Clinical trial NCT03066856: Dietary Intervention and BRCA Penetrance
Official title: Lifestyle and the Penetrance of BRCA Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Dietary Modification
BRCA1 Mutation
BRCA2 Mutation
Breast Cancer
Keywords: BRCA genes
Mutation carriers
IGF-I
Diet
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
Collaborators: name: Istituto Oncologico di Bari
First posted: 2017-03-01
Enrollment: 502
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: SUPPORTIVE_CARE

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.

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.

Primary outcomes:
measure: Reduction of serum levels of IGF-I (ng/mL) (intervention trial).
timeFrame: 6 months of dietary intervention
measure: Case-control analysis: comparison of the affected versus the unaffected BRCA mutation carriers for the baseline IRm levels baseline serum levels of IGF-I and IRm.
timeFrame: 3 years
Secondary outcomes:
measure: Survival analysis: evaluation of the association between IGF-I and IGF-I changes and subsequent BC incidence and BC prognosis (BC incidence for unaffected women and ipsilateral or contralateral BC and BC recurrences for affected women).
timeFrame: 3 years
Other outcomes:
Locations:
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
Study officials:
References:
citation: 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.