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. Author manuscript; available in PMC: 2018 Jul 1.
Published in final edited form as: Eur Urol. 2016 Oct 19;72(1):78–83. doi: 10.1016/j.eururo.2016.10.011

Obesity and Prostate Cancer: A Focused Update on Active Surveillance, Race, and Molecular Subtyping

Adriana C Vidal 1,*, Stephen J Freedland 1
PMCID: PMC5397380  NIHMSID: NIHMS822645  PMID: 27771128

Abstract

Context

In 2012, we published a detailed review on obesity and prostate cancer. Since then, new studies have brought further understanding regarding the role of obesity in selecting active surveillance candidates, and differing associations between obesity and prostate cancer as a function of race and molecular subtype of prostate cancer.

Objective

To review new manuscripts on these new concepts for which there were limited data before 2012.

Evidence acquisition

A PubMed search from July 2012 to March 2016 was performed using the terms “prostate cancer” and “obesity”. Of 450 articles, we included 15 related to these three topics.

Evidence synthesis

Among men on active surveillance or candidates for active surveillance, multiple studies suggest that the risk of upgrading is higher for obese men. No study has shown long-term oncologic differences, and the risk of prostate cancer mortality remains low. One study suggested that the link between obesity and prostate cancer risk is stronger among black men; however, other studies found that obesity is correlated with aggressive disease regardless of race. Two studies found that the associations between obesity and prostate cancer (ie, fewer low-grade cancers and yet more aggressive cancers) was limited to men with TMPRSS2-ERG-positive tumors.

Conclusions

The past 4 yr has seen much new work on the obesity-prostate cancer link. If confirmed in other studies, these findings provide novel insights into not only the link between obesity and prostate cancer but also prostate cancer biology in general.

Patient summary

While their outcomes may be slightly worse, obese men with localized prostate cancer should not be discouraged from active surveillance. Early studies suggest there may be subtypes of patients in whom obesity is more strongly linked to aggressive disease.

Keywords: Prostate cancer, Obesity, Active surveillance, Race, Molecular subtype of prostate cancer

1. Introduction

In 2013, we published a detailed review of the associations between obesity and prostate cancer [1]. In that review we concluded that: (1) obesity is linked to the incidence of aggressive prostate cancer, including prostate cancer–specific mortality; (2) obesity is associated with a lower risk of overall prostate cancer; and (3) the molecular mechanisms linking obesity and prostate cancer have not been fully elucidated. Thus, a better understanding of the mechanisms linking prostate cancer and obesity is needed. Since the publication of our review, several new observations have come to light that have further refined our understanding of the link between these common conditions and in turn provided some interesting insights into prostate cancer biology in general. Thus, our goal in this study was not to perform a new systematic review, but rather to review the link between prostate cancer and obesity, primarily focusing on publications related to three new concepts that have emerged in the past 3 yr: (1) the association between obesity and active surveillance candidates; (2) differing associations between obesity and prostate cancer as a function of race; and (3) differing associations between obesity and prostate cancer as a function of the molecular subtype of prostate cancer.

2. Evidence acquisition

Studies on the association between obesity and prostate cancer risk have been on the rise since 1991 (Fig. 1). Our previous review covered a PubMed search for relevant articles linking obesity and prostate cancer published between 1991 and July 2012 [1]. From July 2012 to March 2016, 450 articles covering this field were published (Fig. 2). From these, we excluded 274 articles that were not relevant articles on the basis of their titles, and reviewed the abstracts of the remaining 176 studies. Our primary goal was not to highlight all new published papers, but rather papers that presented new ideas, not simply validating concepts discussed in our prior review [1]. In reviewing these papers, our opinion was that three new concepts emerged for which there were limited if any data before 2012: (1) the role of obesity in selecting active surveillance candidates; (2) differing associations between obesity and prostate cancer as a function of race; and (3) differing associations between obesity and prostate cancer as a function of the molecular subtype of prostate cancer. For papers that discussed these three new concepts, we also reviewed the reference list for any potential papers before 2012 that may have relevance to the three topics. In total, we identified 15 articles that, in our opinion, addressed these three topics.

Fig. 1.

Fig. 1

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For the search terms obesity and prostate cancer, the number of PubMed publications has been increasing since 1991.

Fig. 2.

Fig. 2

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Flow diagram for the search results.

3. Evidence synthesis

3.1. Obesity and active surveillance

Since our group first reported the adverse effects of obesity among patients with low-risk prostate cancer treated with radical prostatectomy [2], several studies have suggested that obese men who were eligible for active surveillance (generally defined as Gleason <7, prostate-specific antigen [PSA] <10 ng/ml, T1c/T2c, and ≤2 positive cores) but chose to undergo radical prostatectomy were more likely to experience upstaging and upgrading than comparable men of normal weight [3–5]. However, by only looking at men treated with radical prostatectomy, this may have created a bias (ie, those with the lowest risks did not proceed to radical prostatectomy). Thus, while these data suggest that obese men undergoing active surveillance are more likely to harbor occult aggressive disease, this was untested until recently.

