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Breast Cancer: A Role For Trans Fatty Acids?

Two groups from INSERM and Institut Gustave Roussy collaborated to conduct an epidemiologic study on a cohort of French women members of the Mutuelle generale de l'Education nationale (E3N). The scientists showed that the risk of breast cancer was doubled in women having higher serum levels of trans fatty acids. The trans fatty acids studied are those from industrial sources (processed foods, processed bread, processed pastries, cakes, potato chips

Unlike Asian countries, where the protective effect of omega-3 fatty acids from fish on breast cancer risk was clearly demonstrated, a protective effect against breast cancer was not found in this study.

These results are published in the American Journal of Epidemiology.

The E3N cohort is the French part of EPIC, a large European study coordinated by the International Agency for Research on Cancer (IARC), and involving 500 000 Europeans in 10 countries.

The unhealthy effects of trans fatty acids on cardiovascular risk have been well established since the early 1990s, yet their impact on breast cancer risk remained to be elucidated. The teams of scientists from INSERM and Institut Gustave Roussy sought to evaluate the role of various types of fatty acids on breast cancer development, using blood samples collected between 1995 and 1998, amongst 25 000 of the 100 000 women followed up within the E3N study.

In order to assess the health effects of human diet, scientists assayed various biomarkers of diet in the blood, and particularly fatty acid levels. Data on 363 women diagnosed with breast cancer after blood sampling were analysed. Their serum fatty acid levels were then compared with those of breast cancer-free women controls. Two controls were matched to each breast cancer case, for a total of 702 women.

Near-doubling of risk

The analysis of trans and cis fatty acids showed that breast cancer risk increases with the increase in trans fatty acid level, reflecting processed food consumption. These results show that women with elevated serum levels of trans fatty acid have almost twice the risk of developing breast cancer, compared to women with the lowest levels. "At this stage, we can only recommend limiting the consumption of processed foods, the source of industrially-produced trans fatty acid. Particularly, industrial processes generating trans fatty acids (partially hydrogenated vegetable oils) still in use should be curbed, as this has been undertaken in Denmark for a few years. As far as regulations on labeling of processed products, the content in trans fatty acids should be clearly indicated", the report concluded.

Protective effect of omega-3 fatty acids for breast cancer not universal

Also, the authors of the study confirmed the results of other studies conducted in North American and European countries concerning the absence of association between omega-3 fatty acid serum levels, for which the main dietary source is the intake of fish, and risk of breast cancer. While a protective effect of omega-3 fatty acids on breast cancer risk was clearly demonstrated in Asian countries, where fish consumption is much higher than in Europe or in North America, this protective effect could not be measured in this highly-powered French study, probably due to considerably lower per-capita consumption of fish.

In industrialised countries, breast cancer is the most common cancer in women. According to the authors of the study, among the risk factors that may lend themselves to primary prevention, diet shows strong potential, as a single but consistent change in dietary habits could lower the risk of breast cancer, subject to clear identification of responsible nutrients. Among those, dietary lipids could play a major role. Further analysis from the EPIC study will therefore test the hypothesis of a role for trans fatty acids in carcinogenesis in a population with wide variations in the intake of those fatty acids, among other lipids.

The E3n Study

E3N, an epidemiologic study conducted on women members of the MGEN (French National Education workers complementary medical insurance scheme) led by Dr Françoise Clavel-Cahpelon (INSERM-Gustave Roussy), is a prospective cohort study of about 100 000 volunteer French women born between 1925 and 1950, and followed up since 1990.

Data on their lifestyle factors (diet, hormonal treatments, etc.) and their health status were collected by self-administered questionnaire every other year since 1990. These data were complemented by biological measurements, obtained for 25 000 volunteers, from a blood specimen taken for later analysis (case-control studies nested within the cohort). E3N gives primary consideration to breast and colorectal cancers, due to their high incidence rates.

