Epidemiology

Breast cancer is the most prevalent cancer in women, with >1.7 million new cases worldwide in 2012, and the fifth cause of death from cancer overall .

The impact of obesity on the incidence and the evolution of breast cancer is not fully elucidated, due to several confounding factors, such as the use of hormone replacement therapy (HRT), ethnicity and the biology of different cancer subtypes.

Oestrogen receptor (ER)-negative and aggressive tumour subtypes are found more frequently in premenopause, whereas ER-positive subtypes occur more often among postmenopausal women. Obesity is considered a risk factor for postmenopausal breast cancer, whereas it seems to be neutral or even inversely related to the incidence of breast cancer in premenopausal women .

Postmenopausal breast cancer

The association between obesity and the increased overall risk of breast cancer is consistent for postmenopausal women. Large meta-analyses and one very large cohort study confirmed a direct association between BMI and the risk of developing the disease . General adiposity appears to be more strongly related to the risk of breast cancer than measures of abdominal adiposity .

A recent meta-analysis investigated ER and progesterone receptor (PR) status. A correlation between BMI ≥30 kg/m ² and the incidence of postmenopausal breast cancer was found for ER-positive/PR-positive cancer (relative risk (RR) 1.39, 95% confidence interval (CI): 1.14- 1.70), but not for ER-negative/PR-negative cancer. This finding suggests that the effect of obesity in postmenopausal women may be mediated by endogenous sex hormones. Furthermore, the obesity-dependent risk was lower for women under postmenopausal oestrogen–progestin therapy, suggesting that hormonal therapy is a confounding factor in the obesity–cancer relationship.

Premenopausal breast cancer

There is still controversy on the impact of obesity on the risk of premenopausal breast cancer. Body fatness is considered as possibly protective against premenopausal breast cancer . This notion is supported by several cohort studies and meta-analyses. In the most recent study, BMI and the incidence of breast cancer show a linear inverse correlation, with a peak at BMI 22 kg/m , and a decrease as BMI increases further (hazard ratio (HR) 0.89, 99% CI 0.86–0.92) . A large meta-analysis showed that obesity (BMI ≥30 kg/m ² ) is associated with a significantly reduced risk of premenopausal breast cancer (RR 0.83; 95% CI: 0.75–0.91), compared to the risk for normal-weight women. This association seems to apply to receptor-positive breast cancer only, whereas no correlation exists with receptor-negative premenopausal breast cancer .

Contrary to postmenopausal breast cancer, body fat distribution could play a relevant role in the RR of developing premenopausal cancer. While confirming the inverse correlation with BMI, the results of a recent meta-analysis showed a linear positive correlation between WHR and the incidence of breast cancer . From a clinical standpoint, these data should induce to consider trunk–abdominal fat as an independent risk factor for breast cancer in premenopause.

Prognosis

For both premenopausal and postmenopausal women, obesity is associated with an increased risk of recurrence and mortality. This also applies to women with stage 1 disease, independently from age and treatment . Women who are obese at diagnosis of breast cancer have a 30% higher cancer-related and overall mortality, compared to normal-weight women . The association is significant for both BMI (HR 1.33; 1.21–1.47) and WHR (HR 1.31; 1.08–1.58), and it is independent from menopausal status .

Importantly, gaining >10% weight after cancer diagnosis is associated with worse survival rates .

Delayed diagnosis may play a role: patients with a BMI≥ 30 kg/m ² have more advanced disease at diagnosis compared with patients with a BMI <25 kg/m ² .

The impact of weight loss on the risk of recurrence in women with early breast cancer is a matter of current debate. Several studies suggest better breast cancer-specific and overall survival in individuals who are physically active after breast cancer diagnosis ; however, the relative impact of weight loss per se, increased physical activity and changes in diet composition needs further research.

Epidemiology

Endometrial cancer is the sixth most common cancer in women. It is often diagnosed at an early stage, allowing for a high survival rate .

