The Effects of HER2 Receptor Signaling on Human Brown Fat Activity: A 1-year Prospective Cohort Study in Trastuzumab-treated Breast Cancer Patients Versus HER2 Negative Controls
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- BAT activity
研究概览
简要总结
The objective of this observational study is to investigate the significance of the HER2 receptor for brown fat activity in humans. Our preliminary data clearly demonstrates that the ErbB signaling pathway, which includes the HER2 receptor, strongly promotes development and function of cultured human BAT cells. The HER2 receptor is a part of the ErbB signaling pathway, and antibodies against thee HER2 receptor are a part of the standard treatment for HER2-positive breast cancer. Therefore, the hypothesis is that the activity of brown fat will be reduced in patients treated with HER2 blocking antibody compared to patients who are not treated with HER2 blocking antibody. The present study simply takes advantage of the treatment protocol to explore the contribution of the HER2 receptor in the development of brown adipose tissue in humans. Participants will complete two testing days, one before and one after their treatment period of approx. one year. On the testing days, identification of brown fat activity will be performed using cooling and infrared thermography. In addition, resting metabolic rate and a glucose tolerance test will be performed. Since presence of active brown adipose tissue in humans is inversely related to obesity, total and visceral fat mass, plasma glucose levels, presence of cardiovascular disease and diabetes status, it is of great importance to investigate the molecular mechanisms for development of brown fat tissue and may lead to discovery of novel strategies to counteract obesity and obesity related disorders.
详细描述
BACKGROUND:
Breast cancer is the most common cancer among women worldwide, and with increasing survival rates focus on long-term adverse effects of treatment has increased. Weight gain is well documented and common occurrence for many breast cancer patients. Recently, a review reported that 50-96% of women experience weight gain during treatment. Furthermore, many patients report a progressive weight gain in the months and years after treatment and patients rarely return to their pre-diagnosis weight. Moreover, weight gain in breast cancer patients has been linked to a poor prognosis compared to patients without weight gain, and to obesity-related disorders including metabolic syndrome.
Adipose tissue is one of the largest human organs. Two functionally distinct types of adipose tissue exist: white adipose tissue and brown adipose tissue (BAT). While BAT was long thought to be present only in rodents and human infants, it is now clear that active BAT also exists in varying degrees in adult humans. Activated BAT has great capacity for energy consumption and takes up large amounts of blood lipids and glucose to use in thermogenesis, and the presence of active BAT in humans is inversely related to obesity, total and visceral fat mass, plasma glucose levels, presence of cardiovascular disease and diabetes status. In accordance, acute cooling increases energy expenditure compared to thermoneutral conditions and correlates with higher BAT activity. Finding ways to activate BAT in humans is thus an attractive approach to prevent weight gain and ensuing comorbidities.
Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for ~15 % of breast cancer cases, and direct inhibition of the HER2 receptor (also called the ErbB2 receptor) is used as standard treatment of HER2-positive breast cancer.
Our preliminary data clearly demonstrates that the ErbB signaling pathway, which includes the HER2 receptor, strongly promotes development and function of cultured human BAT cells and mouse brown adipose tissue. A potential secondary effect of the HER2 receptor blockade used in cancer treatment, is the binding of these inhibitors to ErbB2 receptors in the adipose tissue subsequently affecting downstream signaling pathways that might influence the activity of brown adipose tissue and thereby whole-body metabolism. In support of this hypothesis, weight gain during chemotherapy in HER2-positive breast cancer patients is associated with a decrease in the activity of brown adipose tissue.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Any other cancer (excluding carcinoma in situ and radically operated localised squamous skin cancer) with clinical activity within the last 2 years
- •Metastatic breast cancer
- •Metabolic diseases such as diabetes (exceptions can be made if the disease is well treated, assessed by the clinically responsible medical doctor (see section 18))
- •Regular use of prednisolone - use in relation to chemotherapy only is ok
- •Pregnancy
- •Untreated or dysregulated hypertension defined as outpatient clinic systolic BP > 155 and diastolic BP > 95
- •Clinically significant ventricular or atrial arrhythmia
- •Untreated coronary artery disease or angina pectoris
- •Symptomatic heart failure (NYHA ≥ 2)
- •Known cold urticaria
结局指标
主要结局
BAT activity
时间窗: One year
Difference in cold-induced BAT activity between HER2+ breast cancer patients and HER2- breast cancer controls measured with infrared thermography (temperature difference).
次要结局
- Change in weight(One year)
- Glycemic control (OGTT) - Insulin(One year)
- Glycemic control (OGTT) - C-peptide(One year)
- Change fat mass(One year)
- Resting energy expenditure(One year)
- Cold induced energy expenditure(One year)
- Glycemic control (OGTT) - Glucose(One year)
研究者
Tora Ida Henriksen
Primary Investigator
Rigshospitalet, Denmark