Source

Serum trans-monounsaturated fatty acids are associated with an increased risk of breast cancer in the E3N-EPIC Study.
V. Chajès; A. C.M. Thiébaut; M. Rotival; E. Gauthier ; V. Maillard; M.C. Boutron-Ruault; V. Joulin; G. M. Lenoir ; F. Clavel-Chapelon.
Am. J. Epidemiol. 2008 (DOI: 10.1093/aje/kwn069)

Alcohol And Genetic Factors Linked To Breast Cancer Risk

US scientists have discovered two genes that play a role in the metabolism of alcohol are linked with increased risk of breast cancer in postmenopausal women who drink.

The study was presented yesterday in San Diego, California, at the Annual Meeting of the American Association for Cancer Research (AACR). The research leaders were Dr Peter Shields, professor of medicine and oncology based at Georgetown University's Lombardi Comprehensive Cancer Center in Washington DC, and Dr Jo Freudenheim, chair of social and preventive medicine at the State University of New York in Buffalo.

The research showed that variations in two genes, ADH1B and ADH1C, that code for an enzyme that breaks down alcohol, were linked with increased risk of breast cancer among women who drink.

Research instructor of cancer genetics and epidemiology at Lombardi, and lead author of the study, Dr Catalin Marian said:

"The higher their alcohol consumption, the higher their risk."

The researchers examined DNA information from 991 women aged 35 to 79 residing in two western New York counties between 1996 and 2001 who had histologically confirmed primary stage breast cancer. These were matched by 1,698 randomly selected healthy participants according to age, race and county of residence.

All participants were taking part in a population-based case-control study called the Western New York Exposure and Breast Cancer (WEB) Study, conducted by Freudenheim.

The results showed that increased breast cancer risk in postmenopausal women was linked to variations in DNA sequences in two genes: ADH1B (sequence rs1042026) and ADH1C (sequence rs1614972).

Among postmenopausal women with the ADH1B (sequence rs1042026) gene variant, the risk of breast cancer for the alcohol drinkers was nearly double that of the abstainers.

Among women with the ADH1C (sequence rs1614972) gene variant, there was a protective effect against breast cancer risk that varied inversely with the amount of alcohol: the more alcohol a woman with this gene variant consumed, the less protection offered, and the higher the risk of breast cancer. (Conversely, this could be viewed as the protection conferred by the gene appeared to get stronger as alcohol consumption dropped).

Marian warned that more research was needed to confirm and replicate the findings before any firm conclusions could be drawn. This study merely suggests that the variants are linked with increased breast cancer risk, it does not suggest they cause it biologically.

Variations in the two genes will impact alcohol metabolism because they are involved in that process, explained Marian, but she was cautious to point out this may not be the whole story:

"We have to keep in mind that the gene sequence variations we observed are not located directly in coding regions, but they may be associated and inherited together with other variations that have this effect on the enzyme function."

According to the National Cancer Institute, in 2008 there will be over 180,000 new cases of breast cancer among women and nearly 2,000 among men, while over 40,000 women and nearly 500 men will die of the disease

Dietary Oil May Need Help In Avoiding Side Effects Of Weight Loss

An oil made of natural fatty acids that is sometimes used as a weight-loss supplement may need to be paired with hormones or other substances to prevent health problems that can follow rapid weight loss, a new study suggests.

Conjugated linoleic acid (CLA), a compound naturally found in some meat and dairy products, can reduce body fat in some studies in humans. But a recent study in mice found that the hormone leptin adds an element of protection against side effects that can accompany fat loss with CLA.

Without leptin, fat loss occurs in mice eating a diet containing CLA, but the mice also become insulin resistant. When mice are fed CLA and given leptin, the same fat loss occurs but insulin resistance does not develop.

So though leptin is not essential to the fat loss, it has important protective effects to maintain insulin sensitivity, said Martha Belury, lead author of the study and associate professor of human nutrition at Ohio State University.

"Fat loss is not dependent on leptin but if we didn't have leptin, CLA could have some short-term effects on insulin resistance," Belury said.

The study appears in a recent issue of the Journal of Lipid Research.

CLA is an essential fatty acid found naturally in trace amounts primarily in beef, lamb and milk. Synthetic forms of CLA are marketed as supplements that help reduce body fat.

