Association of Anthropometric Measures with Prostate Cancer among African American Men in the NCI-Maryland Prostate Cancer Case-Control Study

One of the most prominent cancer health disparities exists in prostate cancer. African American (AA) men have the highest prostate cancer incidence and mortality rates among all population groups in the United States (1–3). Accordingly, prostate cancer is estimated to be a leading cause of cancer deaths for these men. This disparity has been attributed to differences in medical care, tumor growth rates, and disease aggressiveness, and to location and histopathologic variables of the tumor (1, 4–10). Numerous studies examined the possibility of low-penetrance genes contributing to the excessive burden of prostate cancer in AA men. To date, the best characterized risk locus for prostate cancer is located at 8q24. As shown by several studies, this locus confers an increased risk for prostate cancer in men of West African ancestry, when compared with men of European and Asian ancestry (11, 12).

Despite these findings, it is generally thought that modifiable risk factors such as diet and lifestyle account for most prostate cancers globally (13). There is also evidence from migration studies that the environment and adaptation of a Western-type lifestyle modulate prostate cancer risks (14–17). However, other studies, including large prospective cohort studies, could not confirm possible roles of diet and lifestyle factors in prostate cancer etiology (18, 19). As such the evidence that these factors modify prostate cancer risk is not conclusive. Yet AA men experience greater age-adjusted prevalence rates of overall [body mass index (BMI) > 30 kg/m²] or class 3 obesity (BMI > 40 kg/m²) compared with European American (EA) men (20). AA men are also more likely to die from obesity-related conditions such as cardiovascular disease and diabetes. In addition, obesity-derived factors may augment growth and invasion of prostate cancer cells (21). Current research suggests that obesity is only weakly linked to the incidence of localized or low-grade prostate cancer. Instead, it was found to increase the risk of the aggressive disease and prostate cancer mortality (22–28). Observations for men of African ancestry are sparse, and the findings are heterogeneous, although an association of excess body weight with aggressive prostate cancer has been reported (29–35). To address the need for additional studies of the relationship between excess body fatness and prostate cancer risk in AA men, we studied the relationship of BMI, waist circumference, and waist–hip ratio with disease development and presentation in the NCI-Maryland Prostate Cancer Case-Control Study.

The NCI-Maryland Prostate Cancer Case-Control Study has been described elsewhere (36). Briefly, the study was conducted between 2005 and 2015 and approved by the NCI (protocol# 05-C-N021) and the University of Maryland's (protocol #0298229) institutional review boards, and both recruitment and research followed the ethical guidelines set by the Declaration of Helsinki. We obtained informed written consent from all study subjects prior to participation. Eligibility was as follows: Cases with a diagnosis of prostate cancer within the last 2 years prior to recruitment were enrolled from two hospitals, the Baltimore Veterans Affairs Medical Center and the University of Maryland Medical Center. Population-based controls were identified through the Maryland Department of Motor Vehicles from the following areas: Maryland; Washington, DC; and the neighboring border counties in Pennsylvania, Delaware, and Virginia, but most of the recruited men resided in four Maryland counties: Anne Arundel, Baltimore City, Baltimore County, and Howard. All men self-reported to be either AA or EA, were between 40 and 90 years old, were born in the United States, spoke English well enough to be interviewed, and were well enough to participate in an in-person interview. A total of 976 cases (489 AA and 487 EA) were recruited. Of these, 823 patients (or 84%) were defined as incident cases because they were recruited into the study within 1 year after the disease diagnosis with an average interval between diagnosis and enrollment into the study of 4.8 months (4.4 months for AA and 5.2 months for EA men). A total of 1,034 population controls (486 AA and 548 EA men) were recruited, as described elsewhere (36). Because of missing data on predictors and covariates, and exclusion of 15 participants with BMI < 18.5 kg/m² or > 50 kg/m², the final analytical sample included 798 cases (97% of all incident cases) and 1,008 controls (97.5% of all population controls) in the multivariable analysis.

