Introduction

Obesity prevalence is higher among women compared to men, especially in postmenopausal women [1]. Specifically, menopause can contribute to increase total and intra-abdominal fat mass, coupled with decreases in muscle mass, as a result of metabolic changes (e.g., reductions in resting metabolic rate and the production of sex-steroid hormones by the ovaries) [2,3,4]. Excess fat mass accumulation during menopause is related to several chronic diseases, including cardiovascular disease, diabetes, hypertension and several types of cancers [5, 6]. A particularly strong association was found between obesity and invasive breast cancer risk in postmenopausal women [7], a relationship mediated by an increase in estrogen production by adipocytes, inflammation and insulin resistance in peripheral tissues [8, 9]. Therefore, the development of weight management strategies is a major public health priority in postmenopausal women with overweight or obesity to prevent postmenopausal breast cancer risk [10, 11].

Several weight management strategies (e.g., lifestyle, pharmacologic and surgery interventions) have been assessed in clinical settings with the aim of preventing postmenopausal breast cancer [12, 13]. Exercise is a widely used non-invasive strategy to prevent breast cancer risk through fat mass reductions in middle-aged women [10]. Moreover, in postmenopausal women, exercise training can produce multiple additional benefits, such as improved cardiorespiratory fitness [14], insulin sensitivity [15], preserved bone mineral density [16], and increased muscle mass [17]. The American College of Sport Medicine (ACSM) published a position stand in 2009 focused on recommendations for weight loss and weight maintenance, and recommended a minimum of 150 min/week of moderate-intensity physical activity for individuals with overweight and obesity to improve overall health, however, 200–300 min/week were recommended for long-term weight loss [18]. Recently published guidelines from the World Health Organization on physical activity and sedentary behavior also concluded that there is insufficient evidence on the effects of prescribing different volumes of exercise on health outcomes in various populations, including individuals living with chronic diseases [19, 20]. There is currently little evidence of exercise dose recommendations to reduce adiposity outcomes in a population of postmenopausal women with a primary focus on breast cancer prevention through adiposity reductions [21, 22].

The Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial and the Breast Cancer and Exercise Trial in Alberta (BETA) were designed to determine the effects of 12-month aerobic exercise interventions on hypothesized mechanisms of postmenopausal breast cancer risk [23, 24]. In the ALPHA Trial, 320 women were randomized to either 225 min/week of exercise or to a control group without an exercise prescription, finding greater reductions in fat measurements within the exercise group [24]. In BETA, 400 women were randomized to either 300 or 150 min/week of aerobic exercise to provide some evidence of a dose-response effect of exercise volume on biologic markers of breast cancer risk. This study reported that 300 min/week lead to greater reductions in adiposity outcomes, and consequently in reducing breast cancer risk [24, 25].

For the present analyses, we combined data from the ALPHA trial and BETA to assess the effects of an incremental dose of exercise (+75 min/week) on adiposity markers in postmenopausal women. Given the similarities in study populations, inclusion criteria and methods used in the ALPHA trial and BETA, we were able to pool these two large trials to maximize statistical power and assess the effects of three incremental doses of exercise on adiposity markers, and estimate breast cancer risk reductions via adiposity changes. To our knowledge, no other study has compared the effects of three incremental volumes of aerobic exercise on detailed and objective measures of adiposity (e.g., total fat mass and intra-abdominal and subcutaneous fat area) in postmenopausal women. We hypothesized that in postmenopausal women there would be a dose-response relationship between exercise volume and adiposity markers, with greater fat mass reductions occurring with higher exercise volumes.

Materials and methods

Study design and participants

The study design and methods for the ALPHA Trial and BETA are described in more detail elsewhere [23, 26]. Both studies were approved by the Alberta Cancer Research Ethics Committee and the Conjoint Health Research Ethics Board of the University of Calgary and the Health Research Ethics Board of the University of Alberta. Briefly, these studies were both two-center, two-arm, 12-month randomized controlled trials conducted in Calgary and Edmonton, Alberta, Canada. A total of 320 postmenopausal women were recruited in the ALPHA Trial and randomized to either 225 min/week (mid-volume) of aerobic exercise or to a control group (received no exercise prescription). In BETA, a total of 400 postmenopausal women were recruited and randomized to either 150 min/week (low-volume) or 300 min/week (high-volume) of aerobic exercise (Fig. 1). Eligibility criteria for both trials were the same. Women were postmenopausal, aged 50–74 years, had no previous cancer diagnosis, had a BMI between 22 and 40 kg/m2, were able to speak English, non-smokers, not currently taking hormone replacement therapy, inactive (<90 min/week of physical activity), did not have diabetes, received medical approval for participation in an exercise program and were not planning to participate in a dietary intervention or any kind of weight loss program. Written consent was obtained from each participant after a full explanation of the purpose and nature of all procedures used. Numbered envelopes with participant’s allocation were prepared by staff unrelated with the study. The research staff who took body composition measurements was blinded to the randomization group.

