Impact of central obesity on prognostic outcome of triple negative breast cancer in Chinese women

Obesity is becoming more and more popular all over the world. According to a recent report, the world has transitioned from one in which underweight prevalence was more than double that of obesity, to one in which more people are obese than underweight. In 2014 there were triple obese men and twice obese women than 40 years ago (NCD Risk Factor Collaboration (NCD-RisC) 2016). The current status of obesity prevalence among Chinese women is also concerning. In 2014, China had the most obese women in the world (46.4 million), accounting for 12.4 % of global obesity (NCD-RisC 2016). A survey in 2015 showed 45.3 % Chinese women were with obesity or overweight (BMI ≥ 24 kg/m²), among whom 44.6 % were with central obesity (Wang et al. 2015). In our study, 39.3 % cases were with obesity and 34.5 % cases were with central obesity, which closely mirrored recent trends in the Chinese population.

At the same time, the incidence of breast cancer is rising rapidly in China in recent years. Breast cancer was the most commonly diagnosed cancer among Chinese women in 2015, accounting for 15 % of all new cancers in women (Chen et al. 2016). And breast cancer cases in China account for 12.2 % of all newly diagnosed breast cancers and 9.6 % of all deaths from breast cancer worldwide (Fan et al. 2014). Through a combination of multidisciplinary management, the incorporation of newer and more efficacious chemotherapeutic and biological therapies and implementation of aggressive supportive care services, the prognostic outcome of women with breast cancer has improved over the decades. Women with TNBC continue to have worse prognostic outcomes compared with those with non-TNBC (Dent et al. 2007). Researchers have focused on the mechanisms of TNBC progression and potential targets for therapy. Obesity is a modifiable lifestyle risk factor that has been shown to be associated with increased risk of developing breast cancer including TNBC (Phipps et al. 2011), and is known to predict for the development of distant metastases and breast cancer-related deaths (Ewertz et al. 2011). So it is of great importance to evaluate the impact of obesity on the clinical outcome of TNBC.

Our study showed that obese TNBC tended to be older and to have larger tumor mass, which was in accord with most literature (Ewertz et al. 2011; Deglise et al. 2010). Probably patients with obesity might have difficulty in touching a small lesion in relatively large breast, leading to a larger tumor mass when diagnosed. Deglise et al. (2010) pointed out that infiltrating tumor lesion less than 1 cm was more likely to be impalpable in patients with obesity. It was also reported that post-menopausal TNBC were more frequently observed in patients with obesity (Ewertz et al. 2011; Deglise et al. 2010), which was inconsistent with our study, probably due to not enough post-menopausal cases in our study. Meanwhile our study failed to find the association between obesity and histologic grade, pN stage and LVI of TNBC. The association between obesity and breast cancer characteristics above was also inconsistent among the results from various literatures (Loi et al. 2005; Eichholzer et al. 2013).

A substantial body of evidence exists linking obesity to prognostic outcome among women with breast cancer (Protani et al. 2010; Azrad and Demark-Wahnefried 2014; Chan et al. 2014). A systematic review that included 82 follow-up breast cancer studies showed that obesity was associated with poorer overall and breast cancer survival both in pre-menopausal and post-menopausal breast cancer (Chan et al. 2014).

But only limited research has evaluated the associations of obesity on TNBC prognosis, and the findings are mixed (Ademuyiwa et al. 2011; Sparano et al. 2012; Mowad et al. 2013; Tait et al. 2014; Dawood et al. 2012; Turkoz et al. 2013; Hao et al. 2015). Sparano et al. (2012) observed obesity not to be significantly associated with an inferior prognostic outcome among women with TNBC. The largest retrospective study including 2311 women with stage I-III TNBC tumors found no difference in DFS or OS across BMI groups at diagnosis (Dawood et al. 2012). Similar null association between BMI at diagnosis and TNBC survival was also observed in two retrospective studies of TNBC patients (Ademuyiwa et al. 2011; Tait et al. 2014). While Turkoz et al. (2013) confirmed the relationship between obesity and poorer prognostic outcome of TNBC. And a study on Chinese women also drew a conclusion that BMI ≥ 24 kg/m² was a negative prognostic factor of TNBC (Hao et al. 2015).

