Lifestyle and the Penetrance of BRCA Mutation
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 502
- 试验地点
- 1
- 主要终点
- 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.
研究概览
简要总结
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:
- whether a lifestyle intervention significantly reduceIGF-I and the other IRm (randomized trial).
- whether mutation carriers with a previous diagnosis of breast cancer have higher IRm than carriers without breast cancer (case-controlstudy).
- 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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •Unaffected BRCA mutation carriers with bilateral prophylactic mastectomy are not included in the cohort or are censored at the time of surgery.
研究组 & 干预措施
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.
干预措施: Dietary intervention (Other)
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.
结局指标
主要结局
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.
时间窗: 3 years
By classifying the exposure status according to the IGF-I median level and by assuming that : 1. the probability of exposure among controls is 50 %, 2. a case/control ratio of 2/1 (as in a pilot study): 400 women with a previous diagnosis of BC and 200 unaffected, 3. the true odds ratio for BC in exposed versus unexposed subjects ranging between 1.5 to 2 (the lower confidence interval of a pilot study), the investigators will be able to reject the null hypothesis ( that this odds ratio equals 1) with a power ranging from 64% to 97% at the alpha level of 0.05.
Reduction of serum levels of IGF-I (ng/mL) (intervention trial).
时间窗: 6 months of dietary intervention
Final analyses will be performed by intention to treat. By assuming that: a) the planned lifestyle interventions may reduce IGF-I levels by 10%, b) alpha error = 0.05, the investigators shall have 96% power to compare 300 women included in the intervention group versus 300 in the control group.
次要结局
- 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).(3 years)