The prevalence of obesity worldwide has more than doubled from 1980 to 2014.1 In 2014, 13% of the world’s adult population (11% of men and 15% of women) were obese (BMI ≥ 30 kg/m2) and 39% of adults (38% of men and 40% of women) were overweight (BMI 25-29.9 kg/m2). Singapore is also not spared from this obesity endemic, with 8.6% of Singaporeans being obese in 2013.2
Breast cancer is the most common cancer in women worldwide, with nearly 1.7 million new cases of breast cancers diagnosed worldwide in 2012. This represents about 12% of all new cancer cases and 25% of all cancers in women.4
In Singapore, breast cancer is also the most common cancer amongst females5, accounting for 29.2% of all female cancers, and 17.6% of all female cancer deaths. The age-standardised incidence rate (ASIR) of newly-diagnosed breast cancer in females had increased significantly over the years – with a three-fold increase from 23.8 per 100,000 (1975-1979) to 64.7 per 100,000 (2010-2014).
It is well-accepted that obesity increases the risk of breast cancer, although the mechanisms behind it are less well understood.
In post-menopausal women, an increased BMI is associated with an increased risk of oestrogen-receptor positive breast cancer. In the post-menopausal female, the main production of oestrogen is from the adipose tissue, with a small proportion of oestrogens synthesised in breast tissue itself.
As such, the increased breast cancer risk in the post-menopausal female with a high BMI would likely arise from the higher serum oestrogen level associated with the higher body proportion of adipose tissue.
In pre-menopausal women, the link between BMI and breast cancer is more controversial. Most studies show that a higher BMI is associated with a lower risk of breast cancer 3, mainly the hormone-receptor positive breast cancer. 6 Yet, other studies have shown that weight gain before age 50 is associated with a greater risk of breast cancer, in particular, the oestrogen-receptor negative breast cancer.7-9
In addition, obesity is correlated with an increased risk of and complications from breast cancer therapies.
Obesity also impacts on life expectancy, with pre-menopausal and post-menopausal obese women being 1.75 and 1.34 times, respectively, at increased risk of death from breast cancer.10
The underlying molecular mechanisms promoting carcinogenesis in obesity are not well understood. Obesity per se does not appear to have a direct mutagenic mechanism, although the metabolic stress associated with obesity may alter mitochondrial metabolism, leading to an increase in reactive oxygen species production.
There are many explanations on why obesity increases the risk of breast cancer.
Firstly, obesity and obesity-related lifestyle factors (e.g. physical inactivity and high-fat diets) are usually accompanied by elevated glucose metabolism traits (e.g. insulin, glucose, and homeostatic model assessment-insulin resistance (HOMA-IR) levels).11-13
Insulin receptors are mainly found in adipose tissues, muscle and liver cells, and are overexpressed in breast cancer cells. This overexpression of insulin receptors leads to an overstimulation of various signaling pathways, which in turn promote an anabolic state necessary for cell proliferation, differentiation, and anti-apoptosis.
This association is particular strong in post-menopausal women, in whom high insulin levels have been associated with a twofold increase in breast cancer risk.
Secondly, obesity may cause concentrations of circulating endogenous hormones (insulin, insulin-like growth factors, and sex steroids) to fluctuate, distorting the equilibrium between cell proliferation and apoptosis14, in favour of promoting carcinogenesis.
As discussed above, in the post-menopausal women, obesity is associated with higher serum oestrogen levels which can increase breast cancer risk. There are many other local and systemic factors which are simultaneously elevated in obesity, such as insulin, IGF-1, proinflammatory cytokines, blood glucose, free fatty acids and leptin.
The ratios of proinflammatory to anti-inflammatory factors (e.g. adiponectin:leptin) are important to tumour cell proliferation, survival, and invasiveness. Some also propose that a chronically inflamed state (such as that seen in the adipose tissues of obese patients) may modify the tumour microenvironment and potentially drive cancer incidence and metastasis.
Thirdly, a hyperglycaemic state (commonly seen in obese patients) can induce high levels of intracellular glucose, facilitating breast cancer growth. There has been a limited number of population- based epidemiologic studies performed that examine the relationships between glycaemic phenotypes and cancer risk.
