Body mass index increases the lymph node metastasis risk of breast cancer: a dose-response meta-analysis with 52904 subjects from 20 cohort studies

Breast cancer is one of the most common malignant tumors among females worldwide. According to the International Agency for Research on Cancer’s GLOBOCAN 2018 [1], breast cancer was the second most common cancer only after lung cancer and the most frequent cancer among women with an estimated 2.09 million new cases diagnosed worldwide, making up 11.6% of all new cancer cases. Relative to cases, breast cancer ranked as the fourth cause of death from cancer overall (627 thousands), accounting for 6.6% of all cancer deaths. In China, it was estimated that there were 67,328 new breast cancer cases (16.3% of all cancer cases) and 16,178 deaths (7.8% of all deaths) occurred in 2015 [2]. In addition, over the past decades, the prevalence of breast cancer is rising and getting younger gradually [3‐5], which has caused serious economic burden and become an important global public health issue.

Although the rise in obesity and overweight showed some signs of leveling off, data from several countries indicated that obesity has become a worldwide epidemic [6]. Based on linear time trend analysis, a 33% increase in obesity (body mass index, BMI ≥ 30 kg/m²) prevalence was estimated, and obesity rates will be exceed 50% by 2030 [7]. It was regarded as a modifiable lifestyle risk factor for several chronic diseases in a growing body of literature, such as coronary heart disease [8], hypertension [9], type 2 diabetes mellitus [10], hyperlipidemia [11], stroke [12] and some cancers [13, 14]. Among them, several studies have found that overweight or obese women have an increased risk of breast cancer as compared to normal weight women, especially in postmenopausal women. A case-control study [15] conducted in Iran reported that obese postmenopausal women had a threefold increased risk of breast cancer (odds ratio, OR = 3.21, 95% CI: 1.15–8.47). In a pooled analysis [16] of eight representative large-scale cohort studies, the increased risk of breast cancer with higher BMIs was confirmed among Japanese postmenopausal women. Yanzi Chen’s [17] dose-response meta-analysis was performed on BMI and breast cancer incidence, which showed that the breast cancer risk increased by 3.4% for every 1 kg/m² increment of BMI in postmenopausal women. Furthermore, women who are obese with breast cancer diagnosis were reported to have greater disease mortality, higher recurrence rate and adverse overall and disease-free survival [18, 19]. So obesity also plays an important role in the prognosis of breast cancer.

Despite accumulated evidence that obesity may increase breast cancer risk, question remain, whether obesity is associated with lymph node metastasis, the most common form of metastasis in breast cancer? However, there was limited study focused on the relationship between obesity and lymph node metastasis in breast cancer, and the conclusions were inconsistent. For example, in a retrospective review of 1352 breast cancer patients [20], obese patients were more likely to have lymph node metastases compared with non-obese patients (P = 0.026). In another study [21] supporting this viewpoint, obesity was associated with increased number of involved axillary nodes (P = 0.003). On the contrary, Yadong Cui’s [22] case series study found that there was no statistically significant association between BMI and axillary node involvement (adjusted OR = 1.28, 95% CI: 0.90–1.81). Therefore, the present dose-response meta-analysis was conducted to investigate the association between obesity, as measured by BMI, and lymph node metastasis in breast cancer, and sub-analyses by different areas, menopausal status, study period were done to explore potential factors that influence the associations deeply.

