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World Journal of Oncology

Original Article

Volume 14, Number 1, February 2023, pages 75-83

High Body Mass Index Was Associated With Human Epidermal Growth Factor Receptor 2-Positivity, Histological Grade and Disease Progression Differently by Age

Breast cancer is the most commonly occurring cancer in females worldwide [1-8]. According to GLOBOCAN reports, breast cancer is the leading cause of cancer deaths in women from 20 to 59 years of age [9]. Currently, the risk factors for breast cancer include smoking, delayed childbirth, shorter breastfeeding, alcohol consumption, and environmental and genetic factors [10, 11].

Overweight and obesity is a chronic metabolic disease caused by multiple factors such as heredity and environment [12, 13]. In addition, studies have shown that overweight and obesity are related to the occurrence and development of many diseases, such as diabetes, fatty liver, cardiovascular disease, and various cancers [14-17]. Obesity is one of the significant factors for poor prognosis in breast cancer patients. Overweight may be conducive to a higher tumor stage and tumor grade accompanied by distant recurrence, and metastases of luminal molecular subtypes in breast cancer patients. Now-a-days, several reports describe the relationship between obesity and breast cancer incidence [18].

According to the National Institutes of Health (NIH) and World Health Organization (WHO), the body mass index (BMI) is a statistical validity index to evaluate body fat in men and women of any age [19, 20]. However, obesity has no significant influence on the specific overall survival in breast cancer conditions mainly among patients with human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancers (TNBCs). But obesity could influence the overall survival of hormone-specific breast cancer partly by harnessing poor prognosis [21]. A plethora of reports delineated that BMI status can contribute to clinical outcomes in breast cancer patients. In a recent randomized clinical trial of 5,683 patient cohorts, the patients with BMI > 35 were typically associated with a higher risk of recurrence than the patients with BMI < 25 [1-8]. Yet significant research is required to explore the relationship between obesity and clinical outcomes in breast cancer. The effect of BMI during obesity on clinical outcomes in breast cancer patients with recurrence rate was reported through retrospective analysis of SUCCESS trial [22]. Women with obesity exhibited a significant rise in acquiring stage III/IV disease and grade 3/4 tumors in breast cancer conditions [21]. However, the relationship between obesity and breast cancer incidence is still unclear. This study aims to ascertain “the impact of high BMI” reported at different ages on the incidence of breast cancer by deciphering the BMI information of breast cancer patients obtained from the Gene Expression Omnibus (GEO) database. This article provides a prognostic strategy to decipher the impact of “high BMI at different ages” pertinent to the incidence of breast cancer. In addition, the difference between breast cancer patients with different BMI at different ages was delineated.

We entered the keyword search, “BMI and cancer” in the NCBI-GEO database [23] and obtained 7,449 search records; among them, 48 GSE datasets contained information pertinent to patient’s BMI and cancers such as breast cancer, prostate cancer, esophagus cancer, and ovarian cancer. Due to the large abundance of breast cancer data, the GSE datasets containing other tumor information were deleted, and GSE datasets with a sample size of less than 100 were also deleted. GSEs that contain clinical information pertinent to breast cancer patients include GSE24185, GSE54470, GSE70905, GSE70947, GSE78958, GSE93601, GSE115577, whereas the information pertinent to the normal breast tissues includes GSE101961, GSE102088, GSE15289, GSE43973, GSE88781, GSE88782, GSE88783, and GSE88785. R statistical computing software was used to download their clinical information in the GSE dataset. Grouping was performed according to the BMI classification guidelines given by WHO: BMI < 18.5 are considered underweight, whereas BMI of 18.5 - 24.9 are normal, 25.0 - 29.0 is overweight, and ≥ 30.0 are obese, respectively. The overall proportion of obese people is minimal; therefore, we combined the overweight and obese people together and collectively considered to envisage the influence of high BMI on the incidence of breast cancer. Fewer individuals were underweight among the participants. Hence, the data of these people were not considered for further analysis. Due to the incomplete information of a few samples in GSE, we need to exclude the “not available (NA)” data in the statistics.

Statistical analysis was performed using the SPSS statistical package (version IBM SPSS Statistics 21), GraphPad Prism 8.0.1 with P < 0.05 and P < 0.001 indicating statistical significance. R × C Chi-square was performed for ascertaining the trends while binary logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence intervals (CIs).