But continuing research shows that there are consequences associated with the loss of fat. Because fat in the body is energy, it has to go somewhere if it is not burned away by metabolism. When CLA is driving fat out of fat tissue, the fat tends to end up in the liver or in muscles. If that fat can't be used, insulin resistance results. So Belury and colleagues are trying to find out precisely how CLA works to reduce body fat and how to prevent any associated side effects.

"You can reduce body fat, which is a good thing for a person trying to avoid diabetes. But if that body fat is lost too rapidly, the fat has to go somewhere else and in mice, it creates insulin resistance," Belury said. Sometimes, insulin resistance can lead to Type 2 diabetes.

In the animal study, Belury and colleagues tested the effects of leptin by using mice genetically engineered so they have no leptin in their bodies. These mice consume a lot of food and their metabolism is disrupted, so they tend to be quite overweight and are called fatty mice.

"Our thinking was that if you lower body fat, you also lower leptin levels. So if we have a mouse that has no leptin, what does CLA do then?" Belury said.

To create controls for comparison, the researchers gave leptin back to some of the fatty mice. Then they fed regular diets or diets containing CLA to all of the mice to observe the effects of CLA and regular diets with and without leptin present.

Finding that CLA diets can result in weight loss with or without leptin was a new finding. But more significant to understanding the mechanism, the study showed that insulin sensitivity was restored when CLA was fed with leptin present.

That finding answers just one of many questions about possible side effects associated with CLA-induced loss of body fat. The role of fat tissue in regulating metabolism is complex. It stores energy in the form of fat and also produces hormones essential to the metabolism, or burning, of the fat tissue.

In addition to continuing animal studies on CLA's interaction with hormones and other conditions associated with metabolism, Belury is leading parallel human clinical trials on the effects of CLA. So far, the research has shown that CLA can reduce body fat in postmenopausal women with Type 2 diabetes. Another trial is investigating whether CLA can suppress weight gain in people who are gaining weight because of a drug they take for diabetes management.

"People can safely take CLA, but we don't know the most effective dose for weight loss and how long people should take it. We think there are probably some subpopulations that shouldn't take it, but we don't know for sure yet," she said.

Belury conducted the study with former Ohio State nutrition graduate students Angela Wendel, now a postdoctoral researcher at the University of North Carolina; Aparna Purushotham, now with the National Institute of Environmental Health Sciences; and Li-Fen Liu, now a postdoc at Stanford University.

The work was supported by funds from the Carol S. Kennedy professorship, the Ohio Agricultural Research and Development Center, the U.S. Department of Agriculture, College of Human Ecology scholarships, the Natural Health Research Institute Scholarship for Diabetes, the American Oil Chemists' Society, and the J. Parker and Kathryn Webb Dinius Fellowship.

Exploring Infant Feeding And The Development Of Obesity

A symposium at the American Society for Nutrition's annual meeting at Experimental Biology was held in which noted scientists discussed new infant feeding studies that used methodology such as randomized clinical trials (involving breastfeeding promotion) as well as sibling pairs analysis. These studies may offer new insights into possible associations between infant feeding and health outcomes such as obesity.

The symposium, "Infant Feeding and the Development of Obesity: What Does the Science Tell Us?" sponsored by the International Formula Council (IFC)* and chaired by Linda Adair, Ph.D., professor of nutrition at the University of North Carolina at Chapel Hill, brought together international experts in the field of infant nutrition to present their recent findings.


Featured researchers included David Barker, M.D., Ph.D., professor of clinical epidemiology at the University of Southampton, UK and professor of Cardiovascular in the Department of Medicine at the Oregon Health and Science University, whose soon-to-be published study examines breastfeeding in a large group of sibling pairs that were followed into their late 60s.

"This type of study design controls for maternal factors," according to Dr. Barker. "Differences in the long-term effects of breast and bottle feeding may reflect differences in the mothers rather than the effects of feeding itself." Maternal factors include maternal health status, maternal care-giving, mother-child interactions or other health-related behaviors of the mother that may interfere with determining the association of infant feeding and health outcomes and the strength of any possible associations.