Endometrial cancer has been the first tumour to be identified as obesity related . A meta-analysis published in 2010 found that the combined risk ratio of developing endometrial cancer per 5 kg/m ² increase in BMI above 27 kg/m ² was 1.60 (95% CI 1.52–1.68). The association was stronger among never users of HRT, suggesting protective effects of progestins contained in combined HRT . A very recent large cohort study found an HR for endometrial cancer of 1.62 (95% CI 1.56–1.69) per 5 kg/m ² increase in BMI. More than 40% of the endometrial cancers recorded in the study could be attributed to overweight and obesity . Given the secular trends in obesity worldwide, it is expected that endometrial cancer will increase its incidence in future years.

Two types of endometrial cancer have been described: type I (oestrogen dependent), which represents 85% of endometrial cancers, and type II (oestrogen independent). Type I cancers are most commonly low-grade endometrioid tumours, occur more frequently in obese women and are typically preceded by complex atypical hyperplasia; they are associated with an endocrine milieu of oestrogen predominance and tend to be confined to the uterus. Conversely, type II tumours occur more frequently in thin, older patients with an atrophic endometrium; the histology is typically high-grade serous or clear cell, and the prognosis is usually poor .

Most of the available information on risk factors, including the strong association with obesity, pertains primarily to low-grade endometrioid cancers. Recent data, however, suggest that type I and type II tumours could share several pathogenetic factors, such as hyperinsulinaemia, chronic inflammation and oxidative activity, which are commonly associated with obesity .

All these factors are common among women with polycystic ovary syndrome (PCOS), who are actually at an increased risk of developing endometrial cancer, as shown by a recent meta-analysis (odds ratio of 2.79 (95% CI 1.31–5.95)) .

Prognosis

Review papers on endometrial cancer and obesity are mainly focused on incidence rather than survival. Earlier large prospective data showed a significant positive linear trend in death rate for endometrial cancer with increasing BMI, with RRs of 2.53 (95% CI 2.02–3.18), 2.77 (95% CI 1.83–4.18) and 6.25 (95% CI 3.75–10.42) for obese (BMI 30–34.9), severely obese (BMI 35–39.9) and morbidly obese (BMI >40) women, respectively .

Studies on obesity and recurrence of endometrial cancer have failed to find an association with BMI , whereas decreased overall survival has been found only in morbidly obese patients. Within this subgroup, a large proportion of deaths are unrelated to endometrial cancer, thus suggesting that these women have higher chances of dying from obesity-related diseases than from cancer. In support of this notion, a recent multi-centre trial showed obesity to be related to all-cause mortality but not disease-specific mortality. The same study also showed that obese women tend to have lower-risk, lower-stage uterine cancer compared to non-obese ones .

On balance, it seems unlikely that obesity has a major influence on the risk of recurrence of or death from endometrial cancer. The reduction in survival rates would be in most cases the consequence of co-morbidities. For this reason, gynaecologic oncologists should promote lifestyle interventions, referring patients to weight-loss specialists, nutritionists and other physician specialists in the management of co-morbidities .

Epidemiology

Ovarian cancer is the sixth most common cancer in women, with >200,000 new cases diagnosed each year, and approximately 125,000 deaths per year worldwide . It is considered the leading cause of death from gynaecological malignancies: in spite of high response rates to the standard front-line treatment for advanced disease with cytoreductive surgical debulking, followed by platinum/taxane-based chemotherapy, most patients eventually relapse, developing drug-resistant disease. The 5-year survival rates for early-stage disease are above 80%, but for 70% of patients diagnosed with advanced disease, the median 5-year survival rate ranges between 25% and 35% .

The potential correlation between obesity and ovarian cancer is a matter of debate. Systematic reviews report a risk of epithelial ovarian cancer among obese women up to 30% higher than in women with a BMI in the “healthy” range (95% CI 1.1–1.5) .

A recent meta-analysis including 25,157 women with ovarian cancer showed that the RR of ovarian cancer increases with increasing BMI among never users of HRT (RR per 5 kg/m increase in BMI of 1.10 (95% CI, 1.07–1.13)), but not in ever users of HRT. Whereas the increase in risk was independent from women’s age, ethnicity, age at menarche, parity, family history of ovarian or breast cancer, use of oral contraceptives, age at menopause and hysterectomy, HRT largely attenuated the relationship between BMI and ovarian cancer. The authors postulated that the high concentrations of exogenous oestrogens associated with HRT would prevail on the impact of endogenous oestrogens originating from the adipose tissue .