At enrollment, trained interviewers administered a standardized questionnaire eliciting information on personal medical and cancer history, tobacco use, occupational, family medical history, socioeconomic history, diet, and anthropometric factors. Information on height and weight at various life stages and at enrollment was self-reported. Interviewers measured waist and hip circumference twice, with the final variable being the average. We obtained additional information on cases from pathology reports and medical records [e.g., prostate-specific antigen (PSA) levels at diagnosis, disease stage, and grade]. Disease staging was defined according to the 7th edition of the American Joint Committee on Cancer (AJCC) tumor–node–metastasis system for anatomic stage/prognostic groups, and grouped as T1, T2, T3, and T4.

BMI is the most commonly studied anthropometric measure and showed an association with aggressive prostate cancer in previous studies (26, 27). BMI was based on self-reported information and calculated by dividing weight in kilograms by height in meters squared to generate traditional cutoff points of normal weight (BMI of 18.5 to <25.0, reference), overweight (25.0 to <30.0), and obese (30.0–50.0). Three BMI time points were assessed: BMI at time of enrollment, 2 years prior to enrollment, and 10 years prior to enrollment. Waist circumference was stratified according to health-related thresholds within BMI categories (37), yielding four categories [20.8–89.9 (reference), 90–99.9, 100–109.9, and 110–197.8]. For further validation of our observations, we also stratified waist circumference according to World Health Organization (WHO) guidelines into ≤94 (reference), >94–102 = increased risk of metabolic complications, and >102 = substantially increased risk of metabolic complications (38). Waist–hip ratio was calculated by dividing the average waist measurement by the average hip measurement and was operationalized into tertiles [< 0.92 (reference), 0.92–0.98, >0.98) based on the waist–hip ratio distribution among the 1,008 controls.

Tumor histologic grade was determined according to the Gleason score system and grouped as follows: low-grade (2–7) versus high-grade (8–10). Disease stage at diagnosis was based on information obtained from medical records, with low-stage or localized disease being defined as T1 or T2 and high-stage or advanced disease being defined as T3 or T4. Disease aggressiveness was operationalized as a binary measure where a Gleason score ≤ 7 and a stage I or II was considered nonaggressive, whereas a Gleason score > 7 or stage III or IV was defined as aggressive.

All multivariable models were adjusted for age at enrollment (continuous), education [≤high school (reference), some college, college, graduate school], diabetes, first-degree relative with prostate cancer, and smoking [never (reference), former, current]. A never smoker was a man who smoked less than 100 cigarettes in his lifetime according to self-report.

Statistical analysis was performed using STATA software, version 13.0 (Stata Corporation). All statistical analysis was two-sided, and a P < 0.05 was considered statistically significant. We estimated associations between anthropometric variables, prostate cancer, and covariables using the Student t tests and the χ² test. For the main analysis, we evaluated whether anthropometric measures were associated with prostate cancer in strata of Gleason score (low- or high-grade), stage (low- or high-stage), and disease aggressiveness (nonaggressive and aggressive). We calculated ORs and 95% confidence intervals (CIs) using multivariable logistic regressions and tested for interactions under a multiplicative model with the log likelihood ratio test. Linear trend analysis was performed using logistic regression models with continuous predictors. In a prior study, we observed that aspirin modified prostate cancer risk in AA men (36). Given these findings, a sensitivity analysis was conducted to determine whether use of aspirin moderated the relationship of BMI and waist circumference with prostate cancer among AA men by stratifying our analysis by aspirin users and nonusers. Aspirin use was measured by asking participants the following survey question: Have you taken aspirin or aspirin-containing compounds (such as Bufferin, Anacin, Ascriptin, Excedrin) regularly—at least one pill per week for 2 months during the past 5 years—no, yes, or do not know, as previously described (36).

Demographics and the health- and disease-related characteristics of the study population are shown in Table 1. Our analytical sample included 798 incident prostate cancer cases and 1,008 population controls with similar proportions of AA (402 and 474, respectively) and EA (396 and 534, respectively) men and information on BMI, waist circumference, and waist–hip ratio. Men in the control group were slightly older than cases (AA, 64 vs. 63; EA, 66 vs. 65). Cases tended to have a lower education and income level, and a greater proportion of them were smokers and had a family history of prostate cancer, when compared with controls (Table 1). Occurrence of diabetes was not significantly different between cases and controls for either group of men. Aspirin use differed significantly between cases and controls for AA men (42% vs. 51.7%, respectively, P < 0.01) but not for EA men (56.3% vs. 62%, P = 0.08).

