The complex interplay of modifiable risk factors affecting prostate cancer disparities in African American men

Abstract

Prostate cancer is the second most commonly diagnosed non-skin malignancy and the second leading cause of cancer death among men in the USA. However, the mortality rate of African American men aged 40–60 years is almost 2.5-fold greater than that of European American men. Despite screening and diagnostic and therapeutic advances, disparities in prostate cancer incidence and outcomes remain prevalent. The reasons that lead to this disparity in outcomes are complex and multifactorial. Established non-modifiable risk factors such as age and genetic predisposition contribute to this disparity; however, evidence suggests that modifiable risk factors (including social determinants of health, diet, steroid hormones, environment and lack of diversity in enrolment in clinical trials) are prominent contributing factors to the racial disparities observed. Disparities involved in the diagnosis, treatment and survival of African American men with prostate cancer have also been correlated with low socioeconomic status, education and lack of access to health care. The effects and complex interactions of prostate cancer modifiable risk factors are important considerations for mitigating the incidence and outcomes of this disease in African American men.

Introduction

In 2023, an estimated 288,300 new prostate cancer diagnoses were made in the USA and 34,700 men died from the disease¹. However, the incidence of prostate cancer in African American men is 73% higher than in European American men, and the mortality rate is more than double that of men in every other ethnic group, especially European American men. Unsurprisingly, this elevated rate of prostate cancer diagnosis in African American men also correlates with the highest disease-specific mortality rates for this population¹. The factors that contribute to these glaring disparities in incidence and mortality rate are multifaceted and include complex interactions between non-modifiable risk factors, such as age, family history and genetic predisposition, and modifiable risk factors such as diet, socioeconomic conditions, obesity and steroid hormones². PSA screening recommendations for prostate cancer have also fluctuated over the past decade, further exacerbating these confounding variables. Consequently, the pros and cons of modified screening guidelines specific to race or family history remain controversial. Numerous studies have highlighted the advantage of earlier and annual screening for African American men. However, these findings have yet to be translated into clinical application^3,4.

In addition to the reduced screening rates and increased rates of diagnosis experienced by African American men, the biological characteristics of prostate tumours are worse at clinical presentation for this population⁵. Delayed diagnosis limits treatment options and reduces the efficacy of those treatments, contributing to poorer overall survival. Although advanced treatment options are on the horizon for currently incurable advanced prostate cancer, African American men are less likely to participate in clinical trials for several reasons, including insufficient study-initiated recruitment efforts and medical mistrust within this population⁶.

In this Review, we explore the variations of prostate cancer incidence and mortality rates between populations and discuss the crucial need to account for the increased value of updating screening protocols for this group of men in clinical guidelines. We discuss the effects and potential interplay of social determinants of health, diet and nutritional supplementation, steroid hormones and tumour microenvironment (TME) on prostate cancer disparities in African American men. Lastly, we discuss the importance of race-stratified clinical trials within the context of prostate cancer health disparities and provide future direction on reversing these troubling prostate cancer disparity trends.

Prostate cancer mortality and incidence

Prostate cancer is the most common non-cutaneous malignancy in men worldwide⁷. Despite advances in screening and treatment, persistent disparities in incidence and outcomes remain prevalent in some racial and/or ethnic groups. Globally, rates of prostate cancer incidence and mortality vary between populations, and developed nations tend to have higher incidence, whereas developing countries tend to have higher mortality rates⁷ (Fig. 1). Lower mortality rates in developed countries are attributed to increased PSA testing, improved health literacy and wider access to health care. In developing countries, advanced disease and poorer prognosis are due to a lack of access to screening, which is proportionate to increased detection of late-stage prostate carcinoma⁸. In 2020, Africa (south, east, middle and west) and the Caribbean reported the highest prostate cancer mortality in the world, with rates ranging from 16.3 to 27.9 deaths per 100,000 men⁷.

Fig. 1 |. Global prostate cancer incidence and mortality by world areas.

The graph indicates region-specific age-standardized prostate cancer incidence (blue) and mortality rates (red) per 100,000 based on the GLOBOCAN estimates in 2020 (ref. 7). Highest incidence rates were found in northern and western Europe, the Caribbean, northern America and southern Africa. Regions with the highest mortality rates were found in the Caribbean, sub-Saharan Africa (middle and southern Africa) and Polynesia. Mortality rates were sorted from highest to lowest⁷.

Interestingly, although North America reported a low mortality rate of 8.3 deaths per 100,000 from 2016 to 2020 when stratified by race and adjusted for age, African American men experienced a higher mortality rate (37.5 per 100,000) (Fig. 2) than African and Caribbean men (16.3–27.9 per 100,000) (Fig. 1). This number is substantially higher than those for non-Hispanic white men (17.8 per 100,000), Hispanic men (15.3 per 100,000), American Indian men (19.5 per 100,000) and Asian and Pacific Islander men (8.6 per 100,000)⁹ (Fig. 2).

Fig. 2 |. US prostate cancer incidence and mortality rates by race.

The graph shows prostate cancer incidence and mortality rate data from the Surveillance, Epidemiology, and End Results (SEER) database divided according to self-reported race. Age-standardized incidence (2015–2019) and mortality rates (2016–2020) per 100,000 are shown in blue and in red, respectively. Non-Hispanic Black men experienced the highest incidence and mortality rates compared with men from other racial backgrounds, whereas Asians and Pacific Islanders had the lowest incidence and mortality rates.

