Study investigators
 Overview
 Background
 Study Aims and Objectives
 Research Design and Methods
 Data Collection
 Significance
 Ethical Considerations

Study investigators

Co-Principal Investigators

Dr. Christine Friedenreich
Division of Population Health and Information, Alberta Cancer Board, Calgary, Alberta

Dr. Kerry Courneya
Faculty of Physical Education, University of Alberta, Edmonton, Alberta

Co-investigators

Anne McTiernan, MD, PhD; Fred Hutchinson Cancer Research Centre, Seattle, Washington
Rachel Ballard-Barbash, MD, MPH; National Cancer Institute, Rockville, Maryland
Melinda Irwin, PhD; Yale University, New Haven, CT
Martin Yaffe, PhD; Ontario Cancer Institute, Toronto, Ontario
Norman Boyd, MD, DSc; University of Toronto, Toronto, Ontario
Tim Terry, MD; Alberta Cancer Board, Edmonton, Alberta
Rollin Brant, Ph.D.; University of Calgary,Calgary, Alberta
Barbara Cameron; Tom Baker Cancer Centre, Calgary, Alberta
Charlotte Jones, MD, PhD; University of Calgary,Calgary, Alberta

Study Overview

The goal of the study is to examine how a one-year aerobic exercise intervention, as compared to a usual sedentary lifestyle, influences specific biologic mechanisms that are hypothesized to be operative in the association between physical activity and breast cancer risk.

These biologic mechanisms include sex hormone concentrations; measures of adiposity and obesity; biomarkers of inflammation and obesity; mammographic density; insulin-like growth factors; and insulin resistance.

This study is addressing identified gaps in knowledge by examining the simultaneous effect of physical activity on several biologic mechanisms in a controlled trial setting, building on evidence from the only other randomized controlled trial on this topic.

Background

Physical activity is one of the few modifiable lifestyle risk factors for breast cancer that have been identified. Over 55 observational studies have shown that breast cancer risk can be reduced by 30-40% among women who are physically active. These studies have not, however, provided any direct evidence regarding the underlying biologic mechanisms whereby physical activity influences breast cancer risk. Several plausible biological mechanisms have been hypothesized. These include changes in endogenous sexual and metabolic hormone levels and growth factors; obesity and central adiposity; and possibly immune function. The inter-relationships of these risk factors / mechanisms are complex, and the 'true' relationship between physical activity and reduced breast cancer risk is likely to involve multiple mechanisms.

In order to understand what these biologic mechanisms are and what type, level and dose of physical activity influence breast cancer risk, intervention studies are needed that specifically examine possible mechanisms.

The ALPHA Trial specifically addresses the identified gaps in knowledge, in terms of examining the simultaneous effect of physical activity on several biologic mechanisms in a controlled trial setting. The ALPHA Trial is the first such study in Canada, and only the second worldwide.


The main mechanisms that will be examined in this research project are estrogens, androgens, adiposity, obesity and inflammatory markers, mammographic density, insulin-like growth factors, and insulin resistance. The results will provide necessary data for future studies that examine not only the efficacy but also the effectiveness of different exercise interventions for breast cancer risk reduction.

Study Aims and Objectives

This study examines how an aerobic exercise intervention, as opposed to a usual sedentary lifestyle, influences specific biologic mechanisms that are hypothesized to be operative in the association between physical activity and breast cancer risk.

Primary Aim

The primary aim is to determine the effect of the exercise intervention on specific hormonal and biological intermediate endpoints for breast cancer. The project has been funded in two stages. The objectives from the main and ancillary studies are:


Objective 1 

To examine the effect of the exercise intervention on estrogen and androgens (estrone, estradiol, testosterone, androstenedione) and adiposity, risk factors for which there is strong evidence of an association with breast cancer and strong biologic plausibility that exercise may influence these mechanisms.

Objective 2  

To examine the effect of the exercise intervention on mammographic density, insulin-like growth factors (IGF-1, IGFBP-3) and insulin resistance, risk factors for which there is moderate evidence of an association with breast cancer or a moderate to strong biologic plausibility that exercise may influence these mechanisms.

