The impact of caloric restriction versus exercise on tumor and muscle tissue protein synthesis rates in breast cancer patients

Cancer is among the most prevalent diseases worldwide, with predictions that 15
million cases will be diagnosed and 10 million new cancer-related deaths will
occur next year. Despite recent improvements in treatment success rates, there
remains substantial opportunity to further enhance the efficacy of cancer
treatment to reduce tumor growth. Tumor growth is regulated by the net
difference between tumor tissue protein synthesis and breakdown rates. Several
factors regulate tumor protein synthesis, including circulating anabolic
hormones (i.e., IGF-1). Reducing the presence of these factors has been
suggested to reduce cancer incidence and lower tumor tissue growth rates.
Cancer progression and standard treatment are often accompanied by adverse side
effects, such as fatigue and skeletal muscle mass loss, termed cachexia, which
worsens treatment outcomes. Lifestyle modifications, such as diet and physical
activity interventions, represent promising adjunct therapeutic approaches that
may induce anti-carcinogenic effects while reducing fatigue and skeletal muscle
loss. Moderate caloric restriction and exercise are two promising intervention
strategies that may impact tumor tissue protein synthesis rates.

To determine the the impact of 30% daily caloric restriction or daily exercise
training on tumor and muscle tissue protein synthesis rates in breast cancer
patients.

Subjects will be randomly assigned to undergo 7 days of either caloric
restriction, an exercise program, or standard treatment. The caloric
restriction group will undergo a 30% reduction in daily energy intake (~500-600
kcal). The exercise group will increase daily energy expenditure by 30%
(~500-600 kcal) by performing 1 h of combined resistance- and endurance-type
exercise and 30 min of walking. Patients following standard treatment will act
as the control group. All subjects will ingest small amounts of deuterium oxide
(2H2O) throughout the 7-day period. The 7-day period will end with the tumor
resection surgery, during which a tumor tissue sample, skeletal muscle sample,
and plasma sample will be collected. Protein will be isolated from the tissue
samples and analyzed for the increase in 2H-alanine enrichment to determine
average tumor and muscle tissue protein synthesis rates over the 7-day
assessment period (in %/d).

Caloric restriction:
The caloric restriction group will be subjected to a 30% reduction in daily
dietary energy intake (500-600 kcal per day) while maintaining the same
relative macronutrient intake (i.e., 15/55/30% Pro/CHO/Fat) over the 7-day
intervention period. A nutritional program will be generated for each patient,
with total energy based on usual energy intake assessed with a dietary history
with cross-check. During the intervention, subjects will receive standardized
meals and will receive individualized dietary consultation from the researcher
in collaboration with the Department of Dietetics to ensure compliance and
avoid malnutrition.

Exercise:
The physical activity group will increase daily energy expenditure by 30%
(500-600 kcal) by performing 1 h of combined resistance- and endurance-type
exercise and 30 min walking. Participants in the physical activity group will
perform the exercise protocol (either at MUMC+ or at home) under the
supervision of a certified personal trainer. The endurance-type exercise
component will consist of 30 min cycling at 70% estimated maximal heart rate
(estimated maximal heart rate = 220-Age). The resistance-type exercise
component will consist of 3 sets each of leg press (or dumbbell squats), leg
extension (or dumbbell lunges), chest press, and horizontal row performed at
70% of 1-RM or for 8-12 repetitions per set. Subjects will be instructed to
carry-out 30 min of walking (e.g., 2 x 15 min) at home each day in addition to
habitual physical activity.

Control:
The control group will follow standard treatment and not under caloric
restriction or exercise.

The burden and risks involved in participating in this experiment are small.
The tumor and healthy breast tissue collection will occur during the tumor
resection procedure (lumpectomy), which will already be planned as part of the
subjects* course of cancer treatment. Muscle biopsies will be obtained during
the surgery under anaesthesia by an experienced physician, but may cause some
minor discomfort. The discomfort is comparable to muscle soreness or the pain
one has after bumping into the corner of a table. Isotopically-labelled water
(deuterium oxide or *heavy water*) ingestion has been used previously in
numerous published studies and is entirely safe and non-toxic in the amount
provided in the present study. We have chosen to include breast cancer patients
not undergoing chemo or radiotherapy as they are generally non-frail and will
be able to tolerate caloric restriction or daily exercise. Caloric restriction
of 30% lower than habitual dietary intake is commonly prescribed as a weight
management strategy and will not lead to adverse effects (e.g., dizziness) or
compromise preparation for the lumpectomy procedure. Daily exercise (1 h) is
well-tolerated by patients, but participants may experience muscle soreness
induced by unaccustomed exercise.