Low dose TamOxifen and LifestylE changes for bReast cANcer prevenTion: a randomized phase II biomarker trial in subjects at increased risk (TOLERANT Study)

Women between 18 and 70 years old

Healthy participants carriers of a germline pathogenic/likely pathogenetic variant in at least one of the following genes BRCA1, BRCA2, PALB2, ATM, CHEK2, CDH1, RAD51C or RAD51D, or > 5% BC risk at 10 years, using the Tyrer Cuzick or the Breast Cancer Surveillance Consortium Risk models, or with previous diagnosis of intraepithelial neoplasia (surgery for ADH, LCIS, ER positive DCIS) within the last 3 years

Ability to understand and the willingness to sign a written informed consent document.

ECOG performance status ≤1 (Karnofsky ≥70%)

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 bilateral mammogram within 12 months before baseline visit is required. The diagnostic mammogram (i.e. before breast surgery) is acceptable

A negative transvaginal ultrasound/hysteroscopy within 6 months before baseline visit. Women with a previous hysterectomy due to a benign condition, are not required a transvaginal ultrasound.

Diagnosis of ER negative (<10%) DCIS, or history of breast invasive cancer

No hormonal contraception is allowed during study intervention. Non-hormonal methods will be advised for women of childbearing potential (WOCBP).

Previous treatment with 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 or 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