Introduction
The second biggest cause of cancer in the UK is overweight or obesity and this is preventable. Cancer Research UK (CRUK) reports that breast cancer is now the UK’s most common cancer. (CRUK, 2019). According to the World Health Organisation, (WHO) breast cancer is the second most common cancer in the world. WHO have also now estimated that in the last 40 years, the prevalence of obesity worldwide has more than doubled (WHO, 2018). It is expected that cancer incidence is to rise further if the recent trends in overweight and obesity prevalence continue (CRUK, 2019). It has been reported that the worldwide cancer incidence and mortality rates are reflective of the prevalence in overweight and obesity (CRUK, 2019). Taking into account the current obesity epidemic (Flegal et al. 2012), the effects obesity has on the incidence of cancer and the lower standard of outcomes in patients with cancer seem particularly important. Researching the link between cancer and obesity is essential as being obese is a potentially modifiable factor through changes in lifestyle, exercise and if necessary, medication (Cho et al. 2018). Obesity has been associated with an increased risk of post-menopausal breast cancer. Obesity also has been found to cause several complications in the diagnosis and treatment of breast cancer. There is an increasing amount of evidence that obese breast cancer patients are more susceptible to complications related to surgery, chemotherapy and radiation (Lee et al. 2019). Recent evidence from a systematic review suggests that the risk of recurrence or death is increased by approximately 30% in obese women diagnosed with breast cancer (Chan et al. 2014).
Recurrence
The risk of recurrence is increased in breast cancer when the patient is obese. Minimal residual disease (MRD) is one way in which cancer recurrence can arise. Recurrence also comes about because of a collection of residual tumour cells, which happen to survive the primary treatment given to cancer patients (Denmark-Wahnefried et al. 2012). Most of the deaths that result from breast cancer are because of the inability to successfully prevent recurrence of a tumour (Loi et al. 2005). There are a range of non-biological and biological factors that reflect the association between the increased risk of recurring breast cancer and obesity. These include delayed detection which then leads to the presentation being at a more advanced stage at diagnosis (Loi et al. 2005). The chemotherapeutic agent doses used are sometimes not according to body size and this is another factor, also risks of second primary cancers are increased and causes of death not related to cancer (Ecker et al. 2019).
Biganzoli et al. (2017) conducted a study which investigated if being severely overweight or even obese at diagnosis, which was reflected by the patient’s increased body mass index (BMI), could be related to patterns of breast cancer recurrence. The study looked at the patterns of recurrence over time after the patient’s primary cancer treatment. The recurrence dynamics of breast cancer patients have previously been explored many times and the results showed that there was a multi-peak pattern. The pattern is defined by a high peak which begins early as a steady incline and then peaks at around the second year. This is then followed by a smaller and more delayed peak at around 5 or 6 years (Demicheli et al. 1999).
The results for breast cancer patients of normal weight are as expected showing the multi-peak pattern discussed above. The first early peak is clearly visible at 2 years (24 months), however the smaller peak at about 5-6 years (60-72 months) is partly distorted due to the first peak being very dominant. The pattern for obese patients differs from the normal weight patients as the first peak is displayed at a much higher risk level. The first peak is followed by a cluster of delayed late distant events.
It is thought that the hazard rates following this stable pattern over time in normal weight patients can be explained by the primary tumour surgery. This surgery may possibly result in the primary tumour/metastasis homeostasis being removed (Cornez et al. 2017). The surgery could also cause disruption of tumour dormancy, which then leads to the synchronisation of metastatic growth (Desmedt et al. 2017).
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It has been hypothesised that the patients increased BMI, and therefore adiposity at diagnosis, could be influencing the breast cancer dormancy. Recent papers have supported this idea and have demonstrated that activation of dormant tumour cells was prompted by inflammatory marker or by abnormal fatty acid metabolism (Pascual et al. 2017). These processes are both present in overweight and obese patients. There is clearly a difference in recurrence dynamics between normal weight, overweight and obese women. However, when comparing the overweight and obese women, the recurrence dynamics of obese women is not an extreme or more intense pattern of the overweight women. This shows that the disparity observed in recurrence dynamics between overweight women and obese women does not simply indicate different degrees of the same biological process (Fornili et al. 2017). If this was to be the case, then the results would have shown a progressive change in recurrence risk across BMI categories.
