Low Dose TamOxifen and LifestylE Changes for bReast cANcer prevenTion

Study Overview
=================
Brief Summary
-----------------
Circulating levels of Sex Hormone Binding Globulin (SHBG) are significantly associated with a decreased risk of breast cancer. The main aim of this clinical trial is to verify whether Low Dose Tamoxifen (LDT) increases circulating levels of SHBG more than lifestyle intervention (LI) with or without intermittent caloric restriction (ICR) after 6 months in women at increased risk of breast cancer (unaffected BRCA1-2 OR PALB2 mutation carriers; or with a >5% risk of developing breast cancer at 10 years according to the Tyrer-Cuzick model) or with a recently resected intraepithelial neoplasia of the breast (IEN). The secondary aims are: to verify whether ICR significantly modulates primary and secondary endpoints such as Homeostasis Model Assessment (HOMA) index, immune and inflammatory markers, lipid profile, Adiponectin/Leptin (A/L) ratio, quality of life (QoL), Body mass index (BMI), fat body composition, safety and toxicity; to verify whether LDT significantly modulates secondary endpoints, such as HOMA-index, immune and inflammatory markers, lipid profile, A/L ratio, QoL, BMI, fat body composition, safety and toxicity; to investigate differences in microbiome composition by arms and the effect of changes in microbiome on QoL taking into account circulating biomarkers, cytokines, immune modulators, and inflammatory proteins in serum; to investigate MD (Mammographic Breast Density) changes by LDT vs. LI, with or without ICR. This aim will be performed in a subgroup of participants (not all the participants will undergo mammography due to younger age).

Detailed Description
-----------------
Italian, multicenter, phase II, biomarker trial. A total of 200 women aged 18-70 years will be randomly assigned (1:1:1:1) to one of the four intervention arms Arm 1: Low dose Tamoxifen (LDT) i.e. 10 mg every other day; Arm 2: Low dose Tamoxifen (LDT) + Intermittent Caloric Restriction (ICR); Arm 3: Lifestyle intervention (LI) using a step counter; Arm 4: Lifestyle intervention (LI) using a step counter + Intermittent Caloric Restriction (ICR). Participants will be stratified by center and by disease status (high risk vs. previous IEN) and intervention will last six months for all arms.

Official Title
-----------------
Low Dose TamOxifen and LifestylE Changes for bReast cANcer prevenTion: a Randomized Phase II Biomarker Trial in Subjects at Increased Risk

Conditions
-----------------
BRCA Mutation, PALB2 Gene Mutation, Ductal Carcinoma in Situ, Lobular Carcinoma in Situ

Intervention / Treatment
-----------------
* Drug: Tamoxifen 10 Mg Tablet
* Other: Intermittent caloric restriction
* Behavioral: Step counter Device


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women between 18 and 70 years old; Healthy participants carriers of a germline pathogenic/likely pathogenetic variant (BRCA1 or BRCA2 or PALB2), or with a > 5% risk of developing breast cancer at 10 years according to the Tyrer-Cuzick model, or with a previous diagnosis of intraepithelial neoplasia of the breast (atypical ductal hyperplasia (ADH), lobular carcinoma in situ (LCIS), estrogen receptor (ER) positive ductal carcinoma in situ (DCIS)) within the last 3 years; Ability to understand and the willingness to sign a written informed consent document; Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1; 5a. For high-risk strata: A negative mammogram or any radiological image based on age and center protocol screening within 6 months before baseline visit; 5b. For IEN Strata: A negative mammogram within 12 months before baseline visit 6. A negative transvaginal ultrasound within 6 months before baseline visit. Exclusion Criteria: Diagnosis of ER-negative (<10%) DCIS, or history of invasive breast cancer; Previous treatment with selective estrogen receptor modulators (SERMs) or any other hormonal treatment for breast neoplasms; BMI < 18.5 Kg/m2 and/or Malnutrition Universal Screening Tool (MUST) score ≥2 and/or any current or past eating disorders; Any diagnosis of invasive neoplasia, except non-melanoma skin cancer, in the previous 5 years; Any tamoxifen contraindications (abnormal liver function, previous ischemic heart disease, endometrial disorder, previous deep venous thrombosis, history of pulmonary embolus, current or suspected glaucoma, retinopathy, and cataract); Current use of warfarin or other anticoagulant drugs Bilateral mastectomy; Pregnancy or desire to become pregnant in the subsequent 9 months after treatment cessation; Diabetes or any other clinical condition that, at the investigator's discretion, contraindicates the proposed intervention. No hormonal contraception is allowed during study intervention. Non-hormonal methods will be advised for women of childbearing potential (WOCBP).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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: Low dose tamoxifen<br>Tamoxifen 10 mg (1 tablet) every other day for 6 months. | Drug: Tamoxifen 10 Mg Tablet<br>* One tablet of Tamoxifen 10 mg every other day for 6 months<br>* Other names: Low dose tamoxifen;|
| Active Comparator: Low dose tamoxifen + Intermittent Caloric Restriction<br>Tamoxifen 10 mg (1 tablet) every other day for 6 months + 5:2 diet (5 days/week at regular energy intake+2 days a week at an average 75% energy deficit) | Drug: Tamoxifen 10 Mg Tablet<br>* One tablet of Tamoxifen 10 mg every other day for 6 months<br>* Other names: Low dose tamoxifen;Other: Intermittent caloric restriction<br>* 5:2 diet: 5 days a week at regular energy intake and 2 days/week at 75% energy deficit (diet will be restricted at 500-800 kcal corresponding to a 75% reduction compared to normal size)<br>|
| Placebo Comparator: Lifestyle intervention<br>Step counter device | Behavioral: Step counter Device<br>* Participants will receive personal advice on healthy lifestyle and a step counter<br>|
| Active Comparator: Lifestyle Intervention + Intermittent Caloric Restriction<br>Step counter device + 5:2 diet (5 days/week at regular energy intake+2 days a week at an average 75% energy deficit) | Other: Intermittent caloric restriction<br>* 5:2 diet: 5 days a week at regular energy intake and 2 days/week at 75% energy deficit (diet will be restricted at 500-800 kcal corresponding to a 75% reduction compared to normal size)<br>Behavioral: Step counter Device<br>* Participants will receive personal advice on healthy lifestyle and a step counter<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post intervention levels of circulating binding globulin | Sex hormone binding globulin level after 6 months of intervention | Through study completion, an average of 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Low Dose Tamoxifen, Intermittent Caloric Restriction, Sex Hormone Binding Globulin, Lifestyle