On bivariate analysis, there were no significant differences in the waist–hip ratio measurements between cases and controls (Table 1). Proportionally, more cases than controls had a waist circumference in the normal weight range (20.8–89.9) for both AA and EA men. In addition, more cases than controls had a BMI in the normal weight range (18.5–< 25) among AA men, whereas the opposite trend was seen among the EA men. At enrollment, 40.6% and 34.1% of AA cases reported to have a BMI in the overweight (25–< 30) or obese (≥30) weight range, respectively; these proportions were different for controls (37.8% and 43.7%, respectively, P < 0.01). At 10 years prior to enrollment into the study, 40.1% and 27.6% of AA cases reported that they had a BMI in the overweight or obese weight range, respectively, compared with controls (44.7% and 33.5%, respectively, P < 0.01). In a correlation analysis of anthropometric measures, we observed strong correlations among our three BMI measures (Spearman ρ: 0.77–0.91, P < 0.001), and moderate, albeit statistically significant (P < 0.001), correlations between BMI at enrollment and waist circumference (ρ = 0.45) or waist–hip ratio (ρ = 0.38). The relationship between waist circumference and waist–hip ratio was also rather modest (ρ = 0.37, P < 0.001). We did not note significant differences in these correlations by race/ethnicity.

Among AA men, a BMI ≥ 30 at enrollment was inversely associated with prostate cancer risk in all grade (low-grade: OR, 0.59; 95% CI, 0.39–0.91; high-grade: OR, 0.45; 95% CI, 0.22–0.90), stage (low-stage: OR, 0.65; 95% CI, 0.43–0.98; high-stage: OR, 0.26; 95% CI, 0.12–0.59), and disease aggressiveness strata (nonaggressive: OR, 0.62; 95% CI, 0.40–0.96; aggressive: OR, 0.41; 95% CI, 0.22–0.78; Table 2 and Fig. 1A). Similar associations were observed when we assessed BMI at 2 or 10 years prior to enrollment (Tables 3 and 4). Within EA men, a BMI in the overweight range was significantly associated with increased odds of low-grade (OR, 1.52; 95% CI, 1.06–2.18), low-stage (OR, 1.44; 95% CI, 1.01–2.06), high-stage (OR, 2.14; 95% CI, 1.03–4.43), and aggressive (OR, 1.86; 95% CI, 1.06–3.26) prostate cancer relative to EA men with a normal weight range BMI (Table 2). At 2 or 10 years prior to enrollment (Tables 3 and 4), there was no BMI-associated disease risk for EA men except for high-grade cancer which showed a positive association with a BMI in the obese weight range at 10 years prior to enrollment (OR, 2.28; 95% CI, 1.03–5.04 for BMI ≥30 vs. <25; P for trend = 0.04).

For both AA and EA men, a larger waist circumference at enrollment (≥110) was inversely associated with prostate cancer risk when a waist circumference of <90 cm was used as the reference group (Table 5 and Fig. 1B). Controlling for BMI in the analysis did not have a large effect on these findings. For example, among AA men, having a waist circumference ≥110 cm significantly decreased the odds of low-grade (OR, 0.36; 95% CI, 0.23–0.47), low-stage (OR, 0.38; 95% CI, 0.24–0.60), high-stage (OR, 0.27; 95% CI, 0.08–0.88), nonaggressive (OR, 0.36; 95% CI, 0.23–0.58), and aggressive cancer (OR, 0.43; 95% CI, 0.20–0.94), even after controlling for BMI (Supplementary Table S1). In contrast to the protective effect of a high waist circumference, an increased waist–hip ratio at enrollment was not significantly associated with odds of prostate cancer among AA and EA men (Supplementary Table S2 and Fig. 1C). For EA men, having a waist–hip ratio >0.98 tended to increase the odds of a high-grade (OR, 1.53; 95% CI, 0.74–3.14), high-stage (OR, 1.76; 95% CI, 0.85–3.63), and aggressive (OR, 1.68; 95% CI, 0.92–3.06) disease (Supplementary Table S2 and Fig. 1C).

