Limited Adjuvant Endocrine Therapy for Low Risk Breast Cancer

Study Overview
=================
Brief Summary
-----------------
Phase II trial of 2 years of standard adjuvant endocrine therapy after low risk hormone receptor positive, HER2 negative, node negative breast cancer in women older than 50 at diagnosis. The study hypothesis is that reducing adjuvant endocrine therapy from 5 to 2 years in a population with low risk of breast cancer; as determined by histopathologic criteria and confirmed by low risk genomic analysis using Prosigna®; will be safe and acceptable to this population, and will not compromise the expected excellent breast cancer specific outcomes for this population.

Detailed Description
-----------------
Women older than 50 at diagnosis of an invasive breast cancer which is all of: node negative/N0i+; T1 or T2; low or intermediate grade; with strong or intermediate expression of hormone receptors (ER and PR); and HER2 negative, and who have had adequate local therapy for their tumor, are invited to participate in Prosigna® screening. A sample of their excised tumor is sent for Prosigna® testing. This is a validated and widely approved genomic test to assess recurrence risk in hormone receptor positive/HER2 negative, node negative breast tumors. Tumors with a low risk result, defined as Risk of Recurrence (ROR) less than or equal to 40, are then eligible for enrollment on the LA LEAST study of 2 years of endocrine therapy (tamoxifen for pre/perimenopausal women and aromatase inhibitor for postmenopausal women). To mimic real life, there is flexibility to switch to an alternate standard of care endocrine therapy during the two years if intolerable side effects develop. During the two years of therapy, participants are seen every six months and complete periodic quality of life (QOL) questionnaires designed to measure quality of life, mood, side effects, and anxiety/fear of recurrence. Following two years of therapy, participants have annual study visits until year 10, with similar questionnaires at some but not all time points, and assessment of study endpoints. Primary endpoint is the 5 year distant relapse free interval (DRFI), defined as freedom from distant recurrence or breast cancer death at five years. Secondary endpoints include longitudinal QOL comparisons, 10 year breast cancer free interval and 10 year contralateral breast cancer rate. It is anticipated that about 400 individuals will need to be screened to enroll 290 participants with requisite low score. The sample size is based on an expected 5 year DRFI of 96.8%, one sided alpha of 0.05 and a rejection of the alternate hypothesis if the lower boundary of the one sided confidence interval yields an observed DRFI below 95%.

Official Title
-----------------
LA LEAST- Luminal A, Limited Endocrine Adjuvant Systemic Therapy. A Trial of Abbreviated Hormone Therapy for Low Risk Hormone Receptor Positive, HER2 Negative Early Breast Cancer

Conditions
-----------------
Breast Cancer Female, Hormone Receptor Positive Tumor

Intervention / Treatment
-----------------
* Drug: Tamoxifen Citrate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: for Prosigna® screening Diagnosis of invasive breast cancer which is: Unifocal or multifocal (not multicentric) Unilateral Moderate or strongly hormone receptor positive HER2 negative Ductal grade 1 or 2, or lobular any grade, or pure tubular (any grade) or pure papillary (any grade). If mixed lobular-ductal histology, the ductal component must be grade 1 or 2. Stage pT1N0 (tumor </= 20mm, negative node) or pT2N0 (tumor 21-50mm, node negative) or pT1N0i+ (tumor </=20mm and isolated tumor cells in node[s]) or pT2N0i+ (tumor 21-50mm and isolated tumor cells in node[s]) (see Appendix 2). Tumor size must be sufficient for Prosigna® testing. pNX (nodal status unknown) stage is not eligible. Subject must be female Subject must be age > 50 years at breast cancer diagnosis Subject may be pre, peri, or postmenopausal. Subject must have a > 5-year life expectancy based on physician judgement of subject's co-morbid illnesses and age Subject must undergo standard of care loco-regional management (sentinel node biopsy and/or axillary dissection; breast conserving surgery or mastectomy; radiation to breast following breast conserving surgery, with radiotherapy details per local institution practice). Surgery will have been no more than 24 weeks prior to endocrine therapy start. Subjects having repeat surgeries after radiation, regardless of indication, should count the date of last surgery that preceded radiation. Subjects may undergo Prosigna® screening prior to completion of radiation. The breast surgery will have achieved negative surgical margins. Tumours with positive margins that are not re-resectable are eligible if followed by radiation with a boost (partial mastectomy) or chest wall radiation (mastectomy) No (neoadjuvant or adjuvant) chemotherapy given or planned for this breast cancer No other non-breast cancer within the last 5 years, except non-melanoma skin cancer, melanoma in situ, cervix carcinoma in situ, and anal carcinoma in situ No prior hormone receptor positive invasive breast cancer. Prior contralateral DCIS treated with standard of care local therapy, and prior lobular carcinoma in situ (LCIS) are allowed, provided no endocrine therapy with any of tamoxifen, ovarian suppression, raloxifene, or aromatase inhibitor was given Subject will have not have started endocrine therapy prior to enrollment Subject has signed a screening informed consent form Subject has intent to be adherent to endocrine therapy for two years in the absence of serious toxicity Inclusion criteria for study enrollment: Prosigna® score in the low risk range, defined as an ROR of 40 or lower Subject has not yet initiated endocrine therapy Subject has signed study informed consent form Exclusion Criteria: • Does not meet every inclusion criteria listed above

Ages Eligible for Study
-----------------
Minimum Age: 51 Years

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm phase II study exploring reducing the duration of endocrine therapy from five to two years in low risk population with early breast cancer
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: standard of care endocrine therapy for two years<br>Standard of care adjuvant endocrine therapy for two years. for postmenopausal women, initial therapy will be aromatase inhibitor unless contraindicated, in which case tamoxifen may be used. For premenopausal and perimenopausal women, initial therapy will be tamoxifen unless contraindicated, in which case an lutenizing hormone releasing hormone (LHRH) agonist with / without aromatase inhibitor may be used. | Drug: Tamoxifen Citrate<br>* current standard of care is 5 years endocrine therapy after early breast cancer. Intervention will test if 2 years is adequate for population with low recurrence risk based on genomic tissue based test<br>* Other names: aromatase inhibitor;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distant Relapse Free Interval at five years | freedom from distant recurrence or breast cancer death at 5 years | 5 years after the last patient is enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ten year breast cancer free interval | freedom from local, regional, distant breast cancer recurrence or death from breast cancer or ipsilateral or contralateral ductal carcinoma in situ or contralateral invasive breast cancer at ten years | ten years after the last patient is enrolled | 
| Ten year contralateral breast cancer incidence | breast cancer occurring in the contralateral breast, including ductal carcinoma in situ (DCIS) and invasive breast cancer, within ten years of enrollment. | ten years after the last patient is enrolled | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
endocrine therapy