**6. What biological mechanisms explain the associations between physical activity and colon and breast cancer**

Evidence for the underlying mechanisms involved in the pathways between physical activity and cancer is emerging. Numerous biological mechanisms have been proposed and in some cases tested in randomized controlled trials (for a review see (Friedenreich et al., 2010;Rogers et al., 2008; Chan & Giovannucci, 2010).

In 2007 the World Cancer Research Fund examined associations for physical activity and several cancer types. They concluded that there is a statistical association between excess weight and some cancers including colon cancer and breast cancer in postmenopausal

Physical Activity and Cancer: It is Never Too Late to Get Moving! 117

Insulin resistance/hyperinsulinemia\*

**↓** SHBG\* **↑** IGF-1\* **↓** IGFBP-1 **↓** IGFBP-2 **↑** Oestradiol\*

IGF-1 : Insulin like Growth Factor ; IGFBP-1 : Insulin like Growth Factor Binding Protein 1 ; IGFBP-2 :

**↑** free IGF-1\*

Fig. 1. Proposed mechanisms relating diet, physical activity and insulin to breast cancer

For colon cancer, the protective effects of regular physical activity marshal systemic effects of physical activity and local effects (Chan & Giovannucci 2010). Physical activity could also increase colonic motility, although colonic motility has not been definitely linked to colon

Other biological mechanisms of protective effects of physical activity have been suggested, such as the reduction of oxidative stress and effects on immunity. It is clear that the beneficial effects of physical activity depend on many inter-connected mechanisms. However, the level of scientific proof in each case is a matter of debate and further research

is needed in order to determine the preventive mechanisms for each type of cancer.

Insuline like Growth Factor Binding Protein 2 ; SHBG : Sex Hormone Binding Globulin

development of breast cancer

Liver Adipose tissue

(↑aromatase activity\*)

Rich diet + sedentarity

Increased fat mass\*

\*: possible target and effects of regular physical activity

**↑** Free testosterone and

œstradiol\*

cancer risk.

women. These results were confirmed by a large standardized meta-analysis (Renehan et al., 2008). The authors did a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups. The objective was to determine the risk of cancer associated with a 5 kg/m² increase in BMI (which corresponds to weight gains of about 15 kg in men and 13 kg in women who have an average BMI of 23 kg/m²). They analyzed 141 articles, including 282 137 incident cases. In men, a 5 kg/m² increase in BMI was strongly associated with colon cancer (risk ratio [RR]=1.24, p<00001). In women, they recorded positive association between increased BMI and premenopausal (p=0.009) and postmenopausal (p=0.06) breast cancers. Associations were stronger in men than in women for colon (p<0.0001) cancer. Associations were generally similar in studies from North America, Europe and Australia, and the Asia–Pacific region.

Mechanisms that link excess weight and cancer risk are not fully understood, though three hormonal systems -the insulin and insulin-like growth factor (IGF) axis, sex steroids, and adipokines - are the most studied candidates (Renehan et al., 2008). All three systems are interlinked through insulin (Figure 1).

Obesity and a sedentary lifestyle induce insulin-resistance and a compensatory hyperinsulinism. Chronic hyperinsulinaemia decreases concentrations of IGF binding protein-1 and IGF binding protein-2, which increases bioavailable or free IGF-I with concomitant changes in the cellular environment (mitogenesis and anti-apoptosis) that favor tumour formation (Rogers et al., 2008). Circulating total IGF-1, which is a major determinant of free IGF-1 concentrations, is also associated with an increased risk of colorectal cancer, and with premenopausal rather than postmenopausal breast cancer (Renehan et al., 2008). For postmenopausal breast cancer, the increase in risk might be explained by the higher rates of conversion of androgenic precursors to oestradiol through increased aromatase enzyme activity in adipose tissue. Furthermore, chronic hyperinsulinaemia might promote tumorigenesis in oestrogen-sensitive tissues, since it reduces blood concentrations of sexhormone-binding globulin, and in turn, increases bioavailable oestrogen (Calle & Thun, 2004).

Beyond these mechanisms, other candidate systems include obesity-related inflammatory cytokines, altered immune response, oxidative stresses, the nuclear factor κB system.