Furthermore, prostate cancer risk increases with age and about two-thirds of all prostate tumours are diagnosed in men aged ≥65 years^10,11. Men aged >55 years are more likely to present with more-aggressive clinical and pathological features associated with high-risk prostate cancer (HRPC) than younger men¹¹. Although risk increases substantially for European American men after the age of 50 years, risk increases at 40 years for African American men with an extensive family history of prostate cancer¹⁰. In a 2007 study, Powell¹⁰ observed pronounced differences in PSA levels, tumour grading, advanced disease and recurrence rates between African American and European American men in their 50s. Additionally, in a meta-analysis of 19 studies that involved 6,024 men, African American men consistently demonstrated earlier onset of prostate carcinogenesis, as young as their 30s, even when undiagnosed prostate cancer was detected by histology at autopsy¹². Beyond existing disparities for increased risk by age, racial disparities have been reported for age and mortality. Results from a 2017 meta-analysis suggest that the racial disparity gap lessens with advanced age and, therefore, highlights the urgent need to address young African American populations by implementing targeted screening guidelines and treatment protocols¹³.

The effect of blanket prostate cancer screening recommendations

Updates to the prostate cancer screening recommendations that emphasize the importance of shared decision-making between patients and physicians before undergoing PSA-based screening might have exacerbated disparities in African American men. For more than 30 years, total circulating PSA levels have been the gold standard for prostate cancer screening. However, screening via PSA testing is complicated by issues that include high rates of false positives, overdiagnosis of indolent cases and ambiguity in identifying aggressive cases^14–16. To better understand the uncertainty around PSA screening, one must understand the commonly used PSA screening recommendations and the multiple factors that can contradict these recommendations. First, that patients with PSA levels between 0 and 2.5 ng/ml are unlikely to have prostate cancer is well established; thus, the recommended PSA cut-off threshold is 4 ng/ml for prostate cancer screening¹⁷; a follow-up biopsy is often recommended when PSA levels >4.0 ng/ml are detected. However, many clinically significant prostate tumours remain undetected when adhering to this specification — for example, the Prostate Cancer Prevention Trial (PCPT) reported that prostate cancer was detected in 15% of men with PSA levels <4.0 ng/ml¹⁸. As rising PSA levels positively correlate with the likelihood of prostate cancer diagnosis, data suggest that PSA levels might be best measured and interpreted as continuous risk.

Multiple factors stimulate total PSA fluctuation, including an enlarged prostate, benign prostatic hyperplasia, age, prostatitis, ejaculation, specific urological procedures and medications¹⁹. These confounding interpretations were factored into the 2012 United States Preventive Services Task Force (USPSTF) decision to recommend against blanket PSA-based screening for prostate cancer²⁰. In 2018, the USPSTF amended its decision to a grade C recommendation for shared decision-making between the patient and their clinician, which involves discussion of the potential benefits and harms of screening for men aged 55–69 years^21,22 (Table 1). In agreement with this decision, the American Urological Association (AUA) further acknowledged that African American men are at increased risk of developing the disease and The American Cancer Society recommends screening at 45 years for African American men and 40 years for African American men with an extensive family history of prostate cancer, with repeat annual PSA testing for men with serum PSA levels >2.5 ng/ml^23,24 (Table 1). Recognizing the benefits of earlier screening for African American men, the Prostate Cancer Foundation endorses similar guidelines²⁵ (Table 1). Further studies have shown that serum PSA levels and PSA density (that is, serum PSA level to prostate volume ratio) are often higher in African American men than in European American men²⁶. Thus, additional metrics such as PSA velocity, PSA density, free versus bound PSA, proenzyme PSA (proPSA), prostate health index (PHI) and the 4K (four-kallikrein) score test may be taken into consideration to enhance the specificity or sensitivity of PSA²⁷.

Table 1 |.

Prostate cancer screening recommendations by organizations in the USA

Organization	Screening age for patients at average risk of disease (years)	Screening age for patients at high risk of disease (years)	PSA screening interval (years)
United States Preventive Services Task Force	Shared decision-making for patients beginning at age 55–69	Evidence is insufficient to support one method of PSA-based screening over another	NR
American Urological Association	Shared decision-making for patients beginning at age 50–69	Begin at age 40–45	For men of low to average risk: every 2–4 years
Prostate Cancer Foundation	Shared decision-making for patients beginning at age 45	Begin at age 40	NR
American Cancer Society	Begin at age 50, if life expectancy is >10 years	Begin at age 40–45	Annually if PSA is >2.5 ng/m1

NR, not reported.

