Review article: Obesity as a risk factor for development and poor prognosis of breast cancer

Authors


Mrs AR Carmichael, Department of Surgery, Russells Hall Hospital, Dudley DY1 2HQ, UK. Email homepac@doctors.org.uk

Abstract

The evidence that obesity adversely affects women’s health is overwhelming and indisputable. The risk of postmenopausal breast cancer increases with obesity; measured as weight gain, body mass index, waist–hip ratio or percent body fat. It is also established that obesity is associated with poor prognosis of breast cancer. This review examines in detail the possible mechanisms by which obesity causes poor prognosis of breast cancer such as estrogenic activity, advanced or more aggressive disease at diagnosis and high likelihood of both local and systemic treatment failure. After careful consideration of the available evidence, the author concludes that obesity contributes towards development and poor prognosis of breast cancer; therefore, weight management should be an integral part of any strategy to prevent and improve the outcome of breast cancer.

Obesity and development of breast cancer

The evidence that obesity adversely affects women’s health is overwhelming and indisputable. Obesity increases the risk of all-cause mortality in women.1 Obesity in women is a recognised risk factor for metabolic syndrome, type II diabetes mellitus, cardiovascular disease and several major cancers including breast and endometrial cancer. All measures of obesity such as waist–hip ratio (WHR), weight gain, body mass index (BMI) or percent body fat are associated with the increased risk of postmenopausal breast cancer. The public health implications of obesity and breast cancer are immense. Twenty percent of all postmenopausal breast cancers and 27% of cancers in women more than 70 years of age may be attributable to obesity.2 It is estimated that up to 50% of postmenopausal breast cancer deaths in the USA can be attributed to obesity.3 Cancer Prevention Study II concluded that up to 18 000 deaths in US women of age more than 50 years may be avoided if women could maintain a BMI of less than 25 kg/m2 throughout their adult life.3

Breast cancer and weight gain

Adult weight gain is associated with increased risk of breast cancer. It is estimated that for every 5-kg gain in weight, the relative risk of breast cancer is increased by 1.08 (95% CI 1.04–1.12).4 As compared with women with a stable weight, the relative risk of developing breast cancer for a weight gain of 5 kg is 1.05 (1.02–1.08) and a weight gain of 15–20 kg is associated with 1.5 times increased risk of developing breast cancer (95% CI 1.06–2.13). Women with weight gain >21 kg have a relative risk of developing breast cancer of 1.75 (95% CI 1.11–2.77) compared with women with low weight gain.5

Breast cancer and BMI

A one-point gain in BMI is estimated to increase the risk of postmenopausal breast cancer by 3%.6 The relative risk of developing breast cancer in postmenopausal women with a BMI of more than 30 kg/m2 ranges from 1.23 (95% CI 1.00–1.59) to 2.52 (95% CI 1.62–3.93).7,8 A pooled analysis of data from seven prospective cohort studies involving 337 819 women and 4385 invasive breast cancers concluded that in postmenopausal obese women, the relative risk of developing breast cancer was 1.26.9 Several large-scale studies have confirmed this association.10–20 Data from the European Prospective Investigation into Cancer And Nutrition (EPIC) Study showed that obese women have a 31% increased risk of developing breast cancer compared with nonobese women.4

Breast cancer and WHR

The evidence for anthropometric factors influencing breast cancer risk and mortality is consolidating. Hip circumference was positively associated with breast cancer risk at 5 years of follow up among nonusers of hormone replacement therapy in a study of 73 542 premenopausal and 103 344 postmenopausal (1879 incident invasive breast cancers) women from nine European countries taking part in the EPIC Study.4 Earlier results reported from part of the same population confirmed the increased risk of breast cancer in postmenopausal obese women.4,21,22 A meta-analysis of the published literature on WHR and breast cancer risk reported that the overall risk for developing breast cancer in women with high WHR was 1.62 (95% CI 1.28–2.04). The summary risks were 1.79 (95% CI 1.22–2.62) for premenopausal women and 1.50 (95% CI 1.10–2.04) for postmenopausal women.23

Breast cancer and percent body fat

Together with body weight, weight gain, BMI and anthropometric measurements, percent body fat is also positively associated with risk of breast cancer as shown in the Malmo Diet and Cancer Study. In this prospective cohort study of 12 159 postmenopausal women (246 breast cancer), the percent body fat showed the strongest association with breast cancer. Relative risk of developing breast cancer was 2.01 (95% CI 1.26–3.21) in the highest versus lowest quintile. Authors concluded that percent body fat is a more discriminating risk factor for breast cancer risk than the commonly used BMI.5