Other study designs such as the randomized clinical trial on breastfeeding and health outcomes in infants in Belarus recently conducted by Michael Kramer, M.D., a pediatrician and perinatal epidemiologist at McGill University in Montreal, provide evidence that research design can have a significant impact on infant feeding study results. In a randomized infant feeding clinical trial, known as the gold standard in research, infants would be randomly assigned to be breastfed or formula-fed; however, such trials are generally not feasible in infant feeding research, since most mothers determine their infant's feeding method. Dr. Kramer randomly assigned hospitals to implement breastfeeding promotion practices and standard care. He found that despite the substantial increase in prolonged and exclusive breastfeeding among mothers receiving the intervention, there were no differences between their children (n= 7,108 subjects) and the children of mothers from the control hospitals (n= 6,781 subjects), that did not implement breastfeeding promotion practices, on several measures of adiposity at 6.5 years of age.

These findings challenge the concept that breastfeeding reduces the risk of obesity in childhood, as some other studies have found. Speaking of the strength of his study design and the fact that other studies due to their design may have been prone to inherent bias, Dr. Kramer noted, "Previously reported beneficial effects on these outcomes (measurements of obesity) may be the result of uncontrolled confounding and selection bias." The study performed by Dr. Kramer represents the largest randomized trial done to date in the area of human lactation.

Other researchers at the symposium presented the outcomes of more traditional epidemiologic studies that were based on observational designs and thus had limitations such as not being able to control subjects' behavior. Beth Mayer-Davis, Ph.D., R.D., professor of nutrition and diabetes researcher at University of North Carolina at Chapel Hill, discussed findings from her research on infant feeding and diabetes in ethnic groups in a United States population. In her observational study of less than 300 subjects, mothers of children with diabetes were asked to recall if and for how long they breastfed their infant. Dr. Mayer-Davis reported that breastfeeding appeared to reduce the risk for development of type 2 diabetes in youth, possibly mediated in part by weight status in childhood.

Nancy Butte, Ph.D., professor of pediatrics at the Children's Nutrition Research Center at Baylor College of Medicine, discussed early infant feeding practices and effects on obesity. Dr. Butte presented her work from the VIVA LA FAMILIA study, an observational study with a cohort of 1,030 Hispanic children. Dr. Butte noted that although breastfeeding appeared to have a small protective effect against childhood obesity, other genetic and environmental factors "far supersede infant feeding practices as risk factors for childhood obesity."

Weight Loss Drug Rimonabant May Not Slow Progression Of Heart Disease

According to a recent study published in JAMA, a clinical trial testing how well the anti-obesity medication rimonabant slowed the development of coronary artery disease in patients with abdominal obesity and pre-existing coronary disease resulted in mixed conclusions. Called STRADIVARIUS (the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant - The Intravascular Ultrasound Study), the trial was conducted by Steven E. Nissen, M.D. (Cleveland Clinic) and several STRADIVARIUS investigators.

Nissen and colleagues write that, "Abdominal obesity, even in the absence of type 2 diabetes, is associated with a constellation of metabolic and physiological abnormalities that amplify the risk for atherosclerotic cardiovascular disease." Some examples of metabolic syndrome are high triglyceride levels, low HDL (good) cholesterol levels, high blood pressure, and high blood glucose (blood sugar) levels.

Atherosclerotic disease is more commonly known as "hardening" of the arteries, and it occurs when the inner walls of the arteries accumulate plaque deposits. Abdominal obesity is a fundamental cause of atherosclerotic disease, but currently there are few treatment options available for the condition. The drug rimonabant, a selective cannabinoid type 1 receptor antagonist, is one possible treatment option. Lacking the approval of the U.S. Food and Drug Administration, the drug is only available in other countries.