Objective 3

To examine the effect of the exercise intervention on inflammatory markers (IL-6, TNF-α, leptin, adiponectin, C-RP), biomarkers for which there is a hypothesized role in the association between physical activity and breast cancer risk. 

Secondary Aim

The secondary aim is to evaluate the feasibility and acceptability of the exercise intervention and understand the longer-term maintenance of exercise habits in a group of  previously sedentary postmenopausal women.

Objective 1

To describe the effects of the exercise intervention on quality of life among the participants.

Objective 2

To describe the rates and determinants of recruitment and adherence to the exercise trial.

Objective 3

To assess the maintenance of exercise activities among the exercise group 12 months after completion of the intervention and to examine the predictors of exercise maintenance.


Research Design and Methods

The study enrolled a group of 320 postmenopausal, sedentary women and randomly assigned half to an exercise program, and half to continue with their regular lives.

Participant recruitment was initiated through Screen Test, the provincial breast cancer screening program, and through media campaigns.


Eligibility criteria ensured that participants were: a) in an appropriate target group for breast cancer risk reduction; b) were physically fit to undertake the exercise program; c) had a risk profile amenable to change as result of exercise intervention; d) had no other outside factors to influence estrogen metabolism; e) were logistically able to complete the study.

Participants were randomized to one of two groups: an exercise intervention, or a control group. No change in dietary intake was made for either group. The Edmonton and Calgary exercise oncology facilities worked in collaboration, and each included both the controls and exercise intervention arms of the trial.

Exercise Group

The exercise group undertook a monitored, structured program of exercise five times per week for twelve months. At least three sessions per week were facility-based and up to two were home-based.


Each exercise session consisted of 60 minutes of exercise at moderate-to-vigorous intensity (including time for warm-up and cool-down), employing activities that promote fat loss and were appropriate for the participant. Examples of activities include brisk walking on a treadmill or outdoors, swimming, stationary cycling, or cross-country skiing.

The exercise intervention was closely supervised and facilitated by on-site exercise trainers, who were available to counsel and motivate participants, and who worked individually with participants to design appropriate activities for both the facility-based and home-based components.

The length and intensity of exercise sessions increased slowly over the first 3-4 weeks to reduce chance of injury and to acclimatize participants to frequent exercise.

Adherence to the exercise intervention was enhanced by several measures including individual, ongoing counseling with on-site trainers who designed an exercise program that was both appropriate for the fitness level of the participant and that interested the participant.

Substantial evidence in the literature and in the experience of the investigators demonstrates that sedentary older women can successfully complete an exercise program of this intensity.


Control Group

The control group was asked not to change their current level of activity for 12 months. The validated Past Year Total Physical Activity Questionnaire - developed by the principal investigators and tested for validity and reliability - was administered at baseline and end-of-study to monitor the level of participants' total physical activity (including recreational, occupational and household activity components) in the previous 12 months. As an additional incentive, participants enrolled in the control group were offered an exercise program at the end of the 12 months. This included a choice of exercise programs, such as sessions with a personal trainer or free membership at a fitness facility.

Data Collection

Data collection involved both biological sampling and self- and interviewer-administered questionnaires.

Baseline assessments were obtained of serum sex hormones (estrone and estradiol), measures of obesity and adiposity, biomarkers of obesity and inflammation, breast tissue density, serum IGF-1, insulin resistance, aerobic capacity, and psychosocial health measures.

At the end of the study, all baseline assessments were repeated and compared between the two groups. The study size had sufficient power to enable investigators to detect statistically significant differences of 5-20% in each of the breast cancer risk factors being investigated.

 
Significance

This study will result in a significant contribution to the literature on breast cancer etiology and prevention. It is on the cutting edge of epidemiologic research, and brings together the expertise of scientists from a wide range of disciplines and institutions in the United States and Canada. It will be one of the first empirical studies published demonstrating the effect of increased activity on the biological mechanisms operative in breast cancer etiology.

Ethical Considerations

This study has passed ethical review by the University of Calgary, the University of Alberta and the Alberta Cancer Board. All study participants provided informed consent at the outset of the study. All data provided are kept confidential in locked cabinets and no identifying information is available on study questionnaires and documents. The risks and benefits were clearly outlined and described to participants prior to obtaining informed consent.

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