Endocrine Therapy
Endocrine therapy is of major therapeutic value for patients with hormone receptor positive breast cancer, which is also known as oestrogen receptor positive breast cancer. Endocrine therapy lowers levels of oestrogen and reduces the growth of the cancer. This therapy aims this by either inhibiting the production of oestrogen or blocking the effect of oestrogen on a receptor level. There are several different classes of endocrine therapy and they all achieve the aim of endocrine therapy in different ways. The two most common classes of endocrine therapy used are selective oestrogen receptor modulators and aromatase inhibitors (Awan and Esfahani 2018). Other classes include selective oestrogen receptor down regulators, luteinising hormone releasing agonists, high-dose oestrogens and targeted therapies (Reinbolt et al. 2015). According to the BNF and NICE guidelines (2019) tamoxifen, which is a selective oestrogen receptor modulator, is recommended as the initial adjuvant endocrine therapy for men and premenopausal women with oestrogen receptor positive invasive breast cancer. An aromatase inhibitor, for example anastrozole, should be given as first-line treatment in postmenopausal women with oestrogen receptor positive invasive breast cancer. Aromatase inhibitors work by blocking the aromatase enzyme from converting androgens to oestrogens. This then prohibits the growth of new, residual, or dormant breast cancer cells. In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, it was found that there were significant improvements in breast cancer outcomes in women taking Arimidex versus tamoxifen (Tremont et al. 2017) Arimidex is a brand name for the drug Anastrozole. Across all BMI levels, tamoxifen was found just as effective as Arimidex with regard to overall recurrence. This suggests that obesity had no effect on the effectiveness of tamoxifen (Sestak et al. 2010).
An 8 year follow up was conducted and it was found that almost 20% of women using Arimidex had breast cancer recurrence (Azrad and Denmark-Wahnefired 2014). Compared to patients who were of normal weight, obese women were much more likely to experience distant recurrence and disease recurrence. It was also reported that obese women with breast cancer had a significantly increased recurrence rate, this included overall and at distant sites. This suggested that the suppression of the aromatase enzyme by Arimidex could possibly not be entirely effective in postmenopausal women who are obese (Howell et al. 2005). In another trial, the results for treatment with anastrozole showed significant differences when looking at the risk of recurrence and even overall survival in normal weight women and obese women. In additional analysis, obese women taking anastrozole tended to have a much greater risk for reduced disease-free survival compared to obese women who were taking tamoxifen. The data collected form these studies collectively show a worse prognosis for obese women being treated with endocrine agents (Lee et al. 2019). They also suggest that AIs may be of reduced effectiveness than tamoxifen in this group of patients.
Other treatments
Surgery is another treatment option for breast cancer patients. Obesity is a known cause of complications with mastectomy, causing both minor and major surgical complications such as increased risk of bleeding and infections (Garland et al. 2018). For chemotherapy, recent guidelines have recommended administrating the full weight based doses for obese patients rather than using ideal body weight. This has been based on studies that have showed reduced survival rates in obese patients which is due to the under-dosing of cytotoxic therapies (Argolo et al. 2018).
Conclusion
In conclusion, breast cancer patients who are obese illustrate a unique patient population. From many studies, it is known that are at a higher risk for breast cancer development and experience more difficulties with surgery and therapy. Even with appropriate treatment, they still have an increased recurrence risk compared to women of normal weight. Furthermore, endocrine therapy in obese women has proven to be less effective, and there is the idea that tamoxifen is of more effectiveness than AIs in obese patients. Taking all this into account, obesity is often an indicator of an unhealthy lifestyle consisting of excess intake of saturated fats and unsatisfactory levels of physical activity. These are now being recognised as risk factors for worse prognosis of cancer. Based on these challenges, more investigations are needed to assess the effective treatment mechanisms required to successfully target breast cancer in the obese women population.
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