The results for this sensitivity analysis are shown in Supplementary Table S3, wherein aspirin use modified the relationships between BMI and prostate cancer, but not the relationship between waist circumference and the disease. The aspirin effect was most obvious when a BMI prior to disease diagnosis was assessed (2 and 10 years prior to enrollment of the cases). For example, in the nonstratified analysis for BMI at 10 years prior to enrollment, a BMI in the overweight and obese weight range were both associated with decreased odds of prostate cancer risk compared with a normal weight range BMI (OR, 0.68; 95% CI, 0.48–0.97 and 0.54; 95% CI, 0.37–0.81, respectively). After stratification, this association remained significant only among nonusers of aspirin (OR, 0.39; 95% CI, 0.24–0.63 and 0.46; 95% CI, 0.27–0.81, respectively), but not for aspirin users (OR, 1.61; 95% CI, 0.92–2.82 and 0.81; 95% CI, 0.45–1.46, respectively). A test for interaction revealed significant interactions between aspirin and BMI among overweight, but not obese men, when a BMI prior to disease diagnosis was assessed (P_interaction < 0.01).

In this study, we found inverse relationships between two anthropometric measures, BMI and waist circumference, with prostate cancer in AA men that were consistent across strata and time points. Waist–hip ratio did not associate with the disease in these men. The inverse relationship between waist circumference and prostate cancer among these men was also observed when we used WHO guidelines to select health-related cutoff points for waist circumference (Supplementary Table S4). In contrast, a high BMI and waist–hip ratio tended to increase the risk of advanced/aggressive prostate cancer among EA men, although less consistently than the inverse associations in AA men. The positive relationship between an elevated BMI and waist–hip ratio and advanced/aggressive disease in the EA men in our study is consistent with other reports (23, 32, 39, 40). There is also supporting evidence from a meta-analysis that a high BMI increases prostate cancer–specific mortality among these men (25).

Here, we aimed to explore potential differences in the association of body fatness with prostate cancer between AA and EA men. Waist circumference and waist–hip ratio are measures for central body fatness, whereas BMI is a proxy for overall body fatness. The International Agency for Research on Cancer working group on the relationship of body fatness with cancer reported that observations based on BMI were generally consistent with those reported for waist circumference (41). We hypothesized that excess body fatness, measured as BMI, waist circumference, or waist–hip ratio, may partly explain the excessive risk of prostate cancer among AA men. However, in our cohort, AA men with a high BMI and waist circumference were significantly less likely to have prostate cancer than men with body fatness in the normal range. The relationship between BMI and the disease did not change whether we used BMI at time of recruitment or BMI 10 years prior to it in our analysis. In two case–control studies of Caribbean men, mostly of African descent, BMI was not a risk factor for prostate cancer (31, 33). Nevertheless, a high waist–hip ratio was positively associated with prostate cancer in both studies, which contrasts with our findings for AA men. Nemesure and colleagues (33) also found a positive association for waist circumference and concluded that central adiposity may be more predictive of prostate cancer than BMI in men of African descent. From our data, we would not come to the same conclusion. The discrepancies in the observations between our study and the study by Nemesure and colleagues with African Barbadian men cannot readily be explained. Few differences in the data analysis approach exist between the two studies. We stratified the waist–hip ratio into tertiles, whereas Nemesure and colleagues used quartiles in their analysis. In addition, the definition of normal range and quartiles for waist circumference was somewhat different between the two studies. Average body mass was higher in our AA population than the African Barbadian population with mean BMIs of 27.7 versus 25.8 among cases and 29.8 versus 26.0 among the controls. Yet both are case–control studies of comparable size and used incident cases identified from hospital records and population-based controls. Furthermore, both have a similar age distribution, smoking prevalence, and diabetes history among cases and controls. The two studies also obtained the measurements for waist–hip ratio and waist circumference at time of enrollment using trained personnel, but our study had additional information on BMI for 2 and 10 years prior to recruitment.