Dose-response meta-analysis results showed that there was a linear dose-response relationship between BMI and lymph node metastasis in breast cancer. For every 1 kg/m² increment of BMI, the risk of lymph node metastasis increased by 0.89%. After grouping by areas, no significant geographical variation was detected, and the risk of lymph node metastasis increased by 0.99, 0.85, and 0.61% for every 1 kg/m² increment of BMI in Asian, European, and American women, respectively. Higher proportions of overweight and obese black or African-American breast cancer patients in the United States were mentioned in Ronny’s study [45] and some other researches [49], which also tended to have poorer outcomes than white patients. An observation study of 223,895 women diagnosed with invasive breast cancer classified all patients into 8 race/ethnic groups including non-Hispanic white, Hispanic white, black, Chinese, Japanese, south Asian, other Asian, and other ethnicity [50]. Black women were significantly more likely to present with lymph node metastases than non-Hispanic white women (24.1% vs 18.4, P < 0.001), and lower probability was observed in Japanese women (14.6% vs 18.4%, P < 0.001). Whether this race/ethnicity disparity existed when BMI were assessed remained unknown, although confounding factors, such as socioeconomic status and treatment imbalance, contributed in part. Also, in Chinese Han women, a possible interaction between Interleukin-18-137G/C, −607G/T polymorphisms and BMI in breast cancer patients was identified [51]. Overweight and obese (BMI ≥ 24 kg/m²) patients with G/T genotype had a 5.45-fold (95%CI, 1.74–17.06) increased risk of lymph node metastasis relative to those with T/T homozygotes. Subgroup analyses grouped by race/ethnicity or genotype would be more accurate to explore the linkage between obesity and lymph node metastasis in breast cancer, unfortunately, which was not available in the selected studies.

Besides, the lymph node metastasis risk of breast cancer with BMI in premenopausal women (1.44%/1 kg/m²) was similar to that in postmenopausal women (1.45%/1 kg/m²). In postmenopausal patients, obese women would have a high concentration of circulating estrogen, since most estrogen is produced in the adipose tissue [52]. Moreover, in the peripheral adipose tissue, obese women have a high activity of aromatase enzyme, which converts androstenedione to estrogen and testosterone to estradiol in turn stimulated by both interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) [53]. Elevated levels of estradiol are important to the development and growth of breast cancer, including lymph node metastasis, which are consistent with our results that shown increasing lymph node metastasis risk with BMI in postmenopausal women. Conversely, among premenopausal patients, systemic levels of estrogens are mainly produced by the ovaries, so not influenced by peripheral aromatization. It seems that obesity is not a independent factor in carcinogenesis and tumor metastasis in young breast cancer patients. Nevertheless, BMI was associated with a increased incidence for triple-negative subtype, but no association was shown in postmenopausal patients [54]. Similar findings also indicated that the association between obesity and TNBC was significant only among premenopausal women [55]. In addition to TNBC patients tended to present higher disease grade, more aggressive course, and high rate of recurrences [56], which may partly explained our results of similar lymph node metastasis risk in premenopausal and postmenopausal women. Due to small sample size in TNBC, subgroup analysis were not be conducted, as well as the interaction between triple-negative subtype and menopausal status. On the other hand, estrogen receptor (ER) positive in obese women also associated with menopausal status, although remained a matter of controversy in different studies [57, 58]. Only one included study [40] demonstrated results with ER positive and ER negative separately, and subgroup analysis was also failed.

When subgroup analysis was done for study period, it should be noted that a prominent increased risk (2.22%/1 kg/m²) of lymph node metastasis with BMI occurred in less than 5 years compared with more than 5 years (0.61%/1 kg/m²). A possible explanation is the apparent older participants (Table 1) in three included studies [34, 37, 44] followed less than 5 years, which constitutes approximately 80% of the subgroup patients. Another explanation is the substantial proportions (57–75%) of overweight and obese patients distributed in this subgroup, especially in large sample size study (75%) [37], which mainly resulted in higher lymph node metastasis risk in breast cancer patients.