Obesity and prognosis of breast cancer

Obesity leads to poor prognosis in women diagnosed with breast cancer as shown in systematic review of the literature.24 Twenty-six out of 34 studies involving 29 460 women demonstrated a worse outcome in obese women with breast cancer, leading to the conclusion that increased body weight is associated with adverse prognosis of breast cancer.24 A meta-analysis review of the English literature including 12 published articles with a total of 8029 cases of breast cancer found that the overall adverse effect of obesity on the prognosis of breast cancer was 1.56 (95% CI 1.22–2). The adverse effect of obesity on breast cancer may have been underestimated in this meta-analysis because of publication bias against negative studies.25 Obesity is associated with poor outcome of breast cancer even in early-stage disease.26 The women with breast cancer in the highest quartile of BMI are 2.5 times as likely to die of their disease within 5 years of diagnosis compared with women in the lowest quartile of BMI as shown in a study of 1177 premenopausal women.27 Several large-scale cohort studies and critical reviews such as Nurse’s Health Study and Cancer Prevention Study II have also confirmed this association between obesity and increased mortality from breast cancer.3,28–33 Obesity is also associated with significantly worse outcome in women with inflammatory breast cancer.34 Having established that obesity is associated with poor prognosis of breast cancer, this review examines in detail the possible mechanisms by which obesity causes poor prognosis of breast cancer.

Possible mechanisms by which obesity leads to poor prognosis of breast cancer?

In both premenopausal and postmenopausal breast cancer, several mechanisms are described by which body weight and obesity affect the prognosis of breast cancer such as estrogenic activity, or advanced or more aggressive disease at diagnosis or high likelihood of treatment failure (Table 1).

Table 1.  Why should obesity affect the prognosis of breast cancer?
Host-related factors
Hormones
Deprivation
Nutrition
Physical activity and weight gain
Shape and build
Tumour-related factors
Size
Markers of aggressive disease
Lymph node metastasis
Hormone receptor negative tumours
Treatment-related factors
Surgery
Radiotherapy
Chemotherapy
Endocrine treatment
Biological treatment

Host-related factors

Hormones

Data from both laboratory experiments and epidemiological studies support this hypothesis that obese breast cancer survivors have higher bioavailable concentrations of tumour-promoting hormones such as estrogen and testosterone, which may contribute to poor survival (Figure 1).35 Obese women have 35% higher concentrations of estrogen and 130% higher concentrations of estradiol compared with nonobese women.36 Testosterone concentrations also increase with increasing levels of adiposity.36 Obesity is strongly and inversely associated with sex-hormone-binding globulin (SHBG) levels, suggesting that central obesity with associated low plasma level of SHBGs promotes bioavailability of androgens and estrogen.35,37,38 Concomitant hyperinsulinaemia found in some obese women may promote mammary carcinogenesis by increasing the levels of insulin-like growth factor (IGF) and leptin which have a synergistic effect to estrogen on mammary epithelial cells by promoting angiogenesis and transcriptional factors.39–41 Leptin belongs to the group of adipocytokines which are produced by adipocytes and have been associated with carcinogenesis, tumour migration and invasion, enhancement of angiogenesis and increased aromatase activity in laboratory experiments. It has been suggested that leptin may mediate adverse prognostic effects of obesity in breast cancer. This association has not been confirmed in clinical studies yet.33 This may be due to the effect of physical activity on adipocytokines. An analysis of 710 women with breast cancer from the Health, Eating, Activity, and Lifestyle Study (HEALS) found that the levels of C-peptide and leptin were significantly higher in obese women, while statistically significant lower IGF-I levels were associated with higher BMI. The study reported that the levels of C-peptide and leptin were lower and levels of IGF-I and IGF-binding protein-3 were higher in obese women with breast cancer who had higher level of physical activity.42 Clearly, more research is needed to clarify these issues.

Figure 1.

Abdominal obesity and hormonal changes leading to increased incidence and poor prognosis of breast cancer. FFA, free fatty acid.

Nutrition

Despite the fact that the association between breast cancer risk and dietary factors has long been recognised and extensively researched,43 the complex relationship between obesity, nutrition and breast cancer is only partly understood. Obesity in women presenting with breast cancer may be a marker of poor dietary habits such as excess intake of saturated fat which is a recognised factor for adverse prognosis of breast cancer.44–46 There are several large-scale nutrition intervention trials continuing at present, including Nurse’s Health Study, Women’s Healthy Living, Women’s Health Initiative Dietary Modification and Eating Study and Women’s Intervention Nutrition Study; when matures, these will resolve the issue of nutrition and its possible link with death and recurrence of breast cancer.

