U.S. Army Medical Research and Materiel Command

June 9, 2005

DIETARY MEASURES AND EXERCISE:
NEW TWISTS ON THE LINK TO PREVENTION AND METASTASIS OF BREAST CANCER

Points of Contact:
Lynn Rudinsky phone 212/886-2200, email lrudinsky@cooneywaters.com
In Philadelphia 6/8 - 6/11
Pennsylvania Convention Center, 215-418-2155
Gail Whitehead, Public Affairs Coordinator, phone (301) 619-7783, email gail.whitehead@amedd.army.mil

Research Results from the "Era of Hope "Department of Defense Breast Cancer Research Program Meeting

PHILADELPHIA, June 9, 2005 - Scientists have long sought a better understanding of the role of lifestyle factors - everyday choices people make about activities such as eating and fitness regimens - in causing or preventing disease. At the "Era of Hope" Department of Defense Breast Cancer Research Program meeting, researchers funded through this program will present on a range of these issues from new angles. The findings explore the role of exercise in restoring the immune system after chemotherapy or radiation, the potential benefit of "yo-yo" dieting and consumption of a turmeric compound in preventing breast cancer and metastases.

Exercise Can Help Repair Chemotherapy-Damaged Immune Systems in Breast Cancer Survivors
Exercise after chemotherapy for breast cancer boosted the activity of infection-fighting T cells in women who worked out regularly, according to data from a study conducted at Penn State. These findings indicate that exercise can help restore immune systems damaged by anti-cancer drugs, which destroy healthy as well as malignant cells.

Women between the ages of 29 and 71 were assigned to an exercise group (28 women) or a non-exercise group (21 women). In the intervention arm, women began the exercise routine usually within a month of completing post-surgical therapy. All exercisers followed a similar regimen - stretching to warm up, use of Flexbands for resistance training, and an aerobic activity of their choice: treadmill, exercise bike, or walking. In the exercise group, each woman was paired with a kinesiology intern who served as a personal trainer.

"For the first three months, the women worked out with the trainers at our clinical research center three times a week for about 60 to 90 minutes, at a level the trainers determined was appropriate," said Andrea Mastro, Ph.D., professor of microbiology and cell biology at Penn State in University Park, PA. "We designed an exercise program that could be done without a gym so that during the second three months, participants had the option of working out at home."

Testing was conducted before the intervention, at three and six months. Measurements for some immune functions improved; exercisers showed more activated lymphocytes than non-exercisers. In addition, concentrations of IFN-?, an inflammatory substance that indicates trauma (e.g., from treatment), decreased in exercisers but increased in non-exercisers during the first three months. Another assay suggested that lymphocytes damaged or killed by therapy were replaced with new and responsive lymphocytes - which divide to create more invader-fighting cells in response to foreign substances - more quickly in exercisers.

"We know that chemotherapy-induced decreases in T cells can persist for many years, and data from the literature suggest that, in the period immediately following chemotherapy, the surviving T cells may be weakened as well," Dr. Mastro said. "That's why we're pleased to find evidence that appropriate exercise can help a breast cancer survivor's immune system bounce back after therapy." She noted that during the recruitment phase, some women said that their doctors had counseled them not to exercise after therapy.

Additional test results showed improvements in various physical functions such as endurance, upper-body strength (grip strength, biceps, triceps), and maximal oxygen intake (VO2_max). For women who exercised throughout the program, the physical function measures were better at six months than at three months. On a standard questionnaire, exercisers also scored higher on overall quality of life, social well-being, and experienced lower fatigue levels than the non-exercisers. There were no differences in results between women who exercised at home or at the research center.

Most exercisers preferred to continue with the personal trainers at the research center. Women who chose to work out at home kept an exercise log, which they discussed with the trainer during telephone interviews or weekly visits to the Penn State campus. During the first three months, compliance with the exercise regimen was about 82%, dropping to 76% during the second three-month period. According to feedback, distance from the university was a factor in the dropout rate.

There were no significant differences between the two groups in education, cancer treatment or stage, age, overall health, body mass index, or diet. In both groups, equal numbers of women had lumpectomy or mastectomy, most of the women had the same chemotherapy followed by radiation therapy, and most reported doing little if any regular exercise before diagnosis. Among those who had exercised before their diagnosis, walking was generally the activity of choice. The study excluded women who had other serious health conditions or took drugs that could affect the immune system.

