The Interrelationship between Obesity and Race in Breast Cancer Prognosis: A Prospective Cohort Study

Purpose Obesity is associated with an increased breast cancer risk in postmenopausal women and may contribute to worse outcomes. Black women experience higher obesity and breast cancer mortality rates than non-Black women. We examined associations between race, obesity, and clinical tumor stage with breast cancer prognosis. Methods We conducted a prospective cohort study in 1,110 breast cancer patients, using univariable and multivariable Cox regression analyses to evaluate the effects of obesity, race/ethnicity, and clinical tumor stage on progression-free and overall survival (PFS and OS). Results 22% of participants were Black, 64% were Hispanic White, and 14% were non-Hispanic White or another race. 39% of participants were obese (body mass index [BMI] ≥ 30 kg/m2). In univariable analyses, tumor stage III-IV was associated with worse PFS and OS compared to tumor stage 0-II (hazard ratio [HR] = 4.68, 95% confidence interval [CI] = 3.52–6.22 for PFS and HR = 5.92, 95% CI = 4.00-8.77 for OS). Multivariable analysis revealed an association between Black race and worse PFS in obese (HR = 2.19, 95% CI = 1.06–4.51) and non-obese (HR = 2.11, 95% CI = 1.05–4.21) women with tumors staged 0-II. Obesity alone was not associated with worse PFS or OS. Conclusion Results suggest a complex interrelationship between obesity and race in breast cancer prognosis. The association between Black race and worse PFS in tumor stages 0-II underscores the importance of early intervention in this group. Future studies are warranted to evaluate whether alternative measures of body composition and biomarkers are better prognostic indicators than BMI among Black breast cancer survivors.


INTRODUCTION
The increasing prevalence of obesity in the United States presents a public health challenge. About 42.4% of American adults are obese and non-Hispanic Black adults are disproportionately affected. [1] Obesity is a risk factor associated with multiple health consequences, including diabetes, hypertension, dyslipidemia, stroke, and all-cause mortality. [2] Importantly, accumulating evidence suggests that obesity is linked to breast cancer incidence, recurrence, and worse clinical outcomes. [3][4][5][6] Women who are obese are more likely to present at a later stage of the disease, with larger tumors and more positive lymph nodes at the time of diagnosis. [4,7,8] Additionally, obesity is associated with more treatment complications and reduced e cacy of chemotherapy and hormone therapy, contributing to higher rates of locoregional recurrence compared to non-obese women. [5] Obesity is linked to an increased risk of developing a second primary cancer, particularly of the contralateral breast, endometrium, and colon, [3,4,9] and a greater risk of distant metastases at ten-year follow-up. [7] Finally, obesity is associated with worse overall and disease-free survival. [3,5,8,10,11] Multiple mechanisms underly the association between obesity and breast cancer outcomes. Increased aromatase activity in adipose tissue raises circulating estrogen levels. Estrogen has a proliferative effect on breast tissue, contributing to incidence and recurrence. [5] Second, adipose tissue is highly metabolically active. [3,5] Production of proin ammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin six (IL-6) in adipose may contribute to breast cancer pathogenesis. [5] The adipokine leptin, which regulates appetite and energy balance and increases in proportion to body mass index (BMI) is also thought to be implicated in cancer progression and metastasis. [3,12] High levels of leptin have been shown to promote tumor cell migration and invasion, induce epithelial-to-mesenchymal transition, stimulate angiogenesis, and promote breast cancer stem cell survival. [3] The prevalence of obesity varies by race and breast cancer prognosis. [13] Although the risk of developing breast cancer is similar in Black and White women, Black women are more likely to die from breast cancer. [13] Racial disparities in prognosis are thought to be driven by multiple biological and non-biological factors. [13] Low socioeconomic status and other social factors experienced by Black women may limit access to healthcare and cause delays in screening, detection, and treatment. [13][14][15] The higher prevalence of comorbid conditions, including obesity, diabetes, hypertension, and cardiovascular and respiratory disease, among Black women is also hypothesized to contribute to worse clinical outcomes. [5,13,14] In addition, the incidence of triple-negative breast cancer (TNBC), an aggressive and treatment-resistant subtype, is also higher among Black women. [14] Biological factors underlying racial differences in outcomes include differences in the tumor microenvironment, gene expression, tumor suppressors, and genetic susceptibility loci. [13,16] Multiple studies have identi ed differences in the expression of cancer-associated genes in Black women compared to White women. [17][18][19] Because gene expression can be altered by environmental and/or lifestyle factors, epigenetic in uences may mediate the link between non-biological factors such as race or obesity, and the biological factors associated with worse breast cancer prognosis.
There is accumulating evidence suggesting that the relationship between obesity, race, and clinical tumor stage in breast cancer prognosis is complex.[16, 20-26] The current study aims to build upon our previous work by evaluating the characteristics associated with progression-free and overall survival in the same racially and ethnically diverse cohort of breast cancer patients. [22] We assess the interrelationship among BMI, race, and clinical tumor stage in breast cancer prognosis to improve patient counseling and guide the development of targeted interventions for high-risk groups.