Deprivation

Obesity is associated with both deprivation and poor prognosis of breast cancer, suggesting that host factors such as cellular immunity and nutrition which determine metastatic and recurrence potential of breast cancer may be unfavourable in deprived obese women.47,48 A study of 1208 women with breast cancer from Oxford found that women in social class IV and V have a lower risk of dying from breast cancer as compared with women from higher classes.49 This adverse effect of social class becomes statistically significant after adjusting for stage and nodal status.49 This poor survival may be caused by increased high incidence of obesity in deprived women, advanced disease at presentation and poor utilisation of healthcare facilities by deprived women who are more likely to be obese.47,50–56 These findings have been disputed in other studies presenting conflicting results.54

Physical activity and weight gain

While there is little direct evidence to show that lack of physical exercise leads to the development or poor prognosis of breast cancer, there is strong evidence to show that regular physical activity after a breast cancer diagnosis may reduce the risk of death from this disease. The greatest benefit is seen in women who performed the equivalent of walking 3–5 hours per week at an average pace.57 Despite the evidence that physical activity may enhance the survival from breast cancer, most of the breast cancer survivors are not meeting the physical activity recommendations proposed for the general adult population.58

Shape and build

Central obesity and elevated WHR is shown to be associated with increased risk of breast cancer mortality. In postmenopausal women, elevated WHR is associated with statistically significant increased relative risk of dying from breast cancer of 3.3 (95% CI 1.1–10.4).59 The Iowa Women’s Health family has re-confirmed that the previously reported interaction between family history and WHR was still (weakly) evident.60 It was suggested that metabolic changes including high levels of insulin in these women may lead to poorer survival.61

Tumour-related factors

Size

Obesity is associated with larger size of breast cancer at the time of diagnosis.62–64 The Iowa Women’s Health study demonstrated that obese women are more likely to present with tumours bigger than 2 cm in size and with metastatic disease.65 A study of 1177 premenopausal women who had invasive ductal breast carcinoma confirmed that women who were in the highest quartile of BMI had large tumour size (2 to <5 cm: odds ratio 2.3; 95% CI 1.5–3.1; or ≥5 cm: odds ratio 2.7; 95% CI 1.5–4.8) compared with the tumours of women whose BMI was in the first quartile.27 The poor prognosis of breast cancer in obesity may be a reflection of delayed diagnosis of breast cancer as it may not be physically possible to detect small tumours in large breasts of obese women on self-examination of breast.66 A study on mastectomy specimens showed that on presentation, women with big breasts have larger tumours and more involved lymph nodes than women with small breasts.67

Markers of aggressive tumours

The tumours of the obese women are more likely to have markers of high cellular proliferation than those of lean women. Daling et al.27 demonstrated that the tumours of the women in the highest quartile of BMI are more likely to have a high S-phase fraction, high histological grade and high mitotic cell count. Similarly, the large tumours in women in the highest BMI quartile are more likely to express markers of high proliferation when compared with the large tumours (≥2 cm) in women in the lowest BMI quartile, suggesting a more aggressive malignant phenotype in obese women.

Lymph node metastasis

It is possible that the potential for lymph node metastasis may be higher for breast cancer in obese women. A 10-kg weight gain after the age of 18 years is associated with a two-fold increase in the risk of developing breast cancer, which is more likely to be stage II.68 The incidence of axillary nodal involvement increases with body weight and BMI, particularly in women with estrogen-receptor-positive tumours.66 Obese women with estrogen-receptor-positive tumour have a 66% chance of nodal involvement; twice as much as their lean counterparts (33%). This trend was seen even after adjustment for age and tumour size. These findings are also confirmed in other studies.69,70

Hormone-receptor-negative tumour

The association between obesity and hormone receptor status of the tumour is complex. Obesity is more likely to be associated with estrogen-receptor-negative (ER−) and progesterone-receptor-negative tumour.27 The family-history-positive women in the upper quintile of WHR are at 2.2-fold greater risk of having progesterone-receptor-negative tumours compared with those in the lowest quintile (95% CI 0.9–5.8).64 A cohort study of 1169 women with breast cancer at 4 years of follow up concluded that BMI and estrogen receptor level independently influence survival from breast cancer but BMI affects survival only in women with no positive axillary nodes.71 These data are challenged by the recent publication of the National Surgical Adjuvant Breast and Bowel Project clinical trials for node-negative, ER− breast cancer, which demonstrated that compared with those of normal weight, disease-free survival from breast cancer was poorer for obese women (hazard ratio 1.16, 95% CI 1.01–1.33).72 Obesity did not increase the risk of recurrence but was associated with greater risk for second cancers, contralateral breast cancer and mortality, particularly nonbreast cancer deaths. To add to the complexity of the argument, in obese women, hormone-receptor-negative tumours are more likely to be associated with nodal metastases.73 In a study of 1211 women with breast cancer, overall, obese women had a 1.53 higher risk of lymph node metastases, which increased to three times for progesterone-receptor-negative breast cancer as compared with slim women.74