Fig. 1: Participant flow diafram for the ALPHA Trial and BETA, Alberta, Canada, 2008–2012.
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ALPHA, the Alberta Physical Activity and Breast Cancer Prevention trial; BETA, the Breast Cancer and Exercise Trial in Alberta; DXA, whole-body Dual X-ray Absorptiometry; Min/week, minutes per week; VO2peak, Peak Oxygen Consumption.

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Exercise interventions

The exercise prescription in the ALPHA Trial was moderate-to-vigorous intensity aerobic exercise (70–80% of heart rate reserve) for at least 45 min on 5 days/week (225 min/week) for 12 months. Women in BETA completed aerobic exercise at moderate-to-vigorous intensity (65–75% heart rate reserve) on 5 days/week during 30 min/session (150 min/week group) or 60 min/session (300 min/week group). For both trials, the exercise sessions were supervised on at least 3 days/week by certified exercise trainers at fitness facilities in Calgary and Edmonton. The exercise prescription (intensity, volume, and frequency) was gradually increased in both trials over 3 months and then maintained for an additional 9 months [23, 24]. The exercise trainers re-assessed their cardiorespiratory fitness every 3 months to adjust exercise prescription. Adherence to the intervention was monitored with a Polar® heart rate monitor and weekly exercise logs completed by participants and the trainers. Study participants in both trials were asked to maintain their usual diet [23, 24], which was assessed with the Canadian Diet History Questionnaire-II at each time point. Total physical activity time was also assessed at each time point with the validated Past Year Total Physical Activity Questionnaire [27]. These results have been published elsewhere [25, 26]. Briefly, in the ALPHA Trial, there were no statistically significant differences in non-recreational physical activity levels, however, decreases in energy intake were significantly greater in the control versus the exercise groups (−161 kcal/day versus −45 kcal/day) [26]. For BETA, there were no statistically significant group differences in energy intake, dietary fat intake, and non-recreational physical activity time at 12 months between groups [25].

Body composition measurements

Anthropometric measurements were collected using the same protocol for the ALPHA Trial and BETA. At baseline and 12 months, height and body weight were measured using standardized methods with a conventional stadiometer and balance beam scale. Measurements were taken by research staff in duplicate, if differences between the two measurements were noted, a third measure was taken, and the average was used in the analyses.

In both trials, fat-free mass (kg), fat mass (kg) and body fat percentage (%) were measured using whole-body dual X-ray absorptiometry (DXA). Full-body scans were taken with a Hologic DXA system in Calgary (Hologic Inc, Bedford, MA, USA) for both studies, and a General Electric Lunar iDXA in Edmonton using the enCORE Software 6.70.01 before November 2004 and version 8.60 after November 2004 (Lunar General Electric Medical Systems, Madison, WI, USA), to analyze the data. Research staff calibrated the DXA scanner every day before use. All scans were done following a standardized procedure in Calgary and Edmonton.

In the ALPHA Trial, intra-abdominal and subcutaneous fat area were measured by computed tomography with a single slice at the umbilicus. In Calgary, a PQ5000 VisionMaster CT scanner (Marconi, Cleveland, OH, USA) was used, and in Edmonton a MX8000 multi-slice CT Scanner (Phillips Medical Systems, Cleveland, OH, USA) was used. Images were sent to the study radiologist who used an image software (Silicone Graphics Inc., Sunnyvale, CA, USA) to identify the subcutaneous and the intra-abdominal fat areas. For BETA, these measurements were also made using computed tomographic scans using four single slices centered at the umbilicus. A Phillips Brillance Big Bore and a Toshiba Aquilion were used. In BETA, images were sent to the study radiologist who used an image software (Aquarius Intuition byTeraRecon, Inc) to quantify and identify subcutaneous and intra-abdominal fat areas (cm2). Scans had very high reliability with an intraclass correlation >0.99.