An ethics statement was not required for this study type, and no human or animal subjects or materials were used. This study does not involve any human participant and does not require informed content. The whole study includes datasets acquired from the GEO, a public database, and was executed with complete institutional approval from The First Affiliated Hospital of Zhengzhou University.

GSE samples containing BMI information (4,132) were divided into two groups: 2,507 patients with breast cancer and 1,625 patients in the control group to determine the frequency of breast cancer and its correlation with BMI (Table 1). Among the 4,132 samples with BMI information, Chi-square test reported that the incidence of breast cancer is different among different age groups (P < 0.001) (Table 2). The baseline characteristics of all the patients in this study were given in the Table. 1.

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Table 1. Baseline Characteristics of Patient Demographics by BMI

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Table 2. Chi-Square Test Results Between Breast Cancer Patient Demographics by BMI and Age and Individuals Without Breast Cancer

A significant association was observed between HER2 positivity and BMI status among the age group of breast cancer patients less than 55 years (P < 0.001) (Table 3). Among the age group of breast cancer patients older than 55 years, Chi-square results described the significant difference in the tumor grade between different BMI groups (P < 0.001) (Table 3).

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Table 3. Chi-Square Test for BMI Classification in the Patients With Breast Tumors at Different Ages

The patient’s age group less than 55 years with high BMI are more likely to be HER2 positive (OR = 4.795, 95% CI = 2.517 - 9.136, P < 0.001) when compared to the breast cancer patients with normal weight (Fig. 1a). Furthermore, breast cancer patients older than 55 years were accompanied by high BMI, and they are more likely to have a tumor grade greater than 2 (OR = 0.288, 95% CI = 0.152 - 0.544, P < 0.001) (Fig. 1b) when compared to the breast cancer patients with normal weight (Table 4).

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Figure 1. High body mass index (BMI) was associated with HER2 positivity in younger, but not in older patients, and was associated with lower histological grade in older, but not in younger patients. (a) The patient’s age group less than 55 years with high BMI are more likely to be HER2 positive (odds ratio (OR) = 4.795, 95% confidence interval (CI) = 2.517 - 9.136, P < 0.001) when compared to the breast cancer patients with normal weight. (b) Breast cancer patients older than 55 years were accompanied by high BMI, and they are more likely to have a tumor grade greater than 2 (OR = 0.288, 95% CI = 0.152 - 0.544, P < 0.001).

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Table 4. The Logistics Regression Analysis of BMI Classification of Tumor Patients at Different Ages

In this study, both recurrence and distant recurrence were considered as “disease progression”. High BMI was associated with worse progression-free survival (PFS) in younger, but not in older patients. Figure 2a depicts that the breast cancer patients with high BMI are more likely to have “recurrence and distant recurrence” in a relatively short period (P = 0.0023), when compared to normal BMI patients mainly among breast cancer patients (< 55 years). However, this difference was not observed in breast cancer patients of age group older than 55 years (P = 0.4597) (Fig. 2b). Additional information related to results between breast cancer patients of different ages and people without breast cancer can be found here (Supplementary Material 1, www.wjon.org), as well the BMI classification of breast cancer patients at different ages (Supplementary Material 2, www.wjon.org). Furthermore, PFS periods of different ages by BMI categories are provided (Supplementary Material 3, www.wjon.org). Results between breast cancer patients of different ages and people without breast cancer are given here (Supplementary Material 4, www.wjon.org), whereas the results pertinent to BMI classification of breast cancer patients at different ages are provided (Supplementary Material 5, www.wjon.org). We also provided PFS periods of different ages by BMI categories (Supplementary Material 6, www.wjon.org).

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Figure 2. (a, b) High body mass index (BMI) was associated with worse progression-free survival (PFS) in younger, but not in older patients. Breast cancer patients with high BMI are more likely to have “recurrence and distant recurrence” in a relatively short span of time (P = 0.0023) when compared to the normal BMI patients mainly among the breast cancer patients younger than 55 years (a); however, this difference was not observed in breast cancer patients older than 55 years (P = 0.4597) (b).