The beneficial effects of regular physical activity on the risk of cancer can be explained, among others, by their protective effect on weight gain and the reduction of abdominal adiposity. Independently of the variations of fat mass, regular physical activity decreases insulinemia by increasing peripheral insulin sensitivity (Dwyer et al., 2011). The direct effects of physical activity on IGF-1 are contradictory, some studies showing a decrease and others no variation of plasma IGF-1 levels with physical activity (Duclos et al., 2007). Regular physical activity can also reduce the risk of occurrence and/or recurrence of breast cancer by reducing the endogenous production of the estrogens but also by increasing the SHBG (Sex Hormone Binding Globulin) (Duclos 2001; Chatard et al., 2004). By binding to estradiol or testosterone, the SHBG therefore reduces their biologically active free fraction. The production of SHBG also depends on diet (normal or hypo-calorie intake, high-fibre diet, etc.), and the effects of physical activity are sometimes confused with the effects of diet (Longcope et al., 2000). Figure 1 presents an explanatory hypothesis of the pathways linking physical activity and insulin/IGF-1 /sex hormones to breast cancer development. physical activity could act by inverting these various pathways.

women. These results were confirmed by a large standardized meta-analysis (Renehan et al., 2008). The authors did a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups. The objective was to determine the risk of cancer associated with a 5 kg/m² increase in BMI (which corresponds to weight gains of about 15 kg in men and 13 kg in women who have an average BMI of 23 kg/m²). They analyzed 141 articles, including 282 137 incident cases. In men, a 5 kg/m² increase in BMI was strongly associated with colon cancer (risk ratio [RR]=1.24, p<00001). In women, they recorded positive association between increased BMI and premenopausal (p=0.009) and postmenopausal (p=0.06) breast cancers. Associations were stronger in men than in women for colon (p<0.0001) cancer. Associations were generally similar in studies from North

Mechanisms that link excess weight and cancer risk are not fully understood, though three hormonal systems -the insulin and insulin-like growth factor (IGF) axis, sex steroids, and adipokines - are the most studied candidates (Renehan et al., 2008). All three systems are

Obesity and a sedentary lifestyle induce insulin-resistance and a compensatory hyperinsulinism. Chronic hyperinsulinaemia decreases concentrations of IGF binding protein-1 and IGF binding protein-2, which increases bioavailable or free IGF-I with concomitant changes in the cellular environment (mitogenesis and anti-apoptosis) that favor tumour formation (Rogers et al., 2008). Circulating total IGF-1, which is a major determinant of free IGF-1 concentrations, is also associated with an increased risk of colorectal cancer, and with premenopausal rather than postmenopausal breast cancer (Renehan et al., 2008). For postmenopausal breast cancer, the increase in risk might be explained by the higher rates of conversion of androgenic precursors to oestradiol through increased aromatase enzyme activity in adipose tissue. Furthermore, chronic hyperinsulinaemia might promote tumorigenesis in oestrogen-sensitive tissues, since it reduces blood concentrations of sexhormone-binding globulin, and in turn, increases bioavailable oestrogen (Calle & Thun,

Beyond these mechanisms, other candidate systems include obesity-related inflammatory

The beneficial effects of regular physical activity on the risk of cancer can be explained, among others, by their protective effect on weight gain and the reduction of abdominal adiposity. Independently of the variations of fat mass, regular physical activity decreases insulinemia by increasing peripheral insulin sensitivity (Dwyer et al., 2011). The direct effects of physical activity on IGF-1 are contradictory, some studies showing a decrease and others no variation of plasma IGF-1 levels with physical activity (Duclos et al., 2007). Regular physical activity can also reduce the risk of occurrence and/or recurrence of breast cancer by reducing the endogenous production of the estrogens but also by increasing the SHBG (Sex Hormone Binding Globulin) (Duclos 2001; Chatard et al., 2004). By binding to estradiol or testosterone, the SHBG therefore reduces their biologically active free fraction. The production of SHBG also depends on diet (normal or hypo-calorie intake, high-fibre diet, etc.), and the effects of physical activity are sometimes confused with the effects of diet (Longcope et al., 2000). Figure 1 presents an explanatory hypothesis of the pathways linking physical activity and insulin/IGF-1 /sex hormones to breast cancer development. physical

cytokines, altered immune response, oxidative stresses, the nuclear factor κB system.

America, Europe and Australia, and the Asia–Pacific region.

activity could act by inverting these various pathways.

interlinked through insulin (Figure 1).