Widespread PSA screening decreases the incidence of advanced-stage and lethal prostate cancer diagnosis^24,28. During the screening era (1991–2008), a 53% decrease in mortality rate was observed, which is directly attributable to blanket screening. However, African American men were significantly under-screened for prostate cancer between 2014 and 2019, contributing to poor outcomes in this group²⁶. Although multiple studies suggest the need for updated prostate cancer screening protocols for men of African descent, the implementation of newer guidelines remains controversial. For example, the USPSTF continues to state that the evidence is inadequate to determine whether the benefits of regular screening for high-risk African American men are different from the benefits for average-risk or younger populations. This inadequate evidence was bolstered by the glaringly low sample size of men of African descent included in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; just 4% of the participants) and the European Randomized Study of Screening for Prostate Cancer (ERSPC). No demographic statistics were reported in the ERSPC study. However, seven countries with low populations of men with African ancestry were included in this study. Thus, the probability that most of the participants were of European ancestry is high. Interestingly, results from these two studies were used to formulate the current recommendations²⁹.

Notably, the USPSTF stance contradicts real-world evidence of continued and increased prostate cancer morbidity and mortality in these populations^21,30. Thus, the USPSTF recommendation propagates a sustained hazard to African American men. An example of how the USPSTF current stance can affect high-risk populations, specifically African American men, was reported in a 2022 study that compared two study cohorts with a total of 1,703 patients (76% African American, 14% European American and 11% other) who underwent prostate cancer biopsy, before (group A) or after (group B) the 2012 USPSTF recommendation against PSA-based screening. Results showed a decrease in the annual rate of prostate cancer biopsy by 41% (group B) after the USPSTF recommended against screening, and a twofold increase in the number of positive biopsies. Investigators also found an increase in diagnosis of high-grade prostate cancer (Gleason sum score 7–10) by 8% after the 2012 USPSTF recommendations. Additionally, digital rectal examinations (64%) and PSA-based screening (39%) decreased between the two study groups³¹. Results from this predominantly African American patient population further emphasize the need for the USPSTF to re-evaluate their guidelines by recommending screening in high-risk populations in efforts to mitigate the upward trends of prostate cancer fatalities and reduce disparities. Interestingly, analysis of the Veterans Health Administration (VA) screening patterns between 2009 and 2018 showed that, despite fluctuating USPSTF recommendations, PSA screening rates decreased only moderately (12.1%), with veterans of various races undergoing similar screening rates whereas veterans of varying ages experienced different screening trends (oldest men, who had the highest starting rate of testing, had the largest PSA rate decline (22.6%), and young men, who had lower initial testing rates, had the highest increase in PSA testing (+11.6%))³². Overall, data suggest that VA care might minimize racial disparities in screening.

A 2021 focus-group study, comprising African American and European American men (n = 44), sought to investigate racial differences in reactions to the same prostate cancer screening information³³. Both racial groups reported low baseline familiarity with prostate cancer and screening options, surprise and resistance to the recommendations for reduced testing frequency and negative emotions towards ambiguous messaging in the pamphlet. However, whereas European American groups highlighted the potential benefits of screening, minimized the harms and emphasized personal choice in screening decisions during discussion, the African American participants spent almost no time discussing benefits, found harms to be significant and emphasized both personal and collective responsibility for preventing cancer through diet, exercise and alternative medicine. The African American groups also discussed the role of racism and discrimination in health care and medical research in relation to prostate cancer. Despite being a small study, this work highlights how different perspectives and life experiences between racial groups greatly affect how medical information is received, interpreted and assimilated³³. Although awareness around prostate cancer is increasing, many African American men remain uninformed of the current early detection methods available. Furthermore, other barriers — such as housing and transportation, occupation, educational attainment, a lack of health insurance (and poor access to quality care as a result) and cost of care — might prevent some African American men from accessing screening and treatment^34,35. Minimizing differences in quality health-care availability could be a potentially important pathway to minimize disparities in prostate cancer outcomes.

The effect of social determinants of health

Epidemiological studies have revealed numerous pathways by which individual biology, lifestyle factors and environmental factors influence the risk of prostate cancer development and survival. Although gaps remain in our understanding of the aetiology of prostate cancer, current understanding of risk factors — such as age, race and/or ethnicity and family history — inform early intervention strategies for individuals at high risk and use of behaviour change to reduce the burden of disease. Over the past decade federal research funding opportunities to elucidate the biological basis of prostate cancer disparities, particularly among African American men, have increased; however, the scientific evidence base remains limited, in part owing to a lack of inclusion of African American men in biomedical research studies and clinical trials^36,37. As diverse representation of high-risk populations in research has become a national research priority, the focus on understanding the environmental and societal contributions to prostate cancer is also increasing. The NIH National Institute on Minority Health and Health Disparities Research Framework suggests that, to adequately address the complexities of health disparities, research must consider multiple factors, levels and domains of influence that contribute to disparate health outcomes. As a result, attention on the role and impact of social determinants of health (SDOH) in the context of prostate cancer outcomes has been increasing. SDOH are the conditions in the environments in which people are born, live, learn, work, play, worship and age that affect a wide range of health functioning and quality-of-life outcomes and risks. Conceptually, SDOH are grouped into five domains: economic stability, education access and quality, health-care access and quality, neighbourhood and built environment and social and community context³⁸. A few examples of SDOH include poverty, safe housing, transportation, lack of social support, racism, discrimination, education, access to nutritious foods and physical activity opportunities, and language and literacy skills³⁸.