Generally, lymph nodes involvement has been shown to predict for increased local and distant recurrence, as well as higher breast cancer mortality [59]. On basis of the Surveillance, Epidemiology, and End Results registry data, Brent’s [60] study found a significant association between large lymph node metastasis size and lower breast cancer-specific survival and overall survival even after controlling for other known prognosis factors including number of involved lymph nodes. Moreover, overweight and obesity are not only linked to breast cancer incidence, but women that are obese also have worse outcomes in terms of recurrence and survival. A clinical trial conducted in German [61] showed that obesity constituted an independent, adverse factor in patients with node-positive primary breast cancer. Women who were obese at the time of diagnosis had a shorter disease-free survival and overall survival as compared to women who were non-obese. Thus, BMI, as a modified risk factor, not only plays a crucial role in the occurrence of breast cancer, but also has adverse impact on the outcome and survival of patients. Similarly, we found that BMI had a great influence on the metastasis of various malignant tumors. For example, Zhihong Gong’s case-control study [62], following 752 middle-aged prostate cancer patients, concluded that obesity at the time of diagnosis was associated with an increased risk of developing prostate cancer metastasis, regardless of stage or primary treatment. Changhua Wu’s retrospective cohort study [63], enrolling 796 primary papillary thyroid cancer patients, indicated that the increment of BMI in patients was associated with the lymph node metastases, and other clinic-pathological features, such as tumor size, extrathyroidal invasion and so on.

It could be considered that the harm of tumor metastasis to patients should not be underestimated, but the reason was still unclear. Several hypothetical mechanisms could explain the association between obesity and lymph node metastasis in breast cancer. One is that the breast size of obese patients is larger, the adipose tissue is thicker, and the palpation of the primary tumor or enlarged axillary lymph nodes is more difficult. Therefore, the accuracy and sensitivity of ultrasonography, molybdenum target and other examinations will be reduced, leading to the delayed or even missed diagnosis of patients, so tumors often in advanced stage or have metastasized at the time of diagnosis [64]. Estrogen, most produced in adipose tissue, have a high level in obese or overweight women, via the aromatization of androstenedione to estrone and then converts to estradiol. This process would in turn facilitate tumor growth. In addition, leptin levels are also higher in obese individuals than those of normal weight, which related to tumor cell proliferation [65]. Some other adipocytokines, such as IL-6 and TNF-α released by activated macrophage, results in inflammation, which could be partly responsible for breast cancer development [66]. Other potential mechanisms for obesity-associated pathologic differences include higher insulin levels and insulin-like growth factors among obese women, which may increase estrogen levels and lead to higher proliferative rates [67]. Notably, in obese breast cancer patients, if the actual body surface area exceeds 2 m², dose reductions during adjuvant chemotherapy are frequently applied [68]. Up to 40% of patients may receive limited chemotherapy doses that are not based on actual body weight to avoid possible side effects and toxicity [69]. Meanwhile, aromatase inhibitors, representing an effective endocrine treatment for hormone receptor positive breast cancer patients, were suspected to be less effective in suppression of estrogen levels enough to prevent recurrence in obese women regardless of menopausal status [70, 71]. Finally, obesity patients often have some unhealthy lifestyle habits, such as excess saturated fat intake and lack of physical activity, resulting in the accumulation of body acid cholesterol, trans fatty acid and other harmful lipid, which are recognized as risk factors for adverse prognosis of breast cancer.

Several limitations existed in our study. Firstly, BMI was calculated by measuring height and weight at the time of diagnosis, which was objective and avoided information bias to some extent. But long-term weight and body composition changes were not take into account, as well as some other potential modifiers (eg. waist circumference and waist-to-hip ratio) for the relationship of BMI and lymph node metastasis in breast cancer. Secondly, some included articles didn’t group BMI according to WHO standards, so the accuracy of the results would be affected in the highest versus lowest BMI meta-analysis. Thirdly, we didn’t have access to other key individual-level information except area, menopausal status, and study period, such as race, breast cancer sub-types, ER status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, and obesity associated risk factors (eg. dietary habits and physical inactivity), to examine the roles of these factors in lymph node metastasis. Finally, the retrospective nature of this meta-analysis could not be ignored, so the results should be interpreted with cautions.

In conclusion, BMI significantly increases the lymph node metastasis risk of breast cancer. Overweight and obese breast cancer patients might benefit from adhering to a healthy lifestyle aiming at losing or controlling weight, as part of the comprehensive oncologic therapy. Further original studies are warranted to identify the link of BMI and lymph node metastasis in breast cancer.