Through in vitro studies, obesity-glucose metabolism-related gene signaturebreast cancer risk pathways have been identified. Jung et al.15 studied 16 glucose metabolism-related SNPs (single nucloetide polymorphisms), of which three were associated with breast cancer risk. Comparing non-obese and obese carriers, there was a difference in the associations of these SNPs with cancer.
This suggests that obesity as well as modifiable lifestyle-related factors can both influence glucose metabolismrelated SNPs’ interactions and have an impact on cancer risk.
Surgery is the mainstay of breast cancer treatment, and is either performed as the initial form of curative treatment, or performed after neoadjuvant therapy. Not only does obesity and its associated comorbidities increase the risk of general anaesthesia for their surgeries, obesity is also associated with a poorer surgical outcome.
Obesity is associated with
nearly 12- fold increased odds of a post-operative complication after elective breast procedures.16 Obesity is also known to contribute to increased operating and recovery times, more blood loss, poorer healing, flap necrosis, seromas, haematomas and high infection rates.17
risk of lymphoedema after breast cancer surgery is also higher in obese women.
Obesity also has an impact on adjuvant therapy. For adjuvant radiotherapy, the set-up for an obese patient is more difficult – their body surface is more mobile, and there is an increased vulnerability to instability and reduced reproducibility of skin contours and treatment positions. There tends to be a shift in the delivery of external-beam radiation in obese patients, resulting in the target location not receiving the full dose.18
Also, there are increased side effects as the skin folds and the larger volume of breast/axillary fat that sag will result in a greater amount of normal tissue inadvertantly included in the treatment fields.
As for chemotherapy, the doses required will be higher in obese patients, as the therapeutic doses are based on body surface area. There is however no evidence to suggest difference in toxicities for patients with extremes of weight. There is also the potential of undertreating a severely obese patient if there is a cap to the maximum dose of chemotherapeutic agents that can be administered.
Obesity is also associated with a 35% to 40% increased risk of breast cancer recurrence and death and therefore poorer survival outcomes. This relationship is most clearly established for oestrogen-receptor positive breast cancer, but not so for the triple-negative and Her2-positive subtypes.18
Obesity increases the risk of developing a second primary malignancy – a 37% increase in the relative risk of contralateral breast cancer, a 97% increase in the relative risk of endometrial cancer and an 89% increase in the relative risk of colorectal cancer.20 However, these findings are likely because obesity itself is also a risk factor for developing other cancers, such as endometrial and colorectal cancers.
The prevalence of obesity and breast cancer are on the increase worldwide and there are some associations linking both these conditions.
Obesity increases the risk of oestrogen- receptor positive breast cancer in post-menopausal women. The mechanism in which obesity increases the risk of breast cancer is not fully understood, but it is believed to be through the increased oestrogen levels, as well as through the increased levels of endogenous hormones and inflammatory mediators.
Obesity also increases the morbidity of the surgical and adjuvant treatments of breast cancer, and is associated with a higher rate of recurrence and a second malignancy.
However, there are still a lot of questions that remain unanswered:
But what we do know is this – we know that obesity increases the risk of cancers, in addition to increasing morbidity and mortality through its multiple associated systemic conditions.
As such, obesity affects the individual, and has healthcare and economic implications at a national and global level. It is therefore important to fight obesity, not just at the individual level, but also as a community, and at a national and global level.
GPs can call for appointments through the GP Appointment Hotline at 6436 8288 (NCCS), 6321 4402 (SGH), 6788 3003 (CGH), 6472 2000 (SKH), 6294 4050 (KKH).
By: Dr Sim Yirong, Associate Consultant, Division of Surgical Oncology, National Cancer Centre Singapore; SingHealth Duke-NUS Breast Centre
Dr. Sim Yirong is an Associate Consultant at the Division of Surgical Oncology at the National Cancer Centre Singapore and SingHealth Duke-NUS Breast Centre.
Dr. Sim graduated with a medical degree and PhD from the University of Cambridge in 2009, and obtained her fellowship with Royal College of Surgeons Edinburgh in 2016. Her focus and interests are in breast cancer research and in education.
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**Thank you to Dr Wong Fuh Yong and Dr Kiley Loh for their contributions to this article.
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