Another study, conducted in a similar population by Canadian researchers and published in the April issue of the Journal of Applied Physiology, also found that exercisers had a greater percentage of activated T cells. Although that research was conducted for three months rather than six and examined aerobic conditioning rather than resistance training, Dr. Mastro considers the two studies complementary.

As a follow up, Dr. Mastro hopes to conduct a retrospective study of breast cancer survivors to determine whether their immune systems are still depressed five years after treatment.

Animal Study Finds Potential Benefit to On-Off Dieting in Preventing Breast Cancer in Post-menopausal Women
Post-menopausal women are counseled to achieve or maintain a healthy weight to prevent breast cancer, but many slip into a pattern of pounds lost and regained. New data from two studies in mice suggest that cycles of on-off dieting are not necessarily bad and may actually have a protective effect in prevention of breast cancer, according to researchers at University of Minnesota.

"Yo-yo dieting is the way that a lot of people live now, and humans used to live in feast-or-famine cycles, so intermittent calorie restriction may be natural," suggested Margot Cleary, Ph.D., associate professor at the University of Minnesota's Hormel Institute, Austin, MN.

Dr. Cleary and her colleagues examined the effects of reduced-calorie diets in transgenic mice-animals bred to develop a high incidence of breast cancer. The mice they studied develop tumors much later in life than most mouse models, which provides a better approximation of postmenopausal breast cancer, where environmental factors such as diet and body weight are more apt to have an impact.

In the first study, the control ad libitum (AL) group received a standard diet and ate at will; the intermittent restricted (IR) and chronic restricted (CR) groups received the same total amount of vitamins, minerals, proteins, and fats but in different ways. The IR group was limited to 50% of the AL diet for three weeks and then allowed to feed freely for three weeks; the CR group's caloric intake was reduced by 25% every day for the entire six weeks. Mice were started on the regimens as young adults and followed for a total of 12 restriction/refeeding cycles. The second study followed the same protocol, but for unknown reasons, the IR mice ate significantly more during the free feeding period. In the IR group, calories were cut by 50% because people usually reduce calories by half when they diet but try to keep proportions of nutrients the same, Dr. Cleary explained.

At the end of the first study, the first AL group had a 77% breast tumor incidence, compared with 44% for the CR mice (43% reduction) and 3% for the IR mice (96% reduction). In the second study, breast tumors appeared in 84% of AL mice, 37% of CR mice, and 15% of IR mice.

"The caloric cycling of the intermittent restricted group was very protective, but overeating in the second study reduced the benefit somewhat," noted Dr. Cleary.

To learn more about how caloric restriction exerts the observed benefits, the researchers are investigating IGF-1 and leptin. Serum IGF-1 is a growth factor associated with the protective effects of calorie restriction, and leptin is a neurotransmitter made in fat tissue and involved in regulation of appetite.

"The ultimate goal is to identify how intermittent caloric restriction prevents breast cancer so that we can develop dietary or drug prevention strategies for this disease," Dr. Cleary said.

Turmeric Derivative Significantly Decreased Spread of Breast Cancer to Lungs in Mice
Curcumin, a non-toxic component of the spice turmeric, significantly reduced the spread of breast cancer to the lungs in mice. The study used a human breast cancer cell line specifically engineered to metastasize to the lungs, one of the leading sites for the spread of breast cancer.

"Curcumin acts against transcription factors, which are like a master switch," explained Bharat B. Aggarwal, Ph.D., chief of the Cytokine Research Section, Department of Experimental Therapeutics at The University of Texas M. D. Anderson Cancer Center in Houston. "Transcription factors regulate all the genes needed for tumors to form. When we turn them off, we shut down some genes that are involved in the growth and invasion of cancer cells."