Prostate cancer outcomes can vary across racial and/or ethnic groups and by status of SDOH. However, African American men bear a disproportionate burden of having the worst SDOH status and prostate cancer adverse health outcomes relative to other racial and ethnic groups^39,40. Previous studies have speculated that disparities arise owing to the inequalities in access to quality health care^41–43; indeed, some data suggest a reduction in prostate cancer disparities when patients receive equal and/or similar access to adequate health care^5,35,44,45. By contrast, other studies have shown conflicting evidence^44,46. One notable study examined the differences in prostate cancer outcomes within five racial and/or ethnic groups in the SEER database across USA county-level socioeconomic status (SES) profiles (n = 239,613 prostate cancer cases). Investigators found that insurance status did not improve the relationship between prostate cancer disease severity, SES and health-care utilization⁴⁶. Thus, these data imply that additional measures are needed to address men within low-SES counties beyond simply improvement of insurance status. Furthermore, the authors reported that improved education among African American men did not influence prostate cancer survival compared with European American men. This evidence further supports previous literature that emphasized that patients from minority groups are at a disadvantage of achieving the same health gains and benefits as their European American counterparts regardless of higher SES^47,48. African American men diagnosed with prostate cancer in the USA persistently experience disparities in SDOH, such as decreased access to quality health care, reduced PSA screening, economic instability, receipt of less guideline-concordant cancer care and poor cultural competency among physicians, disproportionate number of comorbid conditions, increased likelihood of poor management and treatment of comorbid conditions, reduced curative-intent treatment and reduced access to high-volume cancer centres, all of which reflect SDOH that can be associated with disparate health outcomes^35,49–56. A 2023 systematic review and meta-analysis sought to evaluate the association of SDOH with prostate-cancer-specific mortality and overall survival among African American and European American patients with prostate cancer⁵⁰. The authors hypothesized that SDOH were major factors associated with the differences between African American and European American men and that an inverse association between survival outcomes and the extent of disparities in SDOH would be observed between races⁵⁰. A total of 47 studies were identified, comprising 1,019,908 patients (176,028 identified as African American, 843,880 identified as European American)⁵⁰. The findings indicated a significant interaction between race and SDOH regarding prostate-cancer-specific mortality and overall survival, with African American men being disproportionately affected by SDOH when accounted for in the study⁵⁰. A related cross-sectional population-based study of 23,555 African American men and 146,889 European American men diagnosed with prostate cancer in the California Cancer Registry sought to ascertain the effect of neighbourhood SES, marital status and insurance type on differences in prostate cancer risk profiles between African American and European American men. The authors concluded that neighbourhood SES was the primary factor associated with racial disparities in high-PSA prostate cancer⁵⁷. Although the cross-sectional research design limits the generalizability of these findings, they do suggest the need for further longitudinal investigation of neighbourhood SES in the context of prostate cancer disparities.

Furthermore, a study that examined neighbourhood social and natural environment suggested that adverse neighbourhood SES and income segregation might influence systemic inflammation, which could affect prostatic inflammation, resulting in different histological signatures through adverse social environments, mediated through limited social capital, civic engagement and employment⁵⁸. A study that examined survival among men with prostate cancer according to neighbourhood archetypes (which consider interactions between many social and built environment attributes, not limited to neighbourhood SES) showed interactions between several domains of neighbourhood social and built environment archetypes and survival⁵⁹. These domains went beyond examination of SES, but included rural or urban status, racial and/or ethnic composition or age of residents, commuting and traffic patterns, residential mobility and food environment⁵⁹.

Although a growing number of studies are beginning to routinely collect different domains of SDOH data, existing data suggest the need for longitudinal research studies to better understand the effect of various SDOH on prostate cancer outcomes and disparities to ensure the development of appropriate multilevel intervention strategies.

Effects of diet and nutritional supplementation

Although nutrition has a role in prostate cancer development, studies agree that no specific diet can prevent or eliminate the disease. In addition, the observed relationship between dietary supplementation and prostate cancer disparities has not been fully determined. Despite our current understanding, studies are ongoing to elucidate the potential for dietary components to enhance current prostate cancer treatments and interventions. Epidemiological studies report mixed results regarding protein, dairy, soy, and saturated and unsaturated fat intake and their associations with prostate cancer risk^60–64. Analysis of the diet history questionnaire data from European Americans (n = 41,830) and African Americans (n = 1,282) in the PLCO project showed a positive association between high-level organ meat intake and aggressive prostate cancer risk, a reduction in risk associated with supplementary iron, copper and magnesium, and that African American men had a lower intake of protein (healthy diet) and a higher intake of organ meat (unhealthy diet) compared with European American men⁶⁵. These data support that the inclusion of these dietary variables in prostate cancer prevention strategies might be beneficial for African American men. However, further investigation of these non-genetic variables is needed.