Treatment-related factors

Surgery

Obesity is most likely to be associated with complications of breast surgery such as infection of surgical site.75–78 Obesity is associated with the need for more extensive axillary surgery in women with breast cancer as the success of sentinel node biopsy, which is a rapidly emerging standard of care for staging the axilla in invasive breast cancer, is inversely related to BMI.79 A review of 2495 sentinel lymph node biopsy cases, women with high BMI were significantly likely to have sentinel node biopsy failed.

Radiotherapy

Obesity is associated with increased incidence of complication of radiotherapy such as lymphoedema of the arm and breast. After breast-conserving surgery and radiotherapy, the incidence of lymphoedema of the ipsilateral breast, arm and combined (breast and arm) is reported to be 10, 8 and 2%, respectively. A review of the literature addressing lymphoedema as a complication of radiotherapy confirmed that radiotherapy contributes to arm and breast oedema and is more common in obese women, particularly after surgery in the upper outer quadrant of the breast and radiation boost.80–82 A uniform radiation dose delivery in obese women with large breasts is challenging; therefore, reduction mammoplasty is recommended in women with very large breasts to allow maximum benefit of adjuvant radiotherapy.83 Mammoplasty in order to carry out resection of breast cancer is not associated with increased morbidity or mortality.

Chemotherapy

Chemotherapy can be a less efficient therapy for obese women because of systematic undertreatment of obese women or decreased effectiveness of chemotherapy in women with obesity. It is postulated that systematic undertreatment of breast cancer in obese women contributes to the poorer prognosis in these women.84 A cohort study of 9672 women undergoing chemotherapy found that first-cycle dose reductions was carried out in 20% of the obese and 37% of the severely obese women.85 The dose reduction of chemotherapy is associated with high likelihood of treatment failure as shown in Cancer and Leukaemia Group B study 8541 including 1471 women.86

Obesity is associated with poor prognosis even in women who receive optimum-dose chemotherapy. A retrospective review of 735 women receiving postoperative adjuvant chemotherapy found that the estimated 10-year, disease-free survival for overweight women was 54% (95% CI 50–58%) compared with 40% (95% CI 33–47%) for obese women.87 After adjusting for other factors, the risk for disease recurrence among obese women was 1.33 (95% CI 1.05–1.68) that of the nonobese population.87 There is indirect evidence to suggest that chemotherapy is less efficient in obese women, as leucocyte nadir counts remained high in obese women, when blood leucocyte count was considered as a surrogate marker for the efficiency of chemotherapy.88 It also takes longer for obese women to develop amenorrhoea on chemotherapy, which may be a sign of increased aromatisation of peripheral androgens, making endocrine component of chemotherapy less effective.

Endocrine treatment

It is postulated that because of increased aromatisation of the peripheral androgens into estrogens, antiestrogen treatment may be less effective in obese women. This hypothesis is supported by the observation that the incidence of amenorrhoea is higher in nonobese women than in obese women. Obese women have significantly higher levels of plasma estrogen than nonobese women, suggesting that peripheral aromatisation may suppress complete ovarian suppression in obese women. The efficacy of tamoxifen has been shown to be equal in obese and nonobese women with node-negative and estrogen-receptor-positive breast cancer.89

Biological treatment

There are no studies reporting the effect of obesity on traztuzumab.

Conclusion

Obesity, however measured, adversely affects the development and prognosis of breast cancer. There is ample data to suggest that obese and physically inactive women with breast cancer may have poorer survival compared with lighter weight and more active women. Obesity is one of the few risk factors for breast cancer that can be modified throughout life. Data from HEALS suggest that increasing physical activity and decreasing body fat may be a reasonable intervention to decrease insulin and leptin levels, thereby potentially influencing breast cancer prognosis.42 Weight gain is a common adverse effect for women receiving adjuvant chemotherapy and may have negative long-term implications for survival. Preventing weight gain by regular aerobic exercise in these women may be important in preventing recurrent disease.90 The strongest evidence that physical activity leading to weight loss and weight maintenance is associated with better outcome with breast cancer comes from Nurse’s Health Study.57 Curbing the twin epidemics of obesity and breast cancer demands changes in diet and lifestyle not only at the individual level but also changes in political, physical and social environment in order to decrease the risk of developing obesity-related postmenopausal breast cancer. Weight management with diet and lifestyle should be an integral part of the follow up of women with breast cancer.

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