Study population
We evaluated 1,115 post-surgical breast cancer patients scheduled to receive adjuvant radiation therapy (RT) at the Sylvester Comprehensive Cancer Center (SCCC) and Jackson Memorial Hospital (JMH) in Miami, Florida, between 2008 and 2014. Participants were recruited for a case-control study and/or a study assessing RT-induced skin toxicity to the intact breast. Each patient completed a self-administered questionnaire with (1) demographic information, (2) self-reported race and ethnicity, (3) self-reported height and weight, and (4) assessment of breast cancer risk factors (including family history, presence of comorbidities, and smoking status). Clinical and pathological tumor characteristics were obtained from pathology reports and medical records. Informed consent was obtained from all participants at the time of enrollment. This study was approved by the Institutional Review Board at the University of Miami and Jackson Memorial Hospital.
Inclusion criteria included female patients aged 18 or older who were diagnosed with breast carcinoma stages 0-IV (American Joint Committee on Cancer), were scheduled to receive treatments at SCCC or JMH between 2008 and 2014 and were able and willing to provide informed consent. Exclusion criteria included patients who were aged less than 18, received prior radiation to the currently treated breast or chest wall, were undergoing concurrent chemotherapy, or were unable to provide written consent. We had a nal sample size of 1,110 following the exclusion of participants who were lost to follow-up or had missing information.

Assessment of patient and clinical variables
We evaluated race (non-Black or Black), obesity status (obese or non-obese), age at diagnosis (< 60 years or ≥ 60 years), and smoking status (never, former, or current) as patient covariates. Former smoking was de ned as having smoked 100 or more lifetime cigarettes and current smoking was de ned as active smoking. Clinical variables, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and triple-negative (TN) status, as well as clinical tumor stage (0-II or III-IV), were determined using medical records. The clinical tumor stage was based on the American Joint Committee on Cancer staging scheme. [27] Body mass index (BMI) was calculated using the National Institute of Health (NIH) conversion formula using self-reported height and weight at the time of enrollment. In the current study, BMI < 30 was considered non-obese and BMI ≥ 30 was considered obese.
Assessment of progression-free survival and overall survival Participants were followed for up to 13 years through a review of the medical records, with the evaluation completed as of July 31, 2021. Progression-free survival (PFS) was de ned as the time elapsed from diagnosis to the earliest date of disease progression (second primary, recurrence, metastasis, or death). Overall survival (OS) was de ned as the time elapsed from diagnosis to death. Event-free patients were censored at the date of the last follow-up.

Statistical Analysis
Descriptive statistics (Number, percent) are presented for patient and clinical characteristics strati ed by obesity status. The bivariate association of obesity status and patient and clinical characteristics was assessed by a Chi-square test for categorical variables. PFS was de ned as the time from diagnosis to recurrence, metastasis, secondary breast cancer, death, or last follow-up, whichever occurred rst. OS was de ned as the time from diagnosis to death or last follow-up. Event-free patients were censored at the date of the last follow-up. Selected covariates associated with obesity or with PFS or OS were included in the multivariable Cox regression model based on univariable analysis and literature review. PFS and OS were estimated by the Kaplan-Meier method and the associations with race and obesity were assessed by a logrank test. Univariable Cox proportional hazard analysis was used for potential covariables on time-to-event outcomes of PFS and OS. Multivariable Cox proportional hazard analysis was used to assess the association between pretreatment obesity and race category with PFS and OS adjusted for selected covariables. Results were reported as hazard ratios (HR) with 95% con dence intervals (95% CI). Statistical signi cance was set at a threshold of P < 0.05. The heterogeneity of obesity effect by race and by tumor stage was assessed in multivariable analyses strati ed by clinical tumor stage (0-II and III-IV). Data analysis was conducted using SAS (version 9.4, Cary, NC).