Increasing numbers of studies have suggested that vitamins can have a protective effect against prostate cancer. For example, lycopene, a non-pro-vitamin A carotenoid that is found in plants such as tomatoes, is known for its protective role in the prevention of cancer, including prostate cancer. Lycopene is recognized for its potent antioxidant properties^66,67. However, epidemiological studies have provided conflicting results around whether lycopene intake is protective against prostate cancer and these studies are limited to European American populations^68–71. A small study that investigated whether the role of lycopene intake in prostate cancer prevention differs between African American and European American men found that, within the combined population, race and/or ethnicity was the only prominent factor that influenced lycopene intake from the daily diet. Sufficient lycopene intake was associated with prostate cancer only in European American men, who had 0.31 times lower odds (95% CI 0.12–0.81, P = 0.02) of having a high risk of prostate cancer. In the study, African American men consumed less lycopene than European American men, but also presented a prostate cancer risk factor of living alone, which could explain the reverse association among African American men⁷². In preclinical studies, vitamins C, E and K have been found to reduce prostate tumour growth; however, results from epidemiological and clinical studies were either mixed or inadequate to make firm conclusions⁶¹. Batai and colleagues⁷³ reported a significant association between high calcium intake and aggressive prostate cancer (odds ratio (OR) quartile 1 versus quartile 4 = 4.28, 95% CI 1.70–10.80) and a strong inverse association between high vitamin D intake and prostate cancer (OR quartile 1 versus quartile 4 = 0.06, 95% CI 0.02–0.54) in African American men. Currently, research into vitamin and mineral supplementation to mitigate prostate cancer risk and progression is lacking. Future work needs to focus on investigating alternative nutritional strategies and interactions between socioeconomic barriers to food and dietary supplemental resources for African American men.

Although the role for most individual nutrients in prostate cancer risk remains unclear, a ‘western dietary pattern’ — usually defined as one that is high in fat, sugar, dairy, red meat and processed foods — has been observed to be associated with increased prostate cancer risk in studies conducted in several countries⁶⁰. A diet high in red meat might increase the risk of prostate cancer because it increases exposure to potentially carcinogenic heterocyclic amines (HCAs), a class of mutagenic chemicals formed during the high-temperature cooking of meats, including beef, pork, poultry and fish. The most abundant HCA is 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which can be metabolized and covalently bind to protein and DNA^74,75. These DNA adducts can facilitate mutagenesis, potentially causing protein structure and function defects that might result in tumorigenesis⁷⁴. Although studies evaluating the association between red meat consumption and prostate cancer have yielded conflicting results overall, those that investigate specific meat cooking methods and ‘done-ness’ levels suggest that high intake of well-done meat, which has increased levels of PhIP, might be a risk factor for the development of prostate cancer^76,77. Consumption of ‘well-done’ and ‘very well-done’ red and processed meat, specifically, has been positively associated with prostate cancer⁷⁸, and especially with advanced or aggressive disease^79,80. Although studies have confirmed that PhIP exposure and DNA adduct formation initiates tumours in the lymphoid tissue in mice⁸¹ and in the mammary glands, colon and prostate of rats^82–85, these associations in humans are still under investigation. The human prostate is capable of metabolizing PhIP^86,87, and PhIP–DNA adducts have been detected in prostate tumour tissue^86,88. However, the role that these adducts play in prostate cancer initiation has not been confirmed. Furthermore, meat consumption and PhIP–DNA adducts might influence prostate cancer disparities that exist between African American and European American men. Studies have suggested that African American men might have diets that include higher amounts of red meat and sources of PhIP than European American men⁸⁹. In addition to the make-up of their diet, red meat consumption and PhIP–DNA adduct levels might have different relationships with both the development of prostate cancer and the presence of clinical features associated with aggressive disease^90,91 in African American and European American men.

In addition to diets high in red meat consumption, more than two in three adults in the USA are considered obese or overweight⁹², with substantial evidence suggesting a strong correlation between obesity and prostate cancer aetiology⁹³. However, the association between obesity and prostate cancer in high-risk populations (such as African American men) remains inconclusive. For example, the association of obesity with prostate cancer risk was analysed among participants of the Selenium and Vitamin E Cancer Prevention Trial (SELECT)⁹⁴. Results suggested that the association between obesity and increased prostate cancer risk was stronger among African American men than among non-Hispanic European American men. Notably, although a positive association between obesity and prostate cancer risk was observed in this large prospective study, no substantial difference in rates of obesity has been reported between African American and European American men, according to the Centers for Disease Control and Prevention⁹⁵. Nonetheless, considering the small effort to investigate diet-related effects in African American men⁶⁰, further studies are needed to elucidate the interplay of socioeconomic barriers that affect healthy food choices (for example, neighbourhoods with ‘food deserts’) in relation to prostate cancer development.

The effect of steroid hormones

Epidemiological studies have shown that African American men tend to be more prone to vitamin D deficiency than European American men⁹⁶, and deficient serum vitamin D₃ levels are associated with increased prostate cancer stage, grade and mortality^97–99. At the same time, the association of vitamin D deficiency with prostate cancer risk and incidence remains inconsistent¹⁰⁰. For example, a large, randomized controlled study, the Vitamin D and Omega-3 trial (VITAL), investigated the efficacy of vitamin D supplementation as primary prevention of cancer within a period of 5 years. After 5 years of follow-up, the vitamin D and omega-3 group had the same overall cancer incidence as the placebo group. Conversely, in this study, prostate cancer incidence among African American participants was reduced by 23% (P < 0.07)¹⁰¹, which suggests that further investigation is imperative to elucidate the potential relationship between vitamin D supplementation and prostate cancer risk reduction in African American men.