Several other studies investigated differences in the association of obesity with prostate cancer risks comparing AA and EA men in the United States. Su and colleagues observed a stronger association of BMI and waist–hip ratio with aggressive prostate cancer in EA than AA men for participants in the North Carolina-Louisiana Prostate Cancer Project, a state cancer registry–based study (32). Because AA had more aggressive disease in general, the authors hypothesized that the association between obesity and aggressiveness may not have been as evident in the AA men. Using the same study population, Khan and colleagues also reported an association of obesity, independent of diabetes, with aggressive disease in EA men, but not AA men (35). Barrington and colleagues observed a significant association of BMI with prostate cancer and high-grade disease for AA men but not EA men in the Selenium and Vitamin E Cancer Prevention Trial (34). Like Khan and colleagues, this study assessed only BMI as a measure of body fatness. Last, analyzing 308 radiotherapy-treated patients, Allott and colleagues found significant associations for both BMI and waist circumference with high-grade disease among severely obese AA patients (42). In summary, these investigations tended to find an association of increased body fatness with advanced or high-grade prostate cancer in AA men, which contrasts with findings in the present study with unselected patients.

The biological mechanisms through which excess body fatness could influence prostate cancer incidence are complex, potentially explaining differences in findings among observational studies. A gene expression profiling study described effects of obesity on chromatin modifications in prostate tumors (43). If epigenetic differences exist in prostate tumors among patient groups at baseline, as they have been described (44), obesity may have different effects on tumor biology in these patient groups (e.g., AA versus EA men). Others described a significant modifying effect of the TMPRSS2:ERG fusion gene status on the relationship between obesity and aggressive prostate cancer (45). For patients with oncogenic TMPRSS2:ERG fusion gene rearrangements in their tumors (ERG-positive), obesity increased the risk of lethal prostate cancer, whereas ERG-negative patients did not experience this increased risk associated with obesity. Notably, ERG-negative tumors are more common among AA patients than EA patients (46–48), potentially leading to a reduced risk of lethal disease among obese AA men when compared with EA men. Unfortunately, the ERG tumor status could not be assessed in our study. Last, group differences in susceptibility to inflammation have been described, with an increased susceptibility to inflammation among subjects of African ancestry (49). For prostate cancer, a high baseline inflammation based on histologic evaluation of infiltrating leukocytes in the noncancerous prostate has been linked to a reduced risk of prostate cancer (50). It is possible that AA men in the NCI-Maryland cohort may have had increased baseline inflammation in the noncancerous prostate that was intensified by excess body fatness, leading to a decreased risk of prostate cancer in this group of patients. This hypothesis is partly supported by our observation that regular aspirin use attenuated the inverse relationship between BMI and prostate cancer in the AA men.

Our study has limitations. In general, a case–control study is potentially influenced by inherent biases. We relied on retrospective, self-reported assessment of height and weight to calculate BMI, which may be affected by a recall bias. However, waist circumference and waist–hip ratio were measured by trained personnel and would not be affected by a recall bias. Moreover, self-reported anthropometric measures were found to be reliable and valid (51). On the other hand, cases were more likely to be current smokers but less likely to have a college or graduate degree than controls. These differences between cases and controls were observed among both AA and EA men. We controlled for these differences in our analysis. As a strength of our study, our estimates for BMI prior to enrollment remained consistent with the findings for BMI at enrollment, diminishing the potential of temporal bias in our analysis.

In summary, we found associations of anthropometric measures with prostate cancer among EA men that were generally consistent with the reported literature. However, we observed an inverse association among AA men, where a high BMI and waist circumference associated with a lower disease occurrence.

No potential conflicts of interest were disclosed.

Conception and design: M.S. Pichardo, C.J. Smith, C.A. Loffredo, S. Ambs

Development of methodology: M.S. Pichardo, S. Ambs

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.J. Smith, C.A. Loffredo

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.S. Pichardo, C.J. Smith, C.A. Loffredo, S. Ambs

Writing, review, and/or revision of the manuscript: M.S. Pichardo, C.J. Smith, C.A. Loffredo, S. Ambs

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.J. Smith, T.H. Dorsey, C.A. Loffredo

Study supervision: C.J. Smith, C.A. Loffredo, S. Ambs

This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research (ZIA BC 010499 and ZIA BC 010624).

We would like to thank personnel at the University of Maryland and the Baltimore Veterans Administration Hospital for their contributions with the recruitment of subjects. We would also like to thank Dr. Brid Ryan for critical review of the article.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.