Dietary Intervention and BRCA Penetrance

NCT ID: NCT03066856

Last Updated: 2021-10-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 502 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-01
• Study Completion Date: 2018-12-31

Brief 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.

Conditions

Dietary Modification; BRCA1 Mutation; BRCA2 Mutation; Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

Intervention

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.

Group Type: EXPERIMENTAL

Dietary intervention

Intervention Type: OTHER

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.

Control

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Dietary intervention

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.

Intervention Type: OTHER

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Istituto Oncologico di Bari

UNKNOWN

Sponsor Role: collaborator

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, , Italy

Countries

Italy

References

Bruno E, Oliverio A, Paradiso A, Daniele A, Tommasi S, Terribile DA, Filippone A, Digennaro M, Pilato B, Danza K, Guarino D, Rossi C, Rossi MM, Venturelli E, Giussani M, Peissel B, Pasanisi P. Lifestyle Characteristics in Women Carriers of BRCA Mutations: Results From an Italian Trial Cohort. Clin Breast Cancer. 2021 Jun;21(3):e168-e176. doi: 10.1016/j.clbc.2020.11.002. Epub 2020 Nov 10.

Reference Type: DERIVED

PMID: 33357965 (View on PubMed)

Other Identifiers

106/13

Identifier Type: -

Identifier Source: org_study_id