Vitamin D₃ and vitamin D₃ metabolites (such as calcitriol) are steroid hormones that are essential for normal physiological development, regulation of calcium homeostasis and bone health. Moreover, vitamin D₃ has been extensively studied in in vitro and in vivo preclinical models to elicit anti-tumorigenic effects in many cancers, including prostate¹⁰². For example, in prostate cancer, calcitriol has been shown to inhibit cell cycle progression¹⁰³, inhibit angiogenesis¹⁰⁴, inhibit motility and migration¹⁰⁵, regulate inflammatory and immune responses¹⁰⁶, initiate apoptosis¹⁰⁷ and induce differentiation¹⁰⁸, which suggests that vitamin D is essential in being a suppressive and protective factor during prostate carcinogenesis. However, despite the pleiotropic anti-tumorigenic effects of vitamin D₃ that have been consistently reported, most of the mechanistic studies have been performed in European American-derived cells and tumours from European American men, which might overlook the biological significance of vitamin D transcriptional regulation of signalling pathways that underlies prostate cancer disparities. For example, African American men have been shown to have increased expression of androgen receptor proteins compared with their European American male counterparts¹⁰⁹. Androgens drive cellular growth of prostate cancer cells via androgen receptor-mediated actions, and substantial evidence confirms cross-talk between calcitriol and androgen signalling¹¹⁰. Calcitriol regulates androgen receptor expression to affect cellular differentiation and inhibit growth¹¹¹. Importantly, megalin (encoded by LRP2), an endocytic receptor involved in the process of vitamin D uptake, has an important role in importing testosterone into prostate cells when bound to androgen-binding globulin¹¹². Furthermore, prostatic loss of Lrp2 in mice reduces prostate androgen levels, and vitamin D₃ regulates and suppresses LRP2 expression in prostate cell lines, patient-derived prostate epithelial cells and prostate tissue explants¹¹². These data suggest direct mechanistic links between vitamin D₃ deficiency and prostate cancer disparities observed in African American men, in that LRP2 is part of a compensatory feedback loop to regulate prostatic hormone levels when vitamin D₃ deficiency occurs¹¹². Investigation of vitamin D receptor gene (VDR) genomic functions in African American and European American prostate cancer to assess mechanisms that may contribute to health disparities showed that, in a panel of European American and African American prostate epithelial cells, VDR transcriptional control in the prostate is more potent and dynamic in African American men and significantly regulates inflammatory pathways¹¹³. These data were further supported by a study demonstrating that a short course of vitamin D₃ supplementation led to overexpression of genes associated with immune response and inflammation in African American prostate cancer tumours¹¹⁴. Overall, these data illustrate the importance of further investigation of how vitamin D and vitamin D metabolites regulate mechanisms that underlie carcinogenesis in prostate cancer disparity outcomes.

Research focus has begun to shift to the ‘personalized vitamin D response index’ as an important factor in the success of clinical trials¹¹⁵. This index describes the efficiency of the molecular response to vitamin D₃ supplementation in many human tissues and cell types. Individuals can be classified as either high, mid- or low responders to vitamin D by measuring vitamin D-sensitive molecular parameters. To date, participants in randomized controlled trials have not been stratified into high, mid- and low vitamin D responders, and African American patients can be classified as low responders¹¹⁵. Thus, a better study design that includes a stratification of the participants with an adequate study duration and follow-up could affect the outcomes and conclusions from vitamin D supplementation studies.

Taken together, vitamin D₃ metabolites have vast anti-carcinogenic properties in multiple cancer types. Most mechanistic and/or molecular studies were performed using European American prostate cancer cells and tumours. Given that African American men tend to be more vitamin D₃ deficient than their European American counterparts, increasing studies investigation of transcription regulation of signalling pathways by vitamin D in prostate cancer cells and tumours derived from African American patients will aid elucidation of novel pathways for therapeutic intervention to mitigate prostate cancer disparities.

The effect of glucocorticoid receptor signalling

The emerging role of glucocorticoid receptor signalling in prostate cancer progression is problematic for African American men, as an enhanced physiological response to glucocorticoids has been shown in this population¹¹⁶. Glucocorticoid receptor signalling is triggered by various biological and environmental factors with cumulative negative physiological consequences over time¹¹⁷. Chronically elevated cortisol levels, increased glucocorticoid receptor gene (NR3C1) expression and sustained glucocorticoid receptor signalling in African American men have been partially attributed to cumulative psychosocial stress². Specifically, hyperactive glucocorticoid receptor signalling induces local lasting changes in DNA methylation, which shapes subsequent responses to glucocorticoid exposure and accelerates epigenetic ageing associated with cancer^118,119. The complex interplay between enhanced glucocorticoid receptor signalling and other socioeconomic and genetic factors that increase the occurrence of lethal prostate cancer in African American men might promote an aggressive tumour phenotype as well as increased resistance to standard therapies². This sustained glucocorticoid receptor signalling in African American men is problematic, as glucocorticoids are an integral component of many prostate cancer treatment regimens.

