Evaluation of Changes in the Methylome and Prognosis of Obesity-related Breast Cancer After Nutritional Intervention-induced Weight Loss During the Oncological Treatment
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 220
- 主要终点
- Concentration of inflammatory biomarkers
研究概览
简要总结
Obesity could become the first evitable cause of breast cancer in the near future. Due to the relatively slow rate of development in this field, greater efforts must be applied in this area. The HYPOTHESIS of this work is that "a therapy to lose weight in breast cancer women with obesity during the oncological treatment could contribute to slowing carcinogenesis, and to improve the response to the chemotherapy, survival and prevent future recurrences by erasing deleterious epigenetic marks". A group of breast cancer women with obesity (n=90) will be treated to lose weight during the oncologic treatment with a low calorie-ketogenic diet or a group educational intervention program of healthy lifestyle. The reversibility of the obesity-related breast cancer epigenetic signatures (EPIC array and pyrosequencing) and other molecular features (QRTPCR, ELISA assays) in blood leukocytes and plasma and the progression of disease will be compared with an obesity (n=30) and normalweight (n=30) group under conventional anticancer therapy. A matched-group of tumor-free women (n=60) with obesity will be also treated to lose weight with the same nutritional interventions and compared with tumor-free women with normal weight (n=30) in order to evaluate the potential preventive function of weight loss therapies on cancer-related odds. The outcomes of this project will directly benefit overweight and obese patients from healthcare systems, and also to have an economic value supporting pharmaceutical and food industry companies in the design of innovative treatments, useful biomarkers and preventive tools.
详细描述
Obesity itself is considered the second leading avoidable cause of cancer, after smoking (Renehan and Soerjomataram, 2016;Islami et al., 2019). The worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed with the aim to find new therapeutic targets to counteract the obesity-related cancer in general and breast cancer in particular. The increased morbidity and mortality of obesity-related cancer are mostly attributed to dysfunctional adipose tissue. Therefore, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy.
Breast cancer (BC) is the most common female cancer worldwide and the second common cause of cancer-related death in women. In 2018, around 2 million new cases of BC were diagnosed represented 15% of deaths of the 10 most common cancers (Bray et al., 2018). By 2030 cancer is expected to surpass cardiovascular disease being the prevailing cause of death among all age categories, contributing to a 45% increase in the number of malignancies diagnosis during the next 10 years. This is due to the emergence of the increased prevalence of risk factors, mainly diabesity (diabetes mellitus and obesity) in both developed and developing countries (Christodoulatos et al., 2019).
Risk factors for breast cancer include excess weight and metabolic disorders, which have been linked to a poor prognosis of this disease (Bousquenaud et al., 2018;Kliemann et al., 2019;Le et al., 2019). Thus, the World Cancer Research Fund (WCRF) has concluded that healthy lifestyles may help to prevent up to 70% of cancer cases. These include healthy diet eating, regular physical activity, healthy weight, and avoiding smoking and alcohol drinking (Clinton et al., 2019). Obesity is associated with a greater tumor burden in postmenopausal women diagnosed with breast cancer and with a higher degree of tumor. In addition, obesity and overweight are linked to a worse prognosis and an increase in breast cancer death rate. In fact, recently in a work carried out by our research group (Crujeiras et al., 2012), it was found in a homogeneous population in Spain that the prevalence of obesity among breast cancer patients was significantly higher than the prevalence observed among women of the general Spanish population. This increase in prevalence was especially evident in women with postmenopausal breast cancer (Crujeiras et al., 2012). However, although there is epidemiological evidence of the relationship between obesity and cancer, the molecular mechanisms of this relationship is not well known.
Obesity and cancer mechanisms: Adipose tissue secreted factors, inflammation, oxidative stress, epigenetics.
There are several hypothesis that were proposed to be involved in the relationship between obesity and cancer. Among them, the most of the recent studies are being focused on the effect of the dysfunctional adipose tissue observed in obesity (Cabia et al., 2016). Supporting this hypothesis, a recent work of our research group demonstrated that the obese visceral adipose tissue secretome is able to induce higher proliferation of breast tumor cell lines (Crujeiras et al., 2016).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 50 Years 至 70 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Postmenopausal women
- •Primary, histologically confirmed, incident breast cancer diagnostic
排除标准
- •Thyroid disorder,
- •Diabetes mellitus,
- •Cardiovascular disease,
- •cerebrovascular disease
- •Obesity induced by other endocrine disorders or drugs,
- •Participation in any active weight loss program in the previous 3 months.
- •Known or suspected narcotic or alcohol abuse,
- •Severe depression or any other psychiatric disease,
- •Severe liver failure
- •Uncontrolled hypertension,
- •Orthostatic hypotension,
- •hydroelectrolytic or electrocardiographic alterations
- •Prescription of drugs that may alter the lipid or glucose profile.
研究组 & 干预措施
Energy restriction-ketogenic intervention (VLCKD)-breast cancer arm
Breast cancer patients with obesity will follow an energy-restricted-ketogenic dietary five steps program, which includes lifestyle and behavioral modification support. The first three steps consist of a VLCKD (600 -800 kcal/day), low in carbohydrates (< 50 g daily from vegetables) and lipids (only 10 g of olive oil per day). Throughout these ketogenic phases, supplements of vitamins and minerals supplements, such as K, Na, Mg, Ca, and omega-3 fatty acids will be administered. These three steps will be maintained until the patient lost the target amount of weight, ideally 80%. In steps 4 and 5, the patient started a low-calorie diet (800 -1500 kcal/day) and followed by a maintenance diet that will consist of an eating plan balanced in carbohydrates, protein, and fat (1500 and 2000 kcal/day).