The difference in the study design, the characteristics of study population, duration of follow-up or cut-off value of BMI assessment may be partly contributed to the discrepancy. Most research defined obesity as BMI ≥ 30 kg/m² according to the World Health Organization guideline, which was based on the body size characteristics of western country population. This standard did not fit for Chinese population. As a growing body of evidence suggested a strong link between metabolic syndrome and breast cancer, BMI ≥ 25 kg/m² as obesity standard by international diabetics federation was adopted in our study. It could be observed that a large proportion of TNBC patients with central obesity in our study had some kinds of cardiovascular or metabolic disease.

Our study was the first to specifically evaluate the prognostic outcome effect of central obesity on TNBC. It was concluded that BMI ≥ 25 kg/m² was not an independent prognostic factor of TNBC although it was of statistical significance in univariate analysis. But central obesity was the independent prognostic factor of TNBC, and the effect was even more apparent in central obesity with BMI ≥ 25 kg/m². Probably WC may mistake some tall and strong women as obesity, although which was rarely observed in Chinese women. The implementation of BMI could distinguish TNBC with poorer prognosis even better.

A recent Spanish study pointed out that almost half of the obese population were metabolically healthy obese phenotype (Goday et al. 2016). But central obesity is a key factor in metabolic syndrome, which is linked to the development of diabetes and cardiovascular disease and is also closely related with the development of breast cancer, especially TNBC (Davis and Kaklamani 2012; Maiti et al. 2010). Systematic reviews indicated that central obesity added 79 % risk of breast cancer among premenopausal women and 50 % among postmenopausal women (Connolly et al. 2002; Harvie et al. 2003). And central obesity was associated with poorer outcome of breast cancer as well (Abrahamson et al. 2006).

Central obesity is characterized by the accumulation of visceral fat and WC is a correlate of the amounts of visceral fat. There were apparent differences between visceral fat and subcutaneous fat with regard to receptor distribution, factors secreted by adipose tissue and enzyme activity in adipose cell. Compared with subcutaneous fat, visceral fat have more blood supply and nerve distribution and are more likely to accumulate and decompose. Visceral fat is more metabolically active.

General obesity is linked to elevated levels of estrogen among post-menopausal women. The correlation between general obesity and poorer prognosis of breast cancer may be mediated by increased circulating estrogen levels from excess adiposity through aromatase activity and reduced levels of sex hormone-binding globulins (Rose and Vona-Davis 2009). Such mechanism is more common in postmenopausal obesity patients with positive hormone receptor. In contrast, the main mechanism of central obesity promoting TNBC progression is the disturbance of the ‘insulin-leptin-adiponectin’ axis. Central obesity is an independent predictor of insulin resistance (Seidell et al. 1990) and higher levels of free insulin-like growth factor-1 (IGF-1) (Lukanova et al. 2001) compared with general obesity. Increased level of insulin and IGF-1 in central obesity were mitogenic agents and promoted breast cancer cell proliferation directly (Azrad and Demark-Wahnefried 2014; Demark-Wahnefried et al. 2012). They could also accelerate tumor cell growth and migration by activating tumor neovascularization (Azrad and Demark-Wahnefried 2014). Leptin and adiponectin are both obesity related regulatory proteins secreted by adipose tissue. Leptin increases in obesity. It could enhance IGF-1 receptor activity and promote TNBC cell proliferation and migration. It could also promote survival of cancer stem cells in vivo, consequently promoting breast cancer (Zheng et al. 2013; Oh et al. 2011). Meanwhile, the level of adiponectin is low in obese patients. Adiponectin is the intrinsic insulin sensitizer and plays an antitumor effect opposite to leptin. Adiponectin could inhibit hormone receptor negative breast cancer cell proliferation and induce apoptosis through various signal transduction pathways (Jardé et al. 2011). Moreover, the abundant of inflammation cytokines secreted by activated macrophages in the adipose tissue, such as TNFα, IL-6, etc., constitutes tumor microenvironment, which promotes tumor cell migration and invasion (Howe et al. 2013).

It should be noted that our study has some limitations, including the retrospective nature of the study design, relatively small sample size, short follow-up duration, and lack of information on longitudinal change in BMI after breast cancer diagnosis which is known to be of prognostic value (Kroenke et al. 2005; Demark-Wahnefried et al. 2001).