The effects of equivalent weight loss with or without exercise programme on breast cancer risk biomarkers in postmenopausal women: the SHAPE-2 study.

Postmenopausal women who are sedentary or overweight, have an increased breast
cancer risk. In contrast to most other risk factors for postmenopausal breast
cancer, physical inactivity and overweight offer a potential basis for primary
prevention since they are amenable to intervention. However, these two factors
are highly correlated and it is not clear which is most relevant to risk. It is
suggested that physical inactivity and overweight mediate breast cancer risk
mainly through sex hormone-related pathways. Intervention studies give insight
into the interplay between physical activity and intended weight loss and the
biological mechanisms by which behaviour influences breast cancer risk in
postmenopausal women. We recently showed in a randomised study (the SHAPE-1
study) among postmenopausal women that physical activity influences hormone
levels mainly when concordant loss of body fat was achieved. Of the two other
randomised studies conducted, one shows similar results. The other study also
found an overall effect of exercise, but exercisers also lost (-1.8 kg) more
body weight than controls.
So, it seems clear that weight loss (fat loss) reduces sex hormone levels, but
the question is if there is an additional beneficial effect of reaching this by
physical activity instead of nutritional interventions. We, therefore, propose
to study the effect of equivalent weight loss with or without exercise on
hormones known to be related to breast cancer risk.

Primary Objective: To examine the effects of equivalent weight loss with and
without exercise on breast cancer biomarkers (endogenous sex hormones) in
overweight, sedentary postmenopausal women.

Secondary Objective(s): To examine the effects on body(fat) composition and
whether this mediates potential changes in endogenous sex hormones

The SHAPE-2 study is designed as a single blind RCT with three study arms. The
outcome assessors will be blinded for treatment assignment as much as possible.
After a run-in period of 5 weeks, eligible women (n=250) will be randomised
into (D) a diet-induced weight loss group (n=104), (E) an exercise- plus
diet-induced weight loss group (n=104), or (C) a waiting list control group
(n=42). This intervention period will take (a maximum of) 14 weeks. A weight
maintenance period of 2-6 weeks will follow after. The total duration of the
study is 21 weeks.

Block randomisation is used, with a block size of 5, stratified by centrum and
municipality.

During the run-in period, all women will follow a weight maintenance diet
according to guidelines for healthy nutrition (50-60% carbohydrate,
15-20%protein and 20-35% fat) under supervision of a dietician.

Throughout the 14 week intervention period, the diet group will be offered a
diet counselling intervention to reduce this isocaloric diet with 500 kcal/day.
The diet intervention includes 2 individual and 5 group sessions with a
dietician and 9 telephonic contacts.

The exercise- plus diet-induced weight loss group will follow an exercise
programme with a mean energy expenditure of 350 kCal/day. The exercise
intervention consists of 2 group sessions supervised by a physiotherapist and 2
hours of home exercise sessions. De dietprogramma consists of dietinstructions
by the dietician to reach a caloric deficit of 250 kCal/day. They will also
have 9 telephonic contacts with a dietician.

Women in the control group will be asked to stick to the isocaloric diet from
the run-in period and maintain their body weight. They will have telephonic
contact with the dietician four times during the study period.

The study programma, especially the weight loss programmes are quite time
consuming, which can be a burden for participants.
At first participants will visit the nearby hospital (either Utrecht or
Enschede) for a 20 minutes screeningvisit to check eligibility. At baseline
questionnaires will be filled out by all participants about their general
health, medical history, reproductive history and exercise- and diet habits.
They will all have a face-to-face instruction by a dietician about their
isocaloric diet for the run-in period.
Furthermore, all participants need to visit the nearby hospital for
measurements twice, including: physical examination, total body DEXA-scan,
MRI-abdomen, maximal exercise capacity test, blood sampling, checking filled in
questionnaires. During the study a dietary record should be filled in three
times containing (in every record) information on food intake for 2 weekdays
and 1 weekendday. And the actigraph, a non-invasive activity monitor, will be
worn for 1 week two times.

During the intervention period of 14 weeks the diet weight loss group will
follow a hypocaloric diet, which is supervised by a dietician by 2 individual
one-hour contacts, 5 one-hour groupsessions and 9 telephone calls. The
exercise- plus diet-induced weight loss group will follow a sportsprogram in
which they'll practice 2 one-hour sessions of sports in a nearby physiotherapy
clinic and 2 hours of individual nordic walking on a weekly basis. They will
also get a hypocaloric diet, instructed by a dietician and monitored through 9
telephonic contacts by the dietician.

Participants have very low risk on (serious) adverse events or complications.
Due to the exerciseprogramme injuries may occur. The risk is minimized by
gradualy increasing the intensity of the exerciseprogram.
There is a risk on the normal complications of a vena puncture (e.g.
hematoma/flebitis). Incidental findings can be done which will be reported to
participants. During the maximal capacity exercise test (clinically occult)
pre-existing heart problems can be exposed. To reduce the risk of complications
due to ischemia the participant will be screened for ischemic heart disease by
ECG monitoring during the exercise test. Emergency equipment and personnel
trained to deliver appropriate emergency care will be available.

A benefit for the participants is that they will loose weight under supervision
of a dietician and physiotherapist in a healthy way. This also applies to the
control group since they will be offered an adapted weight loss program at the
end of the study.