Cardiorespiratory fitness

Cardiorespiratory fitness (VO2peak) was assessed in both trials using a modified Balke treadmill test protocol and estimated using the ACSM metabolic equations and the multistage model [28]. The submaximal test was completed when participants reached 85% of their age-predicted maximum heart rate or after exhaustion. VO2peak was normalized by fat-free mass [29] to assess changes in cardiorespiratory fitness regardless of body weight changes. Therefore, our results show VO2peak in ml/kg of fat-free mass/min.

Covariate measures

Demographic baseline characteristics were measured with a Baseline Health Questionnaire, which included information on age, medical history (first-degree family history), marital status (married/common law versus unmarried), education (high school or less versus beyond high school), employment (full-time versus not employed full-time), ethnicity (White versus other) and study site (Calgary versus Edmonton).

Statistical analyses

Sample sizes for both trials were based on adiposity [24, 25]. For the present analyses, the power calculation revealed that a sample size of ≥675 women provides a power of 95% to detect differences of 3–4% between the low-volume group and the control group in fat mass (effect size = 0.16; α = 0.05) (v3.1, G*power, Dusseldorf University, Germany). The percentage of change in the mid-volume and high-volume groups is expected to be higher compared to the control and low-volume groups; therefore, our sample provides enough power to detect differences between these groups as well. Quantile-Quantile plots and histograms were used to assess data distribution. Assumptions of homogeneity were assessed by examining the plots of the residuals versus the fitted values. Given the normal distribution of our data, no transformations were needed. One-way analysis of variance (ANOVA) and Chi-squared tests were used with continuous and categorical variables, respectively, to compare groups at baseline.

An analysis of covariance (ANCOVA) was used to analyze the effect of different exercise volumes (control, low-volume, mid-volume and high-volume) on body composition parameters and cardiorespiratory fitness at 12 months after adjusting for baseline outcome values and by study center (Calgary/Edmonton). In a post hoc analysis, linear regression models were used to analyze pairwise comparisons among treatment arms after adjusting for baseline outcome values and study center. In accordance with an intent-to-treat analysis, all women randomized in the ALPHA Trial and BETA with baseline and post-intervention body composition measurements were included in the present analyses.

Effect modification was investigated by determining the statistical significance of the interaction term among each exercise intervention (low-volume, mid-volume, high-volume) with the control group, by each hypothesized moderator (BMI and VO2peak at baseline) on our outcomes of interest after adjusting for baseline outcome values. Intervention effects within all subgroups tested were reported regardless of the statistical significance of the interaction term in the general linear models. Each hypothesized moderator was dichotomized using the mean for VO2peak at baseline normalized by fat-free mass (VO2peak < 47.81 ml/kg fat-free mass/min and VO2peak ≥ 47.81 ml/kg fat-free mass/min), and BMI categories (BMI < 30 versus ≥30 kg/m2).

Analyses were conducted using STATA (version 15.1, College Station, TX: StataCorp LLC). Values are reported as means and 95% of confidence intervals (95% CI), unless otherwise stated. Statistical significance was set at P < 0.05.

Results

Of the 320 women randomized in the ALPHA Trial and the 400 women randomized in BETA, 311 and 386 returned at 12-months for at least 1 outcome measurement, respectively (Fig. 1). Within each study, there were no differences in baseline characteristics except for ethnicity in BETA, whereas statistically significant differences were found between studies for baseline age, employment, education, past year total physical activity participation, fat-free mass, fat (%) and intra-abdominal fat area (Table 1). Body weight change was −0.47 kg, −1.91 kg, −2.26 kg, −2.65 kg in the control, low-, mid- and high-volume groups, respectively. This body weight change resulted mostly from fat mass loss in all groups. Specifically, 76, 77, 98 and 95% of body weight change was fat mass in the control, low-, mid- and high-volume groups, respectively.

Table 1 Participant characteristics at baseline in ALPHA and BETA, Alberta, Canada, 2008–2012, N = 720.
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In the intent-to-treat analysis (Table 2), we noted statistically significant differences among the four groups at 12-months for BMI, body weight, fat mass, fat percentage, intra-abdominal and subcutaneous fat area, whereas no statistically significant differences between groups were noted for fat-free mass. Results were similar when the model was adjusted for covariates such as age, education, employment, ethnicity and marital status (results not shown).