2004).

development of breast cancer

\*: possible target and effects of regular physical activity

IGF-1 : Insulin like Growth Factor ; IGFBP-1 : Insulin like Growth Factor Binding Protein 1 ; IGFBP-2 : Insuline like Growth Factor Binding Protein 2 ; SHBG : Sex Hormone Binding Globulin

Fig. 1. Proposed mechanisms relating diet, physical activity and insulin to breast cancer

For colon cancer, the protective effects of regular physical activity marshal systemic effects of physical activity and local effects (Chan & Giovannucci 2010). Physical activity could also increase colonic motility, although colonic motility has not been definitely linked to colon cancer risk.

Other biological mechanisms of protective effects of physical activity have been suggested, such as the reduction of oxidative stress and effects on immunity. It is clear that the beneficial effects of physical activity depend on many inter-connected mechanisms. However, the level of scientific proof in each case is a matter of debate and further research is needed in order to determine the preventive mechanisms for each type of cancer.

Physical Activity and Cancer: It is Never Too Late to Get Moving! 119

certified exercise trainer should also consider any preexisting conditions and adverse effects

It is necessary to take into account the state of fatigue of the patients before prescribing a program of physical activity. In all cases, the prescription must be individualized and

There is a reluctance of oncologists and of physicians to prescribe physical activity. Many elements prevent them from providing exercise advice: lack of sufficient knowledge of the benefits of being physically active after a cancer diagnosis, fear of side-effects of exercise (cardiovascular risks, lymphedema). Finally most physicians do not have the training or

**7.2 Barriers of physicians to prescribe physical activity in cancer survivors: What** 

**7.2.1 Physician should know, understand and explain the wide spectrum of health** 

In addition to the risk of recurrence of the cancer, cancer survivors are also at risk of chronic fatigue, loss of muscle mass, weight gain. It should be noticed that the average weight gain after breast cancer treatment is 3-5 kg, and that epidemiological studies have shown that weight gain after a cancer diagnosis is associated with an increased risk for recurrence and death compared with maintaining normal weight after diagnosis (Kroenke et al., 2005). Cancer survivors also have the same risks as the general population to develop cardiovascular diseases or metabolic diseases, or even they present an increased risk of developing these as obesity and a sedentary lifestyle are highly prevalent in cancer survivors. Specifically there is evidence that cancer survivors die of noncancer causes at a higher rate than persons in the general population (deaths being primarily from

As detailed in paragraph 3.4, physical activity can reduce risk of other chronic diseases (cardiovascular diseases and diabetes) on one hand, and on the other hand, physical activity

**7.2.2 Physician should know, understand and explain that physical activity in cancer** 

The published work provides sufficient evidence to suggest that exercise is a safe and welltolerated supportive intervention that oncologists can recommend to their patients after the

In one of the largest studies to date, Courneya and colleagues examined the effects of aerobic exercise alone, resistance exercise alone, or usual care, on fitness, muscular strength, body composition, and quality of life in 242 breast cancer survivors initiating chemotherapy (Courneya et al., 2007). There were significant favorable effects of both aerobic and resistance exercise on multiple outcomes including self esteem, fitness, and body composition, as well as increased chemotherapy completion rates compared with usual care. Furthermore, no significant adverse events were reported; lymphedema did not increase or was not exacerbated by aerobic or resistance exercise. Recently, other clinical trials of women with breast cancer have shown no increased risk for or exacerbation of lymphedema

**physicians should know, understand and explain to their patients** 

cardiovascular diseases and diabetes) (Carver et al., 2007).

may help subjects with cancer avoid dying from their cancer.

from either aerobic and/or resistance exercise (Ahmed et al., 2006).

resources to develop individualized exercise prescription for cancer survivors.

of treatment (Irwin et al., 2008).

implemented very gradually.

**benefits of physical activity** 

**survivor is safe and well-tolerated** 

completion of primary treatment.

In summary, exercise can alter biological processes that contribute to both anti-initiation and anti-progression events in the carcinogenesis process. However, more detailed studies are needed to examine each of the potential mechanisms contributing to an exercise-induced decrease in carcinogenesis in order to determine the minimum dose, duration and frequency of exercise needed to yield significant cancer-preventive effects, and whether exercise can be used prescriptively to reverse the sedentarity-induced and obesity-induced physiological changes that increase cancer risk (Rogers et al., 2008).

Moreover, the mechanisms of the beneficial effects of regular physical activity on survival after cancer treatment, and most importantly on the quality of life (decreased post-treatment fatigue, improved symptoms secondary to treatment) have yet to be determined (not to mention the need to know when to begin physical activity in relation to treatment, and at what dose: duration and intensity).