The cellular and pharmacological action of glucocorticoids is mediated primarily by the glucocorticoid receptor and has genomic and non-genomic cellular effects. Glucocorticoid receptor has emerged as a major driver of prostate cancer progression and resistance to prostate cancer treatments, including hormone therapy, chemotherapy and radiotherapy². NR3C1 overexpression has been identified in hormone-resistant prostate cancer tumours and patient biospecimens^120,121. Glucocorticoid receptor has been hypothesized to drive worse prognosis by bypassing the androgen receptor signalling pathway and directly activating androgen receptor target genes associated with worse prognosis¹²⁰. Additionally, liganded glucocorticoid receptor has been shown to induce the upregulation of clusterin (CLU) and lens epithelium-derived growth factor of 75 kDa (LEDGF/ (also known as PSIP1) p75), stress oncoproteins associated with chemoresistance in African American prostate cancer cells¹²². Overall, clinicians and researchers must consider the possibility of differential responses to prostate cancer treatments, including glucocorticoids, in African American men.

The effect of tumour microenvironment and inflammation

The microenvironment of the prostate gland has important effects on the aetiology of prostate cancer progression and clinical outcome, which might contribute to racial disparities observed in prostate cancer outcomes. Studies indicate that insult to the prostate induces cellular stress that leads to immune upregulation and sustained inflammation, which are established hallmarks of carcinogenesis¹²³. Histological and clinical data confirm increased innate and adaptive immune responses, which might lead to a sustained pro-inflammatory cascade response that contributes to the onset and progression of cancer by altering the stromal phenotype leading to increased ECM remodelling and initiating epithelial–mesenchymal transition (EMT)¹²⁴.

Although strong evidence suggests that TME immunomodulatory and pro-inflammatory signalling contribute to prostate carcinogenesis and aggression, very few studies have been performed to investigate differences in the TME that might potentially underlie prostate cancer disparities observed between African American and European American men^125,126. For example, a study of differential gene expression associated with tumour tissue and adjacent ECM showed that 35% of significant pathways (P < 10⁻³) were associated with EMT, whereas 25% were associated with immune response genes (especially those encoding IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-13, IL-15 and IL-22) in African American men¹²⁷. Interestingly, most differentially expressed genes were associated with stromal tissue rather than tumour-specific tissue. Signalling mediators of EMT differences in tissue reveal potential prostate cancer biomarker genes such as phosphoserine phosphatase (PSPH) and crystallin-β B2 (CRYBB2) and highlight tumour-adjacent ECM and stromal influence in prostate carcinogenesis for African American men¹²⁷. Thus, data suggest that altered immune regulation and EMT processes might be causative for development of aggressive prostate cancer in African American men. Significant differences in immunomodulatory and pro-inflammatory signalling have also been reported in tumours isolated from West African men compared with European American men. In this study, 559 genes were differentially expressed in West African men compared with European American men (377 upregulated and 182 downregulated genes, false discovery rate (FDR) <0.05; fold change ≥0.1). Enrichment analysis showed a considerable increase in pro-inflammatory and immunoregulatory pathways, including cytokine signalling, interleukins and interferon-γ response in tumours from West African men¹²⁸. Furthermore, increased expression of enhancer of zeste homologue 2 (EZH2), a known transcriptional regulator involved in modulation of the tumour immune microenvironment through the epigenetic machinery, was also observed in tumours from West African men¹²⁸. Thus, the active immune microenvironment observed in West African men explains why men of African descent respond favourably to immunotherapies^129,130. An investigation of the function of fibroblasts isolated from prostate cancer tissue in both African American and European American men demonstrated several characteristics unique to African American-derived cells¹³¹. They observed that the African American-derived prostate cancer cell line, E006AA, had increased tumorigenicity in the presence of fibroblasts from African American men, and that pro-inflammatory paracrine mediators (BDNF, CHI3L1, DPPIV, FGF7, IL-18BP, IL-6 and VEGF) were all increased in African American-derived fibroblasts¹³¹. Unfortunately, further investigation and validation of these results are needed as the E006AA cell line was erroneously misclassified by race and disease type.

Taken together, African American men are disproportionately burdened by more-aggressive prostate cancer, resulting in a prostate cancer mortality rate twice that of European American men. Emerging data have demonstrated that the TME is an important key contributor to prostate carcinogenesis and aggression and a determinant of clinical outcomes. Moreover, the interaction between prostate cancer cells and surrounding TME components (immune, vascular and stromal) is being studied to understand its broader roles in pathobiology and disease manifestation. Thus, studies that involve large datasets from diverse patient populations would provide more strengths to TME differences and their association with clinical outcomes, especially for high-risk under-represented populations.

The potential of race-stratified clinical trials

African American men diagnosed with prostate cancer are more likely to experience poorer prognoses linked to a delay in treatment administration^132,133; however, timely exposure to treatment can reverse this trend of worse outcomes. Clinical trials report that African American men responded better than other men to several treatment options for advanced prostate cancer. Longer median overall survival was reported in African American men treated with sipuleucel-T for metastatic castration-resistant prostate cancer compared with European American men¹³⁴. In addition, longer overall survival was reported in African American men treated with docetaxel plus prednisone compared with other men despite the younger age, worse performance status, higher testosterone, higher PSA and lower haemoglobin described within this population¹³⁵. In a separate study, African American patients experienced longer median PSA progression-free survival as well as increased rates of PSA decline compared with other men¹³⁶. These reported results highlight a remarkable opportunity to further define the mechanisms that drive differences in treatment outcomes for African American men with prostate cancer.