Table 2 Mean differences in adiposity markers and VO2peak among exercise interventions at 12 months in ALPHA and BETA, Alberta, Canada, 2008–2012, N = 720.
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Mean body weight among women randomized to the high-volume group was estimated to be −2.21 kg (95% CI: −3.07, −1.34; P < 0.001) lower than women in the control group at 12-months (Table 2). In the mid-volume group, body weight was estimated to be −1.83 kg (95% CI: −2.73, −0.93; P < 0.001) lower than the control group. For the low-volume group, body weight was estimated to be −1.47 kg (95% CI: −2.34, −0.59; P = 0.001) lower compared to the control group. However, no statistically significant differences were found among the three exercise groups for body weight change. Compared with the control group, BMI significantly decreased in the three exercise groups (P < 0.001, Table 2). Thus, a greater reduction in BMI was noted in the high-volume group compared with the low-volume group at 12-months (−0.36 kg/m2; 95% CI: −0.68, −0.04; P = 0.03).

Greater decreases in total fat mass were achieved with a greater amount of exercise. Compared to the control group, all exercise groups showed a significant decrease in fat mass (P < 0.01; Table 2). Furthermore, compared with the low-volume group, we found a statistically significant decrease in fat mass at 12-months in the mid-volume group (−0.86 kg, 95% CI: −1.58, −0.13; P = 0.02) and in the high-volume group (−0.97 kg, 95% CI: −1.64, −0.29; P = 0.01). No differences were found between the high-volume and mid-volume exercise groups for fat mass. Body fat percentage showed similar results than those presented for fat mass (Table 2).

Intra-abdominal fat area (cm2) and subcutaneous fat area (cm2) showed a statistically significant decrease for all exercise groups compared with controls (P < 0.01; Table 2). Significantly lower intra-abdominal fat area was noted in the mid-volume group compared to the low-volume group (−8.13 cm2, 95% CI: −12.86, −3.39; P = 0.001). A statistically significant increase in intra-abdominal fat area was found in the high-volume group compared to the mid-volume group (6.81 cm2, 95% CI: 2.15, 11.46; P = 0.004). For subcutaneous fat mass area, a statistically significant decrease was found in the high-volume versus mid-volume groups (−10.79 cm2, 95% CI: −19.31, −2.28; P = 0.01).

Mean increases in VO2peak (ml/kg of fat-free mass/min) at 12-months were estimated to be 5.74 ml/kg/min (95% CI: 3.66, 7.81; P < 0.001; Table 2) higher in the high-volume group compared with the control group after adjusting for baseline differences. In comparison with controls, the mid-volume group also had higher VO2peak at 12 months (4.31 ml/kg/min, 95% CI: 2.16, 6.46; P < 0.001), as did the low-volume group (4.72 ml/kg/min (95% CI: 2.63, 6.80; P < 0.001). No differences for VO2peak were found between exercise groups.

When testing for effect modification, significant interactions were found between the exercise groups and BMI at baseline for changes in body fat percentage and fat-free mass (Supplementary Table 1). The stratified analyses indicated that the effects of exercise dose on body fat percentage was greater among women randomized to the low-volume group who had a BMI < 30 kg/m2 at baseline when compared to the control group (Supplementary Table 1). For fat-free mass, women in the high-volume group with a BMI < 30 kg/m2 at baseline had a statistically significant increase in fat-free mass at 12-months compared with the control group, whereas an inverse pattern of response was noted in women with a BMI > 30 kg/m2. Although the interaction term was not statistically significant, a greater reduction in fat mass and body weight with increasing exercise volumes for women with obesity (BMI ≥ 30 kg/m2) was observed in the stratified analysis (Supplementary Table 1). Lastly, there was no evidence of effect modification in the association between VO2peak at baseline and exercise volume on any body composition parameters (Supplementary Table 2).

Discussion

In this pooled analysis of data from two previously conducted exercise intervention trials in inactive postmenopausal women without comorbidities, we found a dose-response effect of prescribed exercise volume on adiposity outcomes. Specifically, after 12 months of aerobic exercise, we found that increasing aerobic exercise volumes from no exercise up to 300 min/week resulted in statistically significant reductions in BMI, body weight, fat mass (kg and %), intra-abdominal fat area and subcutaneous fat area. In addition, participants randomized to the mid- and high-volume groups had greater reductions in these outcomes compared to the low-volume exercise group, and small non-statistically significant differences in these outcomes were seen between the mid- and high-volume exercise groups, except for intra-abdominal fat mass that showed a statistically significant increase in the high-volume exercise group compared to the mid-volume group. No changes were found for fat-free mass. In addition, there were statistically significant differences for all adiposity markers and for cardiorespiratory fitness between the three exercise volumes prescribed and the control group.

