Dietary Intervention and BRCA Penetrance
Condition: Dietary Modification; BRCA1 Mutation; BRCA2 Mutation; Breast Cancer
Study type: Interventional

Summary: 
      Insulin-like growth factor I (IGF-I) and other markers of insulin resistance (IRm) might
      modulate the penetrance of BRCA genes mutation.

      The investigators have designed a demonstration project with BRCA mutation carriers (with or
      without a previous diagnosis of breast cancer) to test:

        1. whether a lifestyle intervention significantly reduceIGF-I and the other IRm (randomized
           trial).

        2. whether mutation carriers with a previous diagnosis of breast cancer have higher IRm
           than carriers without breast cancer (case-controlstudy).

        3. whether IRm and their change over time affect subsequent breast cancer incidence and
           prognosis (cohort follow-up).

      The investigators expect to significantly reduce IGF-I and IRm, to find that BRCA mutation
      carriers with a previous breast cancer have higher IRm levels, and, in the long term, that
      women with persistent higher IRm levels have higher penetrance and worst prognosis.

      Confirming a significant reduction of IRm and the impact of their levels on prognosis would
      help to develop primary prevention recommendations for high risk families.
    

Detailed description: 
      Abdominal obesity and high body weight are associated with a greater risk of breast cancer
      (BC) in women belonging to high risk families than in women without family history of BC. A
      case-control study showed that high energy intake, usually associated with higher
      bio-availability of growth factors, is associated with BC risk in BRCA mutation carriers. A
      multinational case-only study on 3000 young BC women suggested that patients with BRCA
      mutation had higher consumption of milk. Milk directly stimulates insulin production and
      release, and is associated with higher plasma levels of insulin-like growth factor I (IGF-I).

      In a case-control analysis on 308 high genetic risk women, investigators showed that high
      serum levels of IGF-I are associated with a significantly increased penetrance.

      Consistently, mechanistic studies hypothesized a functional interaction between the BRCA
      genes and the IGF-I system.

      The lifetime cumulative risk (penetrance) of BC associated with BRCA mutations is of the
      order of 50%, and a sizeable proportion of mutation carriers does not develop the disease.
      Therefore, the penetrance of the genetic trait may be regulated trough other genetic or
      environmental factors, including dietary, metabolic, and growth factors. The investigators
      hypothesized that markers of insulin resistance (IRm), such as plasma level of glucose,
      insulin, IGF-I and the presence of metabolic syndrome, which affect risk and prognosis of
      sporadic BC, are relevant also for hereditary BC.

      The investigators have designed a demonstration project with BRCA mutation carriers (with or
      without a previous diagnosis of BC) to test:

        1. whether a lifestyle intervention significantly reduce IRm (randomized trial).

        2. whether mutation carriers with a previous diagnosis of BC have higher IRm than carriers
           without BC (case-control study).

        3. whether IRm and their change over time affect subsequent BC incidence and prognosis
           (cohort follow-up).

      In a pilot phase the investigators have randomized 150 BRCA mutated women to a dietary
      intervention and a control group for a short term (6 months) trial to test the reduction of
      IRm levels. In the present study the investigators to recruit 600 BRCA mutation carriers to
      test if blood levels of IRm and their change over time influence the risk of BC and of BC
      relapse. All participants will receive the WCRF Decalogue for the prevention of cancer.
      Participants will be then randomized in an active lifestyle intervention group (6 full days
      of life-style intervention activities along the subsequent 6 months) and in a control group
      that will remain with the baseline recommendation. After 6 months also the control group will
      be invited to an active intervention.

      The investigators expect to significantly reduce IRm, to find that BRCA mutation carriers
      with a previous BC have higher IRm levels, and, in the long term, that women with persistent
      higher IRm levels have higher penetrance and worst prognosis.
    

Intervention name(s): Dietary intervention
Intervention type(s): Other
Intervention description(s): The main aim of the trial is to reduce serum levels of IGF-I and IRm with a a low- calorie and low-protein diet. In humans, calorie restriction alone does not seem to significantly lower IGF-I; protein restriction is also required. In detail, recommendations for participants included in the intervention arm include:
reducing protein intake, mainly milk and animal protein (except fish), down to 10-12% of total calorie intake.
reducing high glycemic index food and high insulinemic foods.
reducing sources of saturated fat (red and processed meat, milk and dairy products).
eating mostly food of plant origin, with a wide variety of seasonal products.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: BRCA mutation carriers, with or without breast cancer, aged 18-70 years and without metastases are eligible. After the baseline examinations, women are randomized to an active dietary intervention or to a control group. The intervention group should attend six full days of activities over the next six months.
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: BRCA genes; Mutation carriers; IGF-I; Diet