BMI and breast cancer survival relationship can be deciphered depending on the obesity and prognosis-related tumor characteristics. Biological pathways significantly involved in the adiposity include the local and systemic release of “inflammatory markers, insulin growth factors, steroid receptors, adipokines”, which can affect several signaling cascades [8, 24] in breast cancer cells by modulating the JAK/STAT3 signaling, insulin/insulin-like growth factor (IGF) signaling, and estrogen signaling. Subsequently, these alterations can promote metabolic reprogramming, cancer cell proliferation, angiogenesis, and metastasis directly or indirectly in the tumor microenvironment [23, 25-30]. Normally, women with obesity and breast cancer exhibit typically a higher cancer cell proliferation rate [28, 31]. Altered BMI could promote adverse tumor characteristics and suggest the possibility of delayed initial cancer detection as an alternate cause for the poor prognosis in obese women with breast cancer [28, 32, 33]. Failure in the initial detection could lead to the delayed identification of metastasis, and recurrence, and affect overall survival of obese women with breast cancer. The current study is based on the GEO database to analyze the relationship between BMI and breast cancer at different ages. Our study reported that the difference in the BMI status between breast cancer patients and non-breast cancer individuals is not statistically significant. In addition, the logistic regression analysis reported that women with less than 55 years of age are accompanied by a higher risk of getting breast cancer than women older than 55 years. High BMI was associated with HER2 positivity in younger, but not in older patients, and was associated with lower histological grade in older, but not in younger patients. Besides, the breast cancer patients with relatively higher BMI exhibited an increased risk of pathological grade greater than 2 when compared to the patients with normal BMI (> 55 years old). Our results showed that the patients with high BMI are more likely to possess recurrence or distant metastasis in a relatively short period of time.

Overweight and obesity can be referred to as significant predictors for higher risk of 5-year breast cancer relapse and mortality [13, 33]. Another study by Jiralerspong et al (2013) [34] described the hazard ratios for the risk of recurrence and mortality in breast cancer patients with obesity (relative to the normal weight) as 1.18 (95% CI: 1.02 - 1.36) and 1.23 (95% CI: 1.00 - 1.52), respectively. According to this report, the overweight did not influence the recurrence and suggested that obesity was not a predictor for mortality in breast cancer patients [34]. In African TNBC patients, the mortality and recurrence of breast cancer patients were related to the overweight [34]. The risk of acquiring distant metastasis has a significant correlation with obesity in Danish breast cancer patients and suggested that both overweight, and obesity in women mitigated the overall survival in breast cancer patients when compared to the patients with normal weight [34]. This may be related to differences in steroid receptor expression, and lncRNAs at the molecular level in young breast cancer patients, which requires extensive molecular studies [35]. However, some studies stated that aging is a risk factor for breast cancer [36-38]. Therefore, the relationship between age and breast cancer incidence may be more complicated and require substantial studies to elucidate the underlying mechanisms.

BMI status in premenopausal women is negatively correlated with the risk of acquiring breast cancer [16, 39-42]. This may be related to the higher incidence of irregular menstruation and anovulatory cycles in women with high BMI [43]. In addition, studies have shown that women with high BMI are associated with low amounts of estradiol and progesterone than the women with normal BMI [44, 45]. Another study by Widschwendter et al concluded that chronic obesity with BMI greater than 40 is reported with worse clinical outcomes in high-risk early TNBCs [22]. Furthermore, it has been suggested that obese and postmenopausal women could have an increased risk of breast cancer [16, 40, 46-48]. The risk of acquiring stage III/IV and grade 3/4 tumors is substantially higher in obese women; luminal A and luminal B molecular subtypes in obese patients are likely associated with low overall survival than the patients with normal weight [21]. Pajares et al observed poorer clinical outcomes in breast cancer patients with BMI greater than 35 when compared to the patients with BMI less than 25 and subsequently concluded the “effect of BMI” was attributed to being same breast cancer subtypes such as estrogen receptor (ER)/ progesterone receptor (PR) (+), HER (-)/HER (+), TNBCs [49]. In addition, the higher mortality rate in obese women with breast cancer is prominently due to the ER+/luminal molecular subtypes [22, 34, 50-57]. However, our results reported that the association between obesity and postmenopausal breast cancer is not obvious, which may be due to our limited statistical data.

