, reported at a median follow-up of 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Duration of time from randomization to death from any cause, or was censored at the date last known alive. (Note, for patients who withdrew consent or were lost to follow-up but follow-up for survival was possible through hospital or registry records, OS was censored at the date last known alive rather than date of last follow-up/withdrawn consent). | 5-year estimates, reported at a median follow-up of 60 months | 
| Distant Recurrence-free Interval (DRFI) | Duration of time from randomization to the first indication of invasive breast recurrence at a distant site. In the absence of an event, DRFI was censored at the date of last follow-up visit or date or death without distant recurrence.* *This endpoint replaced DDFS, which was specified in the protocol | 5-year estimates, reported at a median follow-up of 60 months | 
| Breast Cancer-free Interval | Duration of time from randomization to the first indication of the following events: invasive breast recurrence at local, regional or distant sites; a new invasive cancer in the contralateral breast (second non-breast malignancies are ignored). In the absence of an event, BCFI was censored at the date of last follow-up visit or date of death without prior breast cancer event. | 5-year estimates, reported at a median follow-up of 60 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IA breast cancer, stage IB breast cancer, stage II breast cancer, stage IIIA breast cancer