Patient and clinical characteristics
The study population included 1,110 breast cancer patients, 918 (82.7%) of whom were progression-free by the last follow-up and 192 (17.3%) of whom experienced disease progression (including 105 deaths, seven second-primary cancers, 48 breast cancer recurrences, and 123 metastases). 75 women (6.8%) experienced two or more outcomes. The mean age at diagnosis was 54.7 years (range: 24.5-85.0). 30.5% of participants were ≥ 60 years old at diagnosis and 69.5% were < 60 years old. Most of our sample self-identi ed as Hispanic White (64.1%), 21.7% of participants identi ed as Black, and 14.1% identi ed as Non-Hispanic White or another race/ethnicity. Non-Hispanic White and Other categories were combined due to their similar progression-free and overall survival. 76.4% of participants had stage 0-II disease upon enrollment and 23.6% of participants had stage III-IV disease.

DISCUSSION
This study uses a large racially and ethnically diverse population to evaluate patient and clinical characteristics associated with worse PFS and OS in early (clinical tumor stages 0-II) and advanced (clinical tumor stages III-IV) breast cancer. Race and obesity status were combined in multivariable models to evaluate their joint effects. In the early breast cancer group, obese and non-obese Black women had signi cantly higher hazards of progression compared to non-Black, obese women. Our results emphasize the importance of race as a prognostic indicator in breast cancer that, when combined with obesity status, may contribute to worse outcomes. We know from prior studies that Black women are more likely to have worse breast cancer prognosis despite a similar risk of developing breast cancer compared to their White counterparts. [13] Reasons for this disparity include racial differences in the tumor microenvironment, gene expression, socioeconomic status, and access to healthcare.
We found a signi cant association between combined race and obesity with worse PFS in early, but not advanced breast cancer (Table 4A and 4B). Differences in gene expression by race and obesity status may underlie disparities in outcomes; such differences may also vary by tumor stage and subtype. For example, Do et al. observed differential hypomethylation of obesity-associated genes in Black women, which was associated with greater all-cause mortality compared to White women. [20] Xing et al. identi ed increased expression of SOS1, a gene that is activated by a compound secreted from adipocytes, implicated in antiapoptotic pathways, and has been linked to breast cancer progression and metastasis, in Black women compared to White women, as well as altered expression of its epigenetic regulatory elements.
[16] SOS1 is activated by a compound secreted from adipocytes. Finally, resistin is another gene that may mediate this link, as it is associated with obesity, insulin resistance, and breast cancer risk, and is expressed higher in the tumors of Black women than in White women. [21,24] Like our ndings, Vallega et al. observed increased resistin expression in Black women for tumors that were early-stage and receptor-negative. [21] They did not observe any difference in resistin expression in Stage III tumors in interracial comparisons. [21] Importantly, our observation of worse PFS in stage 0-II disease but not at later stages highlights the importance of early intervention strategies in Black women with breast cancer, due to the higher hazard of progression of earlystage disease compared to non-Black women. Future studies are needed to uncover which molecular pathways are differentially activated by race and obesity status and why these pathways are differentially activated, paving the way for potential therapeutic targets and health policy interventions.
Although previous studies suggest that obesity is independently associated with breast cancer incidence, recurrence, and worse clinical outcomes, [3][4][5][6] we did not identify an association of obesity with PFS or OS that was independent of race. It is possible that race is a more substantial driver of outcomes than obesity in this cohort, or that the interaction between race and obesity is a stronger driver of outcomes than obesity alone. Previous works highlight the interaction between race and obesity at the molecular level; epigenetic modulation of multiple tumorigenic molecular pathways in adipocytes has been linked to differences in allcause mortality, progression, and metastasis in Black women compared to White women. [16,[18][19][20][21]28] The lack of independent association of obesity with PFS or OS may also be attributed to the limitations of BMI as a measure of obesity. Emerging evidence suggests that BMI is an oversimpli ed metric, as it does not distinguish between muscle and adipose, nor does it describe patterns of adipose distribution. [29][30][31] Adipose tissue is nonuniform, and while there is some evidence to suggest that subcutaneous fat provides nutritional reserve in advanced cancer, visceral adipose is pro-in ammatory, with a poor cardiometabolic risk pro le that promotes tumor growth. [29] In addition, high muscle mass may be linked to better cancer outcomes, whereas low muscle mass has been associated with recurrence, surgical complications, treatment toxicity, and worse OS. [29] Because BMI does not account for muscle mass, those with higher muscle mass may be misclassi ed as obese despite a potentially lower risk of progression. Finally, in a study of Black breast cancer survivors, higher waist-to-hip ratio and central adiposity were associated with worse breast cancer-speci c and overall survival, whereas BMI was not associated with worse outcomes. [30] The ndings in our study may re ect the limitations of BMI as a measure of obesity and future studies are needed to evaluate whether central obesity or higher adiposity are more sensitive prognostic indicators for predicting PFS or OS in Black breast cancer survivors.