干预措施: Very low calorie ketogenic diet (VLCKD) (Other)
Group educational intervention program (IGOBE)-breast cancer arm
Breast cancer patients with obesity will follow structured program of change of habits that will consist of a balanced hypocaloric diet, following the criteria of both the recommendations from Spanish Society of Study of Obesity (SEEDO) 2007, the American Dietetic Guidelines 2010, the Consensus SEEDO 2012 and the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society Guideline for the Management of Overweight and Obesity in Adults 2014. Coinciding all in pointing out that the hypocaloric diet should represent a deficit of about 500 to 1000 kcal / day with respect to the habitual intake of the patient in question. The intervention group will be included in a structured program of habits change and exercise. In the intensive phase of the intervention patients will assist to 6 additional weekly visits, with 15 patients per group and a duration of 60 minutes each.
干预措施: Group educational intervention program (IGOBE) (Behavioral)
Energy restriction-ketogenic intervention (VLCKD)-tumor free arm
Tumor-free patients with obesity will follow an energy-restricted-ketogenic dietary five steps program, which includes lifestyle and behavioral modification support. The first three steps consist of a VLCKD (600 -800 kcal/day), low in carbohydrates (< 50 g daily from vegetables) and lipids (only 10 g of olive oil per day). Throughout these ketogenic phases, supplements of vitamins and minerals supplements, such as K, Na, Mg, Ca, and omega-3 fatty acids will be administered. These three steps will be maintained until the patient lost the target amount of weight, ideally 80%. In steps 4 and 5, the patient started a low-calorie diet (800 -1500 kcal/day) and followed by a maintenance diet that will consist of an eating plan balanced in carbohydrates, protein, and fat (1500 and 2000 kcal/day).
干预措施: Very low calorie ketogenic diet (VLCKD) (Other)
Group educational intervention program (IGOBE)-tumor free arm
Tumor-free patients with obesity will follow structured program of change of habits that will consist of a balanced hypocaloric diet, following the criteria of both the recommendations from Spanish Society of Study of Obesity (SEEDO) 2007, the American Dietetic Guidelines 2010, the Consensus SEEDO 2012 and the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society Guideline for the Management of Overweight and Obesity in Adults 2014. Coinciding all in pointing out that the hypocaloric diet should represent a deficit of about 500 to 1000 kcal / day with respect to the habitual intake of the patient in question. The intervention group will be included in a structured program of habits change and exercise. In the intensive phase of the intervention patients will assist to 6 additional weekly visits, with 15 patients per group and a duration of 60 minutes each.
干预措施: Group educational intervention program (IGOBE) (Behavioral)
Non intervention arm-breast cancer arm
This arm will include patients with obesity and normal weight women with breast cancer that will follow the normal clinical practice in their oncological therapy without intervention to lose weight in the group of patients with excess body weight.
结局指标
主要结局
Concentration of inflammatory biomarkers
时间窗: 4 months
Changes associated to the interventions in plasmatic levels of cytokines quantified using a commercial multiplex enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's instructions. The following cytokines were analyzed: April, B cell activator factor (BAFF), cluster of differentiation (CD)163, CD30, Chitanase, glycoprotein (Gp)130, interferon (IFN)-α2, IFN-β, IFN-γ, interleukin (IL)-2, IL-6R, IL-11, IL-12(p40), IL-12(p70), IL-22, IL-26, IL-28A, IL-29, IL-35, matrix metalloproteinase (MMP)1, MMP3, Osteocalcin, Pentraxin-3, tumor necrosis factor receptor (TNF)-R1, TNF-R2, Thymic stromal lymphopoietin (TSLP) and Tweak.
Score of Sleep Quality questionnaire
时间窗: 4 months
Changes in the score of Sleep Quality associated to the interventions
Fat mass in kg
时间窗: 4 months
Changes in fat mass induced by the nutritional intervention therapies
Fat free mass in kg
时间窗: 4 months
Changes in fat free mass induced by the nutritional intervention therapies
DNA methylation levels
时间窗: 4 months
Changes in the pattern of circulating DNA methylation
Concentration of Oxidative stress biomarkers
时间窗: 4 months
Among the oxidative stress biomarkers, the levels of malondialdehyde (MDA) and total antioxidative power (AOP) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) will be evaluated in serum. MDA and AOP will be quantified using colorimetric assay kits . An enzyme immunoassay kit will be used for the quantification of 8-OHdG in the serum.
Score of quality of life questionnaire
时间窗: 4 months
changes in the score of Quality of life associated to the interventions
Weight loss
时间窗: 4 months
Changes in body weight induced by the nutritional intervention therapies
Visceral fat mass in kg
时间窗: 4 months
Changes in visceral fat mass induced by the nutritional intervention therapies
Score of Female Sexual Function Index questionnaire
时间窗: 4 months
Changes in the score of Female Sexual Function Index associated to the interventions
次要结局
- Response to Oncological treatment(12 months)
- Diagnostic of cardiotoxicity(12 months)
研究者
Ana Belén Crujeiras Martínez
Senior Researcher
Hospital Clinico Universitario de Santiago