A recent population-based study that used BMI as a linear effect, after adjusting for several potential confounders, showed that each 5 kg/m increase in BMI was associated with an increased risk of ovarian cancer (HR 1.09, 99% CI 1.04–1.14) confined, however, to premenopausal women.

The subtype of ovarian cancer could be of importance in the BMI–risk relationship. A pooled analysis including >13,000 cases from 15 case–control studies reported subtype-specific data: a five-unit increase in BMI was associated with significant increases of 24%, 19% and 17%, in the incidence of borderline serous, mucinous and endometrioid cancer, respectively . However, the analysis found no association with invasive serous cancer. As a whole, these studies suggest that ovarian cancer should be added to the list of obesity-related cancers, although the possibility exists that obesity could impact only on some histologic subtypes of ovarian cancer, and not on the more aggressive high-grade serous cancer, which accounts for the majority of deaths .

In conclusion, available data support the notion of a positive association between BMI and the risk of ovarian cancer. However, more research is warranted regarding the influence of menopausal status and the use of HRT on the association.

Prognosis

Several prognostic indicators for ovarian cancer have been identified, including stage at diagnosis, age, residual tumour after surgery, tumour grade and histologic subtype. The effect of obesity on prognosis is so far unclear: several cohort studies reported conflicting results. Three large meta-analyses are currently available.

Whereas one meta-analysis showed a worse survival for obese women (pooled HR, 1.17; 95% CI 1.03–1.34), independently from the time at which obesity was diagnosed , other systematic reviews showed that only overweight/obesity diagnosed in early adulthood (between 18 and 29 years of age) and/or before cancer diagnosis (1–5 years) were associated with worse prognosis .

Chronic hyperinsulinaemia, the increase in insulin-like growth factor 1 (IGF-1), hyperglycaemia and altered sex hormone metabolism commonly associated with obesity could underlie the link between pre-morbid obesity or obesity during early adulthood, and more aggressive cancer cell biology from the onset. However, whether pre-disease obesity has more impact than obesity at diagnosis remains a matter of current debate.

Epidemiology

Cervical cancer is the fourth most common cancer in women, and the seventh overall, with an estimated 528,000 new cases and 266,000 deaths worldwide in 2012, accounting for 7.5% of all female cancer deaths .

Human papillomavirus (HPV) is the causative agent for virtually over 95% of cervical cancer cases, although several cofactors are implicated in the pathogenesis, including oral contraceptives, multiparity, smoking, immune response, nutritional status and coexisting infectious diseases.

Obesity may potentially increase the incidence of cervical cancer. The largest population-based study published so far evidenced a modest positive association between BMI and cervical cancer (HR 1.10; 99% CI 1.03–1.17) .

Confounding lifestyle factors, such as tobacco use and poor intake of vegetables and fruits, may be related to the increased risk of cervical cancer by allowing persistent infection of HPV through impaired immunological function . Furthermore, overweight and obese women might be less likely to undergo cervical cancer screening . Some studies have suggested obesity to be associated with an increased risk of adenocarcinoma of the cervix, but not squamous cell carcinoma, probably because cervical adenocarcinoma represents a more hormonally responsive cancer . These data would be consistent with observations that rates of adenocarcinoma have been increasing in many countries, matching the rise in obesity . Therefore, obese women should be strongly encouraged to go for regular screening in order to allow for an early diagnosis.

Prognosis

A recent retrospective study found that women with morbid obesity (defined as BMI ≥35) and cervical cancer had a higher risk of both all-cause death (HR 1.26, 95% CI 1.10–1.45) and disease-specific death (HR 1.24, 95% CI 1.06–1.47) than their normal-weight counterparts .

In the morbidly obese patients with cervical cancer, both treatment-related and biological factors may contribute to decreased disease-specific survival.