Published data show that curcumin, which is also an antioxidant, has cancer-preventing properties in cell lines and as a dietary supplement in animal models. In this study, Dr. Aggarwal and his colleagues used grafts of human breast cancer in a mouse model. The grafts were allowed to grow to large tumors of about 10 mm in diameter in 60 animals before treatment began. After these tumors were surgically removed, the mice were randomly divided into one of four groups: a no-treatment control group, curcumin alone, paclitaxel (Taxol®) alone, or curcumin plus paclitaxel. Curcumin was administered as 2% of the daily food consumption daily for five weeks, and paclitaxel was injected on days 17 and 24 at a dose comparable to therapeutic ranges in humans.

At the end of the five-week period, all three treatment arms showed anti-metastatic effect compared with the control group. The greatest impact was in the curcumin-containing regimens: 50% of animals in the curcumin-only group and 22% of animals in the curcumin plus paclitaxel group had evidence of breast cancer that had spread to the lungs.

In the two-agent arm, the tumors were so small that the investigators had difficulty collecting enough tissue for examination. This compares to findings of lung metastases in approximately 75% of animals in the paclitaxel group and 95% of animals in the control group.

Surprised by the apparent magnitude of effect, the researchers replicated the experiment. The second time, the results with curcumin alone not only confirmed its activity against the lung metastases but raised questions about the value of the combined therapy.

"Our results were the same for curcumin by itself and with paclitaxel, with approximately 50% of animals in both groups showing lung metastases," Dr. Aggarwal reported. The only difference between the two studies was that in the second experiment, the primary tumor was allowed to grow slightly longer before being removed.

From both experiments, the researchers conclude that curcumin is effective, but they don't know whether paclitaxel bolsters curcumin's ability to curb metastases.

Curcumin, derived from the bulb of a plant native to India and Southeast Asia, has long been used in traditional medicine to treat a variety of disorders. The average dietary consumption of curcumin in those parts of the world is estimated to be 100-200 mg or more per day; clinical testing in humans has found curcumin to be non-toxic at doses of up to 8 g per day.

"What's exciting about this agent is that it seems to have both chemopreventive and therapeutic properties. If we can demonstrate that it is efficacious in humans, it could be of tremendous value, but we're a long way from being able to make any recommendations yet," said Dr. Aggarwal.

Researchers at M. D. Anderson hope to expand animal studies and then move to a phase I clinical trial of curcumin as a single agent in high risk women - those with a previous breast cancer - to prevent metastases in early-stage breast cancer. Because curcumin is a low-cost, non-proprietary natural product, Dr. Aggarwal expects to rely on federal funding for clinical testing. Phase I clinical trials are already under way at M. D. Anderson with curcumin in multiple myeloma and pancreatic cancer, and other groups are conducting a global study of curcumin to prevent oral cancer.

"Era of Hope" is a forum for the presentation of research supported by the U.S. Department of Defense's Breast Cancer Research Program (BCRP), an unprecedented partnership between the military, scientists, clinicians, and breast cancer survivors. Since 1992, the BCRP has been working to prevent and cure breast cancer by fostering new directions in research, addressing underserved populations and issues, encouraging the work of new and young scientists and inviting the voice of breast cancer survivors to be heard in all aspects of the program. One of many congressional research programs managed by the U.S. Army Medical Research and Materiel Command, the BCRP has received more than $1.8 billion to date from Congress for innovative breast cancer research.

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"The Use of Exercise to Increase Lymphocyte Activation Following Chemotherapy for Breast Cancer"
A Mastro, N Hutnick, N Williams, W Kramer, R Dixon, A Bleznak
Concurrent Symposia Session IV, Symposia 24: Friday, June 10, 6:45 p.m. - 8:45 p.m., Room 204C

"Prevention of Mammary Tumor Development by Intermittent Caloric Restriction. Importance of the Manner in Which Calories Are Consumed"
M Cleary, J Grande, N Maihle
Concurrent Symposia Session II, Symposia 7: Thursday, June 9, 4:15 p.m. - 6:15 p.m., Room 201A

"Curcumin Suppresses Metastasis in a Human Breast Cancer Xenograft Model: Association with Suppression of Nuclear Factor-KAPPAB, Cycloxygenase-2 and Matrix Metalloproteinase"
B Aggarwal, S Shishodia, S Banerjee, R Newman, C Bueso-Ramos, J Price
Concurrent Symposia Session V, Symposia 29: Saturday, June 11, 6:45 p.m. - 8:45 p.m., Room 204A