The three adjuvant clinical trials pertinent to “Eastern Cooperative Oncology Group” were executed for anthracycline-based chemotherapy; and the results of this study reported poor clinical outcomes in breast cancer patients with BMI > 30 when compared to nonobese patients with hormone receptor (HR)-positive disease [22]. A previous study by Blair et al concluded that BMI status exhibited significant relation with all-cause mortality in breast cancer patients [21]. Another study [57] deciphered the effect of BMI on disease-free survival and overall survival of breast cancer patients who received neoadjuvant chemotherapy [57]; and according to this study, the patients with BMI of 30 - 40 and > 40 exhibited relatively minimal disease-free survival and overall survival when compared to the patients with normal weight [57]. In another study, it is evident that the BMI has no significant effect on the overall survival in luminal subtype (ER/PR (+), and HER (-)), and TNBCs but has a profound effect in HER (+) tumors [22]. Our finding showed that patients with high BMI are more likely to be HER2 positive, among the age group of breast cancer patients less than 55 years. High BMI was associated with worse PFS in younger, but not in older patients. However, substantial studies are required to understand the risk factors associated with HER2 subtypes. Furthermore, we concluded that high BMI in breast cancer patients exhibited a pathological grade greater than 2 among patients older than 55 years of age. Therefore, the tumor progression in breast cancer patients with high BMI is relatively faster than those patients with normal BMI. Certain studies already proved that obesity can lead to distant recurrence of breast cancer [58].

The quality of the original data cannot be completely controlled, because of the samples from different GSE databases, which inevitably produces deviations. These clinically significant findings support the need for clinical trials to evaluate the effects of obesity prevention and treatment on breast cancer risk. There is no available information in the GEO database pertinent to the breast cancer subtype or treatment data to demonstrate substantial prognostic information. We gathered the information for the generalizable prognostic information based on potentially more determinative variables such as age, and BMI that would benefit effective clinical management.

Suppl 1. Chi-square test results between breast cancer patients of different ages and people without breast cancer.

Suppl 2. Chi-square test of BMI classification of breast cancer patients at different ages.

Suppl 3. PFS period of different ages by BMI categories.

Suppl 4. Chi-square test results between breast cancer patients of different ages and people without breast cancer.

Suppl 5. Chi-square test of BMI classification of breast cancer patients at different ages.

Suppl 6. The PFS period of different ages by BMI categories.

Acknowledgments

The authors convey sincere thanks to the administrative and technical staff of the Department of Radiation Oncology and Endocrinology Department of The First Affiliated Hospital of Zhengzhou University. Our sincere thanks to Professor Ruitai Fan, MD, Ph.D., director & chairman of Cancer Center, The First Affiliated Hospital of Zhengzhou University for his support during this work.

Financial Disclosure

This study was supported by National Natural Science Foundation of China (No. 81700729), and Henan Province Medical Science and Technology Research Project (No. LHGJ20190249).

Conflict of Interest

The authors declare no conflict of interest.

Informed Consent

This study does not involve any human participants and does not require informed content. The whole study included datasets acquired from the GEO, a public database and was executed with complete institutional approval from the First Affiliated Hospital of Zhengzhou University.

Author Contributions

Di Zhao (DZ), Narasimha M. Beeraka (NMB), Xiaoyan Wang (XW), Runze Zhou (RZ), Haohao Zhang (HZ), Yanxia Liu (YL), Yinghui Zhang (YGZ), Ying Zhang (YZ), Junqi Liu (JL), and Guijun Qin (GQ) conceptualized and designed the study. NMB, DZ, XW, RZ, HZ, YL, YZ, JL, and GQ performed the literature analysis, and wrote the original manuscript draft. NMB, JL, GQ revised, edited, and extended the final draft. All authors have reviewed and approved the manuscript before submission.

Data Availability

This study was executed by acquiring the data from GEO, a public database. Readers can access the datasets as we described in the Methods section under data collection subheading.

Abbreviations

BMI: body mass index; GEO: Gene Expression Omnibus; CI: confidence interval; WHO: World Health Organization; OR: odds ratio; ER: estrogen receptor; HER2: human epidermal growth factor receptor 2

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