To compare rimonabant against placebo, the researchers designed a randomized, double-blinded clinical trial that included 839 patients at 112 centers in North America, Europe, and Australia selected from December 2004 to December 2005. For 18 to 20 months after random assignment, participants received either 20 mg daily of rimonabant or a matching placebo. Part of the selection process maintained that patients were eligible only if they needed coronary angiography for medical reasons. After randomization, participants scheduled clinic visits at 3, 6, 12, and 18 months. The STRADIVARIUS researchers were chiefly concerned with the change in the percent atheroma volume (PAV) and secondarily concerned with the change in normalized total atheroma volume (TAV). Both PAV and TAV indicate how much plaque has built-up on the inner lining of an artery. These markers of atherosclerotic progression were measured by ultrasonographic coronary imaging.

"In the rimonabant vs. placebo groups, PAV increased 0.25 percent vs. 0.51 percent, respectively, and TAV decreased -2.2mm³ vs. an increase of 0.88mm³," write the researchers. "Rimonabant-treated patients had a larger reduction in body weight (-4.3kg [-9.5 lbs.] vs. -0.5 kg [-1.1 lbs.]) and greater decrease in waist circumference (-4.5 cm [-1.77 inches] vs. -1.0 cm [- 0.39 inches]). In the rimonabant vs. placebo groups, high-density lipoprotein cholesterol levels increased 5.8mg/dL (22.4 percent) vs. 1.8mg/dL (6.9 percent) and median (midpoint) triglyceride levels decreased -24.8 mg/dL (20.5 percent) vs. -8.9 mg/dL (6.2 percent)."

The investigators also found, however, that changes in the level of "bad" cholesterol (LDL-C) and changes in blood pressure were not significantly different between groups. "Psychiatric adverse effects were more common in the rimonabant group (43.4 percent vs. 28.4 percent)," with anxiety and depression being the most commonly reported adverse side effects.

In the authors' words: "Administration of rimonabant, 20mg, daily for 18 months did not significantly reduce the rate of progression of coronary disease for the primary IVUS (intravascular ultrasound) end point, the change in PAV." Although, "The secondary endpoint, change in TAV, showed a statistically significant treatment effect favoring rimonabant."

"Because the current study failed to achieve a statistically significant effect for the primary efficacy measure, additional studies will be required to further define the role of rimonabant in the treatment of abdominally obese patients with coronary disease and metabolic risk factors," the authors conclude.

An accompanying editorial by John S. Rumsfeld, M.D., Ph.D. (Denver Veterans Affairs Medical Center and the Department of Medicine at the University of Colorado) and Brahmajee K. Nallamothu, M.D., M.P.H. (Ann Arbor Veterans Affairs Medical Center and the Department of Medicine, University of Michigan) notes that the STRADIVARIUS trial is critical to understanding the effectiveness and safety of rimonabant.

"This drug is clearly efficacious for weight loss, underscoring its promise as a therapeutic option for obesity. However, despite improvements in metabolic parameters, STRADIVARIUS demonstrated no efficacy of rimonabant for coronary artery disease progression while it simultaneously heightened concern about its safety profile," write Rumsfeld and Nallamothu.

They conclude: "The hopes for rimonabant ultimately may be realized if the drug is shown to have a favorable effect on mortality and cardiovascular events. In that case, clinicians will be grateful for a new weapon in the fight against the obesity epidemic but will have to remain vigilant for trade-offs in quality of life, an outcome of equal importance to survival and certainly more important than any surrogate measure."

Effect of Rimonabant on Progression of Atherosclerosis in Patients With Abdominal Obesity and Coronary Artery Disease: The STRADIVARIUS Randomized Controlled Trial
Steven E. Nissen; Stephen J. Nicholls; Kathy Wolski; Josep Rodés-Cabau; Christopher P. Cannon; John E. Deanfield; Jean-Pierre Després; John J. P. Kastelein; Steven R. Steinhubl; Samir Kapadia; Muhammad Yasin; Witold Ruzyllo; Christophe Gaudin; Bernard Job; Bo Hu; Deepak L. Bhatt; A. Michael Lincoff; E. Murat Tuzcu;
JAMA (2008). 299[13]:1547-1560.