Epidemiology

Breast cancer is the most prevalent cancer in women, with >1.7 million new cases worldwide in 2012, and the fifth cause of death from cancer overall .

The impact of obesity on the incidence and the evolution of breast cancer is not fully elucidated, due to several confounding factors, such as the use of hormone replacement therapy (HRT), ethnicity and the biology of different cancer subtypes.

Oestrogen receptor (ER)-negative and aggressive tumour subtypes are found more frequently in premenopause, whereas ER-positive subtypes occur more often among postmenopausal women. Obesity is considered a risk factor for postmenopausal breast cancer, whereas it seems to be neutral or even inversely related to the incidence of breast cancer in premenopausal women .

Postmenopausal breast cancer

The association between obesity and the increased overall risk of breast cancer is consistent for postmenopausal women. Large meta-analyses and one very large cohort study confirmed a direct association between BMI and the risk of developing the disease . General adiposity appears to be more strongly related to the risk of breast cancer than measures of abdominal adiposity .

A recent meta-analysis investigated ER and progesterone receptor (PR) status. A correlation between BMI ≥30 kg/m ² and the incidence of postmenopausal breast cancer was found for ER-positive/PR-positive cancer (relative risk (RR) 1.39, 95% confidence interval (CI): 1.14- 1.70), but not for ER-negative/PR-negative cancer. This finding suggests that the effect of obesity in postmenopausal women may be mediated by endogenous sex hormones. Furthermore, the obesity-dependent risk was lower for women under postmenopausal oestrogen–progestin therapy, suggesting that hormonal therapy is a confounding factor in the obesity–cancer relationship.

Premenopausal breast cancer

There is still controversy on the impact of obesity on the risk of premenopausal breast cancer. Body fatness is considered as possibly protective against premenopausal breast cancer . This notion is supported by several cohort studies and meta-analyses. In the most recent study, BMI and the incidence of breast cancer show a linear inverse correlation, with a peak at BMI 22 kg/m , and a decrease as BMI increases further (hazard ratio (HR) 0.89, 99% CI 0.86–0.92) . A large meta-analysis showed that obesity (BMI ≥30 kg/m ² ) is associated with a significantly reduced risk of premenopausal breast cancer (RR 0.83; 95% CI: 0.75–0.91), compared to the risk for normal-weight women. This association seems to apply to receptor-positive breast cancer only, whereas no correlation exists with receptor-negative premenopausal breast cancer .

Contrary to postmenopausal breast cancer, body fat distribution could play a relevant role in the RR of developing premenopausal cancer. While confirming the inverse correlation with BMI, the results of a recent meta-analysis showed a linear positive correlation between WHR and the incidence of breast cancer . From a clinical standpoint, these data should induce to consider trunk–abdominal fat as an independent risk factor for breast cancer in premenopause.

Prognosis

For both premenopausal and postmenopausal women, obesity is associated with an increased risk of recurrence and mortality. This also applies to women with stage 1 disease, independently from age and treatment . Women who are obese at diagnosis of breast cancer have a 30% higher cancer-related and overall mortality, compared to normal-weight women . The association is significant for both BMI (HR 1.33; 1.21–1.47) and WHR (HR 1.31; 1.08–1.58), and it is independent from menopausal status .

Importantly, gaining >10% weight after cancer diagnosis is associated with worse survival rates .

Delayed diagnosis may play a role: patients with a BMI≥ 30 kg/m ² have more advanced disease at diagnosis compared with patients with a BMI <25 kg/m ² .

The impact of weight loss on the risk of recurrence in women with early breast cancer is a matter of current debate. Several studies suggest better breast cancer-specific and overall survival in individuals who are physically active after breast cancer diagnosis ; however, the relative impact of weight loss per se, increased physical activity and changes in diet composition needs further research.

Epidemiology

Endometrial cancer is the sixth most common cancer in women. It is often diagnosed at an early stage, allowing for a high survival rate .