The ACSM recommends at least 150 min of moderate intensity physical activity to prevent chronic diseases [30], and 200–300 min/week of moderate intensity physical activity for weight loss and weight loss maintenance. During the intervention, a greater percentage of body weight loss was attributed to total fat mass loss in all groups. Furthermore, the percentage of fat mass loss was greater at higher volumes of exercise, specifically at 225 and 300 min/week of aerobic exercise (98% and 95%, respectively). Our results are supported by previous studies that found that aerobic exercise was able to preserve fat-free mass in overweight and obese older adults [31]. In addition, these results support the evidence put forth by the ACSM’s recommendations for weight loss and weight loss maintenance [18], suggesting that greater volumes of exercise are recommended for greater reductions in fat mass, but also suggest that greater volumes of exercise are recommended for maintaining fat-free mass coupled with reductions in fat mass. One previous clinical trial called The Dose-Response to Exercise in Postmenopausal Women (DREW Trial) [14] also tested the dose-response effects of exercise on cardiorespiratory fitness and risk factors for cardiovascular disease in postmenopausal women with high blood pressure at baseline over 6 months. No evidence of a dose-response effect of exercise on body weight and body fat percentage was observed in this trial, which may be partially attributable to the intervention duration (6 months), the differences in exercise prescription and the methods used for body composition measurements in the DREW Trial compared to ALPHA Trial and BETA. The Physical Activity for Total Health Study [32] also reported a dose-response effect of exercise volume on adiposity measures following a per protocol analysis based on exercise adherence during the intervention, where greater decreases in fat mass and intra-abdominal fat area were noted among postmenopausal women who participated in ≥195 min of exercise/week. Two final studies [33, 34] explored the dose-response relationships between walking and health outcomes in postmenopausal women, with one of these studies reporting a dose-response effect of walking volume (150 versus 225 min/week) on fat mass loss over 12 weeks [34]. Therefore, greater volumes of aerobic exercise can produce greater body weight loss, specifically fat mass loss.

Visceral fat mass, independently of total fat mass, may also increase breast cancer risk [35, 36]. Few trials [37] have investigated the effects of exercise on intra-abdominal and subcutaneous fat area using computed tomography scans in postmenopausal women and reported decreases in intra-abdominal fat and subcutaneous fat area in response to exercise only [32], or with exercise plus diet [38, 39]. No trial to date has previously reported the effects of three incremental exercise volumes on intra-abdominal and subcutaneous fat area. Therefore, our results showing a greater reduction in intra-abdominal and subcutaneous abdominal fat area with greater exercise volumes contribute to current exercise prescription recommendations for postmenopausal breast cancer prevention.

To our knowledge, no previous study has investigated the dose-response effects of aerobic exercise on fat-free mass exclusively in postmenopausal women. In this study, no differences between groups were found for fat-free mass. These results are consistent with previous studies where fat-free mass maintenance in response to aerobic exercise was observed in inactive postmenopausal women [17, 40]. It is known that resistance training is a good strategy to prevent fat-free mass loss and/or contribute to gains in fat-free mass in this population [17, 41]. However, the percentage of body weight loss attributable to fat-free mass loss was very low in both the mid-volume (2%) and high-volume (5%) groups, compared to the control (24%) and low volume groups (23%). A narrative review showed that high volumes (>120–225 min per week) of aerobic exercise could have anti-catabolic effects in physically inactive individuals [42]. Furthermore, in severe energy deficit conditions, exercise facilitates muscle mass preservation by promoting the partial inhibition of the autophagy-lysosomal system [43]. Therefore, it may be hypothesized that an aerobic exercise volumes of 225–300 min/week would be a sufficient stimulus to promote the partial inhibition of autophagy, hence mitigating muscle mass loss despite the weight loss experienced by postmenopausal women in this study. Future trials are needed to corroborate this hypothesis and the role of the autophagy-lysosomal system in muscle mass preservation in postmenopausal women. Furthermore, trials that combine different volumes and different types of exercises (e.g., resistance training and aerobic training) during weight loss are needed.