Kaplan Meier survival analyses revealed that non-Black obese women had the lowest hazard of progression among all participants in the tumor stage 0-II group (Fig. 1). Non-Black obese and non-Black non-obese women performed similarly in terms of OS. Accordingly, the non-Black obese group was selected as the reference group in multivariable analyses. Emerging literature describes an 'obesity paradox' in which obesity is associated with worse outcomes in early cancer, but is protective at later stages by providing a nutritional reserve to protect against cachexia. [23,26,32] The ndings in Fig. 1 may re ect a slightly protective effect of obesity. However, we observe this nding in the early-stage group only and not at later stages, which is inconsistent with descriptions of the obesity paradox. Any protective effects of obesity in the advanced group may be obscured by the small sample size attributed to a) the smaller proportion of participants with advanced-stage cancer and b) the smaller proportion of participants with advanced-stage cancer who remain obese despite the associated wasting. Future studies with larger samples are necessary to better characterize the conditions under which obesity may bene t cancer patients.
The strati ed multivariable analyses demonstrate an association of TNBC with worse PFS and OS in the advanced breast cancer group. The association with worse outcomes in this cohort is best explained by the aggressiveness of TNBC. TNBC lacks hormone receptor expression and is thus not susceptible to hormonal therapies, leading to worse outcomes. [33,34] Additionally, TNBC grows faster than other subtypes and is more likely to be diagnosed at a later stage, as evidenced by the higher proportion of patients with TNBC (22.3%) in the advanced breast cancer group compared to the early breast cancer group (13.7%).
Multivariable Cox models revealed a 2.82-fold increased hazard of death in former smokers compared to never smokers in the early-stage breast cancer group (95% CI, 1.47-5.41) (Table 4A). These ndings are consistent with the known association of smoking with widespread organ damage, all-cause mortality, and cancerspeci c mortality. [35] There was a similar 2.61-fold increased hazard of death associated with current smoking, though this nding was not statistically signi cant (Table 4A). The lack of signi cant association of current smoking with PFS or OS in either group or of former smoking with PFS or OS in the advanced-stage group is likely due to the small sample size.
This study has several strengths. First, a prospective study design is appropriate to assess the patient and clinical characteristics associated with PFS and OS. In addition, we utilize a large racially and ethnically diverse cohort that we followed for up to 13 years, enabling us to evaluate inter-group differences in outcomes. Moreover, although many previous studies characterize the patient and clinical characteristics associated with breast cancer risk, few studies focus speci cally on outcomes. This work builds upon our previous study in which we used a PRS to evaluate genetic predisposition to obesity in this same racially and ethnically diverse cohort of breast cancer patients using GWAS data. [22] We found high PRS was associated with obesity, Black race, and high CRP levels, all of which have been hypothesized to contribute to breast cancer incidence and worse outcomes. The current study expands upon these ndings to explore patient and clinical characteristics associated with prognosis in the same cohort. Having both GWAS and outcome data available for this cohort enables us to conduct future research using genetic prediction models to examine the factors that contribute to breast cancer prognosis.
This study has several limitations. First, the lack of association between race, obesity, and worse PFS or OS in advanced breast cancer could be attributed to the small sample size in this group. Future studies with larger sample sizes are necessary to elucidate potential differences. Second, our use of BMI as a primary outcome may not accurately re ect differences in adiposity. Our decision to use BMI was based on its extensive use in previous studies and the patient data that was available from the study enrollment survey. Third, our patient population was highly enriched for Hispanic White women, (which re ects the racial and ethnic composition of the local population); results may therefore not be generalizable to all populations. Finally, our study did not evaluate variables such as socioeconomic status or access to healthcare, which may also contribute to breast cancer outcomes.

CONCLUSION
Our ndings suggest a complex relationship between obesity and race in breast cancer prognosis. The signi cant association of combined Black race and obesity status with worse PFS in early-stage breast cancer highlights the importance of targeted early intervention strategies among Black women with breast cancer due to the higher hazard of progression of early-stage disease. An interaction of race and obesity at the molecular level may contribute to the observed differences in PFS; future studies are needed to characterize how environmental and lifestyle factors may alter the expression of cancer-associated genes. Finally, the lack of independent association between BMI alone and PFS or OS may suggest that alternate measures of body composition better illustrate the role of obesity in breast cancer outcomes. Future studies should evaluate whether central obesity and adiposity are more sensitive prognostic indicators than BMI among Black breast cancer survivors. survival; B, Black race; NB, Non-Black race. Obese was de ned as BMI ≥ 30 and non-obese was de ned as BMI < 30 (kg/m 2 ). P-values were determined using a log-rank test; a p-value <0.05 was considered statistically signi cant.