Endometrial cancer has been the first tumour to be identified as obesity related . A meta-analysis published in 2010 found that the combined risk ratio of developing endometrial cancer per 5 kg/m ² increase in BMI above 27 kg/m ² was 1.60 (95% CI 1.52–1.68). The association was stronger among never users of HRT, suggesting protective effects of progestins contained in combined HRT . A very recent large cohort study found an HR for endometrial cancer of 1.62 (95% CI 1.56–1.69) per 5 kg/m ² increase in BMI. More than 40% of the endometrial cancers recorded in the study could be attributed to overweight and obesity . Given the secular trends in obesity worldwide, it is expected that endometrial cancer will increase its incidence in future years.

Two types of endometrial cancer have been described: type I (oestrogen dependent), which represents 85% of endometrial cancers, and type II (oestrogen independent). Type I cancers are most commonly low-grade endometrioid tumours, occur more frequently in obese women and are typically preceded by complex atypical hyperplasia; they are associated with an endocrine milieu of oestrogen predominance and tend to be confined to the uterus. Conversely, type II tumours occur more frequently in thin, older patients with an atrophic endometrium; the histology is typically high-grade serous or clear cell, and the prognosis is usually poor .

Most of the available information on risk factors, including the strong association with obesity, pertains primarily to low-grade endometrioid cancers. Recent data, however, suggest that type I and type II tumours could share several pathogenetic factors, such as hyperinsulinaemia, chronic inflammation and oxidative activity, which are commonly associated with obesity .

All these factors are common among women with polycystic ovary syndrome (PCOS), who are actually at an increased risk of developing endometrial cancer, as shown by a recent meta-analysis (odds ratio of 2.79 (95% CI 1.31–5.95)) .

Prognosis

Review papers on endometrial cancer and obesity are mainly focused on incidence rather than survival. Earlier large prospective data showed a significant positive linear trend in death rate for endometrial cancer with increasing BMI, with RRs of 2.53 (95% CI 2.02–3.18), 2.77 (95% CI 1.83–4.18) and 6.25 (95% CI 3.75–10.42) for obese (BMI 30–34.9), severely obese (BMI 35–39.9) and morbidly obese (BMI >40) women, respectively .

Studies on obesity and recurrence of endometrial cancer have failed to find an association with BMI , whereas decreased overall survival has been found only in morbidly obese patients. Within this subgroup, a large proportion of deaths are unrelated to endometrial cancer, thus suggesting that these women have higher chances of dying from obesity-related diseases than from cancer. In support of this notion, a recent multi-centre trial showed obesity to be related to all-cause mortality but not disease-specific mortality. The same study also showed that obese women tend to have lower-risk, lower-stage uterine cancer compared to non-obese ones .

On balance, it seems unlikely that obesity has a major influence on the risk of recurrence of or death from endometrial cancer. The reduction in survival rates would be in most cases the consequence of co-morbidities. For this reason, gynaecologic oncologists should promote lifestyle interventions, referring patients to weight-loss specialists, nutritionists and other physician specialists in the management of co-morbidities .

Epidemiology

Ovarian cancer is the sixth most common cancer in women, with >200,000 new cases diagnosed each year, and approximately 125,000 deaths per year worldwide . It is considered the leading cause of death from gynaecological malignancies: in spite of high response rates to the standard front-line treatment for advanced disease with cytoreductive surgical debulking, followed by platinum/taxane-based chemotherapy, most patients eventually relapse, developing drug-resistant disease. The 5-year survival rates for early-stage disease are above 80%, but for 70% of patients diagnosed with advanced disease, the median 5-year survival rate ranges between 25% and 35% .

The potential correlation between obesity and ovarian cancer is a matter of debate. Systematic reviews report a risk of epithelial ovarian cancer among obese women up to 30% higher than in women with a BMI in the “healthy” range (95% CI 1.1–1.5) .

A recent meta-analysis including 25,157 women with ovarian cancer showed that the RR of ovarian cancer increases with increasing BMI among never users of HRT (RR per 5 kg/m increase in BMI of 1.10 (95% CI, 1.07–1.13)), but not in ever users of HRT. Whereas the increase in risk was independent from women’s age, ethnicity, age at menarche, parity, family history of ovarian or breast cancer, use of oral contraceptives, age at menopause and hysterectomy, HRT largely attenuated the relationship between BMI and ovarian cancer. The authors postulated that the high concentrations of exogenous oestrogens associated with HRT would prevail on the impact of endogenous oestrogens originating from the adipose tissue .