Adipose tissue is an endocrine organ with several functions [44]. In an inflammatory state, adipose tissue releases inflammatory proteins and hormones, which may then increase breast cancer risk in postmenopausal women [45]. The degree of fat mass loss seen in women randomized to the high-volume group is estimated to correspond with a 4.4% reduction in postmenopausal breast cancer risk [46]. It is important to note that adipose tissue itself is not the only mechanism by which exercise can reduce breast cancer risk [9]. Skeletal muscle is also an endocrine organ that releases myokines into the bloodstream in response to exercise [47]; these molecules having anti-inflammatory effects can also contribute to reducing cancer risk [48, 49].

We noted that the effects of the intervention on fat-free mass were moderated by BMI at baseline. Fat-free mass was significantly greater in the high-volume group in comparison with the control group in women with a BMI < 30 kg/m2 at baseline, whereas the opposite effect was noted in women with obesity (BMI ≥ 30 kg/m2). These results are not consistent with previous studies that suggest smaller decreases in fat-free mass in individuals with obesity compared to their normal-weight counterparts [50]. It is possible that an infiltration of inflammatory cells (mainly macrophages and monocytes) in skeletal muscles [51, 52] leading to metabolic dysfunction in myocytes [53], may partially explain why participants with obesity may have greater difficulties in maintaining muscle mass compared to lean participants in response to exercise. Given the detrimental consequences of muscle mass and strength loss with age [50], future interventions in postmenopausal women with obesity should focus on exercise prescriptions that could be used to optimize muscle quality by increasing muscle strength and preserving muscle [54]. In addition, we noted that 150 min/week of aerobic exercise may not be sufficient to achieve a significant decrease in body fat percentage for women with obesity, whereas 225–300 min/week of aerobic exercise lead to greater reductions in adiposity in these women compared to those with a BMI < 30 kg/m2. These results suggest that greater volumes of exercise may be needed to induce greater reductions in adiposity in women with obesity, which are consistent with results from previous weight loss trials in women with overweight and obesity and the ACSM position stand on weight loss and weight loss maintenance [18, 55].

Strengths of the ALPHA Trial and BETA include the use of a randomized controlled trial design with a 12-month supervised exercise intervention, a large sample size, very low drop-out rates (97% completion rates for both trials), comprehensive measures of covariates and objective measurements of body composition using DXA and CT scans. Our limitations include: varying adherence rates to the exercise prescriptions throughout the 12-month interventions and between groups, suggesting that the prescribed exercise may not entirely reflect the actual amount of exercise completed [24, 25]. Furthermore, the intensity of the exercise prescription was slightly lower in BETA compared to the ALPHA Trial. In addition, we noted some differences in baseline outcomes between the two trials. We attempted to mitigate this issue by adjusting our analyses for baseline outcome values as covariates, however, the differences seen in intra-abdominal fat mass between the mid-volume and the high-volume groups may be partially attributable to a difference in baseline values. Lastly, our trials included postmenopausal women who were mostly white, married or common law, and had high education levels at baseline, therefore results may not be generalizable to other subpopulations of postmenopausal women.

In conclusion, there was a dose-response effect of prescribed exercise volume on BMI, body weight, fat mass, body fat percentage, intra-abdominal fat area and subcutaneous fat area, whereas no dose-response effects were noted for fat-free mass. These reductions in adiposity markers and improvements in VO2peak with increasing exercise volumes may be beneficial for breast cancer prevention [5]. Results from the present study contribute evidence on the importance of higher exercise volumes not only to promote weight loss, but also to reduce postmenopausal breast cancer risk through reductions in adiposity markers. One observational study found that 5 kg of body weight loss may reduce postmenopausal breast cancer risk by 10% [46]. We also estimate that the mean reductions in body weight noted in the present study may lead to an estimated 4.4, 3.7 and 2.9% breast cancer risk reduction for the high, mid- and low-volume exercise prescriptions. To experience higher risk reductions, an intervention including other lifestyle changes may be needed [56, 57]. While study participants were able to achieve the exercise prescriptions during these trials, the long-term maintenance of exercise may be more challenging. Given the difficulties in long-term exercise adherence in this population, it is important that future research focus on assessing facilitators and barriers to long-term exercise maintenance. Future dose-response trials should also focus on other parameters of exercise prescription, such as exercise type (aerobic versus resistance exercise), to provide more comprehensive and specific information on exercise prescriptions for postmenopausal breast cancer prevention.