Dietary Intervention and BRCA Penetrance

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Status: Completed

Conditions: Breast Cancer; BRCA2 Mutation; Dietary Modification; BRCA1 Mutation

Treatments: Other: Dietary intervention

Study type: Interventional

Funder types: Other

Identifiers

NCT03066856

106/13

Details and patient eligibility

About

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.

Full 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.

Enrollment: 502 patients

Sex: Female

Ages: 18 to 70 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Eligible study subjects are women, aged 18-70, either unaffected or affected with BC, without metastases or previous ovarian cancer, who underwent genetic counselling and fulfilled high-risk selection criteria for genetic testing based on personal and/or family history and resulted carriers of deleterious BRCA mutations.

Exclusion criteria

• Unaffected BRCA mutation carriers with bilateral prophylactic mastectomy are not included in the cohort or are censored at the time of surgery.

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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502 participants in 2 patient groups

Intervention

Experimental group

Description:

After baseline examinations, participants are randomized to an active dietary intervention group.The intervention group is invited to attend six full days of life-style intervention activities over the next six months. These activities include six cookery courses followed by lunch, six physical activity sessions (walking for 45 minutes) and six conferences. The intervention and control groups both complete questionnaires on adherence to the Mediterranean diet (MEDAS) at baseline and at the end of the study, and are asked for at least two 24-hour recalls of the previous day's food intake, and details of their physical exercise during the six-month intervention.

Treatment:

Other: Dietary intervention

Control

No Intervention group

Description:

All participants receive general recommendations for the dietary prevention of cancer. After baseline examinations, women randomized in the control group carry on following the baseline recommendations.