A recent population-based study that used BMI as a linear effect, after adjusting for several potential confounders, showed that each 5 kg/m increase in BMI was associated with an increased risk of ovarian cancer (HR 1.09, 99% CI 1.04–1.14) confined, however, to premenopausal women.

The subtype of ovarian cancer could be of importance in the BMI–risk relationship. A pooled analysis including >13,000 cases from 15 case–control studies reported subtype-specific data: a five-unit increase in BMI was associated with significant increases of 24%, 19% and 17%, in the incidence of borderline serous, mucinous and endometrioid cancer, respectively . However, the analysis found no association with invasive serous cancer. As a whole, these studies suggest that ovarian cancer should be added to the list of obesity-related cancers, although the possibility exists that obesity could impact only on some histologic subtypes of ovarian cancer, and not on the more aggressive high-grade serous cancer, which accounts for the majority of deaths .

In conclusion, available data support the notion of a positive association between BMI and the risk of ovarian cancer. However, more research is warranted regarding the influence of menopausal status and the use of HRT on the association.

Prognosis

Several prognostic indicators for ovarian cancer have been identified, including stage at diagnosis, age, residual tumour after surgery, tumour grade and histologic subtype. The effect of obesity on prognosis is so far unclear: several cohort studies reported conflicting results. Three large meta-analyses are currently available.

Whereas one meta-analysis showed a worse survival for obese women (pooled HR, 1.17; 95% CI 1.03–1.34), independently from the time at which obesity was diagnosed , other systematic reviews showed that only overweight/obesity diagnosed in early adulthood (between 18 and 29 years of age) and/or before cancer diagnosis (1–5 years) were associated with worse prognosis .

Chronic hyperinsulinaemia, the increase in insulin-like growth factor 1 (IGF-1), hyperglycaemia and altered sex hormone metabolism commonly associated with obesity could underlie the link between pre-morbid obesity or obesity during early adulthood, and more aggressive cancer cell biology from the onset. However, whether pre-disease obesity has more impact than obesity at diagnosis remains a matter of current debate.

Epidemiology

Cervical cancer is the fourth most common cancer in women, and the seventh overall, with an estimated 528,000 new cases and 266,000 deaths worldwide in 2012, accounting for 7.5% of all female cancer deaths .

Human papillomavirus (HPV) is the causative agent for virtually over 95% of cervical cancer cases, although several cofactors are implicated in the pathogenesis, including oral contraceptives, multiparity, smoking, immune response, nutritional status and coexisting infectious diseases.

Obesity may potentially increase the incidence of cervical cancer. The largest population-based study published so far evidenced a modest positive association between BMI and cervical cancer (HR 1.10; 99% CI 1.03–1.17) .

Confounding lifestyle factors, such as tobacco use and poor intake of vegetables and fruits, may be related to the increased risk of cervical cancer by allowing persistent infection of HPV through impaired immunological function . Furthermore, overweight and obese women might be less likely to undergo cervical cancer screening . Some studies have suggested obesity to be associated with an increased risk of adenocarcinoma of the cervix, but not squamous cell carcinoma, probably because cervical adenocarcinoma represents a more hormonally responsive cancer . These data would be consistent with observations that rates of adenocarcinoma have been increasing in many countries, matching the rise in obesity . Therefore, obese women should be strongly encouraged to go for regular screening in order to allow for an early diagnosis.

Prognosis

A recent retrospective study found that women with morbid obesity (defined as BMI ≥35) and cervical cancer had a higher risk of both all-cause death (HR 1.26, 95% CI 1.10–1.45) and disease-specific death (HR 1.24, 95% CI 1.06–1.47) than their normal-weight counterparts .

In the morbidly obese patients with cervical cancer, both treatment-related and biological factors may contribute to decreased disease-specific survival.