Despite the advances in these few studies, few data exist from African American men with advanced prostate cancer. Yet, without these race-stratified clinical trials, these improved therapeutic responses would remain unknown and could provide no positive effect on public health¹³⁷. Race-stratified clinical trials are necessary to fully analyse and improve therapeutic responses for all men with prostate cancer. Inadequate diversity in clinical trial enrolment limits the ability of under-represented patients to access cutting-edge treatment options^138,139. We recognize that race embodies social and cultural constructs, and racial classification remains extremely useful for describing health outcomes as most data are reported by self-identified race^137,140,141. Some groups have reported the concept of race-stratified clinical trials to be ‘racist’¹⁴². However, the definition of ‘racist’ is to show prejudice, discrimination or antagonism against a person or people on the basis of their membership of a particular racial or ethnic group, typically one that is a minority or marginalized. For this reason, it is difficult to justify a classification of ‘racist’ towards an intentional inclusion of a minority and marginalized population. Instead, the repeated exclusion of African American men would more appropriately fit this classification. The implementation of race-stratified clinical trials is a strategic attempt to rectify the racist status quo. We do not endorse the non-enrolment or exclusion of non-African American study participants, instead a priori increases in study size are necessary to assess the same desired effect as a study not using such subgroup analyses. We also recommend that for studies that are limited to recruiting a set number of patients, the expected effect size must be increased to conduct race-based subgroup analyses.

To create a platform for precision clinical trials of target therapies, we need to develop thorough assessments of genetic factors, molecular subpopulations and risk profiles. Although race and ethnicity are self-reported sociocultural concepts, human genetic variation is continuous and structured more within than between populations. For these reasons, race-stratified clinical trials should always analyse genetic ancestry within the experimental design.

Because health disparities have not historically been prioritized in the scientific mainstream, a deficiency in diverse enrolment in clinical trials has been previously normalized¹⁴³. Apathetic research efforts coupled with an absence of mandated accountability has resulted in less-rigorous standards in prostate cancer clinical trials that would be unacceptable in trials for diseases that do not report disparate outcomes by race or ethnicity. Missing genetic variants in clinical trials runs the risk of incorporating inapplicable effect sizes and drug dose estimates. Data from a study that investigated the disparity of race reporting and representation in clinical trials leading to cancer drug approvals revealed that one-third of clinical trials leading to approval of new drugs failed to report on the race and/or ethnicity of trial participants^6,137.

The barriers to clinical trial enrolment are many and include access to health care and education, communication gaps and medical mistrust¹³⁷. Given the history of intentional medical victimization of African Americans in the USA, a logical extension of medical mistrust remains for many individuals. Sensitive and strategic initiatives to advance inclusive research are needed to increase clinical trial participation by minority individuals. Successful tactics have included increased funding to encourage inclusive, experimental study design as well as financial incentives to reduce the financial toxicity of trial participation for enrolled patients¹³⁷.

Conclusions

This Review focuses on highlighting the complex interplay of modifiable risk factors that we deemed important and influential to the contribution of prostate cancer disparities in African American men. The mitigation of prostate cancer disparities cannot be fully resolved without addressing systemic, structural and racial health inequalities, which go beyond the scope of this Review.

The potential for improved survival outcomes in African American men with prostate cancer is highly dependent upon substantial efforts to design and execute race-stratified clinical trials and address social determinants of health for underserved populations. Additionally, given the concomitant vitamin D deficiency of African American men suffering disproportionately from prostate cancer risk and mortality, increasing vitamin D levels in African American men via dietary supplementation could mitigate the prostate cancer disparity gap and elucidate novel pathways for therapeutic intervention. By ensuring the diverse accrual of African American study participants, high-risk patients will experience real-time benefits by receiving innovative therapies. Furthermore, treatment plans optimized for different racial groups will shift into standard clinical practice upon trial completion. The advance of precision and personalized medicine is contingent upon thorough assessments of risk factors in race-stratified clinical trials. Without adequate inclusion of African American men, disparities in outcomes will persist and worsen.

Key points.

• Current data emphasize the need for the United States Preventive Services Task Force (USPSTF) to re-evaluate their guidelines by recommending prostate cancer screening in high-risk populations to attenuate the upward trends of prostate cancer fatalities and reduce disparities.

• 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhiP)–DNA adducts can facilitate mutagenesis that may result in tumorigenesis. Data suggest that African American men might have diets that include higher amounts of red meat and sources of PhiP than European American men, contributing to the prostate cancer disparities observed.

• Vitamin D deficiency has been shown to be associated with aggressive prostate cancer and mortality, especially in African American men. Elucidating vitamin D signalling pathways that underlie prostate carcinogenesis might aid mitigation of prostate cancer disparities between African American and European American men.

• Glucocorticoid receptors have emerged as a major driver of prostate cancer progression and resistance to treatments. Clinicians must consider the possibility of differential responses to prostate cancer treatments, including glucocorticoid treatments in African American men.

• Increasing the number of studies investigating immunity and inflammatory regulation in prostate tumours and adjacent tumour microenvironment is imperative for high-risk under-represented populations.

• Sensitive and strategic initiatives to advance inclusive research are needed to increase clinical trial participation by minority individuals.