The association between obesity and active surveillance outcomes was directly tested in a recent study of 565 men diagnosed with low-risk prostate cancer (clinical stage T1c/T2a, Gleason <4, ≤3 positive cancer cores, and no core with >50% cancer involvement) who underwent active surveillance. A total of 22% were obese (body mass index [BMI] ≥30 kg/m2) and 51% were overweight (BMI 25–29.9 kg/m2). Men were followed every 3–6 mo with PSA measurement and digital rectal examination, and all underwent a confirmatory biopsy at 12 mo [6]. The authors examined two primary outcomes: pathologic progression, defined as no longer meeting active surveillance criteria on biopsy, and therapeutic progression, defined as intent to initiate definitive treatment. On confirmatory biopsy at 12 mo, obesity was not associated with pathologic or therapeutic progression, or reclassification defined as upgrading/upstaging. However, during follow-up after the confirmatory biopsy and after accounting for differences between the groups at baseline, obesity was associated with a 50% higher risk of pathologic progression (p = 0.02) and a 40% higher risk of therapeutic progression (p = 0.05). The Kaplan-Meier curves for progression did not separate until approximately 18 mo after diagnosis. Thus, the study showed that obesity did not predict immediate upgrading, but rather long-term progression.

While all of these studies contribute to a general consensus that obesity may predict poorer outcomes on active surveillance, the active surveillance study, which found no association between obesity and upgrading at initial confirmatory biopsy, is at odds with prior studies showing that obese men were more likely to experience upstaging and upgrading at the time of radical prostatectomy (ie, reclassification). However, as obesity is known to be associated with larger prostate volumes and greater growth in prostate volume over time [7], it is possible that larger prostate size made detection of higher-grade tumors more difficult in the active surveillance study. If true, this would suggest that obesity may in fact be correlated with both immediate upstaging/upgrading and progression over time. Such a hypothesis is supported by a recent study [8] that showed that among men undergoing radical prostatectomy, obesity was linked to a greater likelihood of detectable postoperative PSA (ie, more advanced disease at diagnosis). However, even among those with undetectable ultrasensitive PSA values, obesity predicted risk of PSA progression over time (ie, progression even in a “low-risk” cohort).

While the data to date suggest that obesity portends a greater risk of progression among men undergoing active surveillance, and we believe that this should be communicated to obese men, it is our opinion that obese men with low-risk prostate cancer should not be discouraged from active surveillance. First, obesity is a well-established risk factor for overall mortality. Thus, given that obese men have shorter life expectancy than other men, these men may in fact be ideal candidates for active surveillance. Second, some studies suggest that obesity is a risk factor for poorer quality-of-life outcomes after prostate cancer treatment [9], again arguing for a less aggressive treatment course. Finally, given that the risk of prostate cancer death is very low among men who are candidates for active surveillance, even if the risk of prostate cancer death were higher (which has not been shown), the overall risk of death from other causes far exceeds the risk of death from prostate cancer. As we need to continue the mantra of “do no harm”, obesity should not be used as an exclusion criterion for active surveillance.

3.2. Obesity and prostate cancer risk by race

While it is generally thought that obesity increases the risk of high-grade disease but perhaps lowers the risk of low-grade disease [1], a recent paper suggested such associations may vary by race. If true, this is an important observation in that although obesity affects white and black men equally, prostate cancer is particularly burdensome for black men, who have a 67% higher rate of prostate cancer and more than double the risk of prostate cancer death in comparison to white men [10].

The paper that suggested the obesity-prostate cancer link may vary by race was a post hoc analysis of the Selenium and Vitamin E Cancer Prevention (SELECT) trial, which included 26 071 men (3398 black men) [11]. Consistent with many prior studies as reviewed in our previous review [1], the authors found that among white men, obesity was positively associated with high-grade disease (hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.90–1.97; p = 0.01 for trend) but inversely associated with low-grade prostate cancer (HR 0.80, 95% CI 0.58–1.09; p = 0.02 for trend). However, among black men, obesity was positively associated with both low-grade (HR 2.22, 95%CI 1.17–4.21; p = 0.05 for trend) and high-grade disease (HR 1.81, 95% CI 0.79–4.11; p = 0.02 for trend). Moreover, although obesity was associated with high-grade disease in both white and black men, the association was much stronger in black (81% higher risk) than in white men (33% higher risk) [11]. These data are supported by an analysis of the National Health and Nutrition Examination Surveys (NHANES), which included 3152 men without prostate cancer (625 black men) and used elevated PSA (>4 ng/ml) as an endpoint for assessing prostate cancer risk. The study found that while obesity was associated with a 46% lower likelihood (p = 0.02) of having abnormal PSA among white men, obesity was linked to a higher likelihood of having abnormal PSA among black men, although this association was not significant (p = 0.11) [12]. Finally, three other studies deserve mention [13–15]. Before discussing the papers, it is important to note that all three studies included men with prostate cancer and examined predictors of either high-grade disease [14] or recurrence after surgery [13,15] as opposed to the studies discussed above, which focused on predictors of having versus not having prostate cancer. Despite these differences in study design, all the studies found either obesity itself or factors correlated with obesity (visceral fat and serum cholesterol) were only correlated with aggressive prostate cancer in black men and not white men. Thus, these papers lend further credence to the hypothesis that the link between obesity and prostate cancer may differ by race, with obesity more strongly linked to prostate cancer in black men.

However, before accepting the hypothesis that obesity influences prostate cancer risk differently in black men, t should be noted that previous case-control studies found that associations between obesity and prostate cancer did not differ by race [16,17]. Moreover, a recent large study of the Multiethnic Cohort, which included 19 833 white, 9284 black, 23 867 Japanese American, 16 958 Latino, and 5454 Native Hawaiian men, found no statistical differences in the association between BMI and prostate cancer risk across the racial/ethnic groups [18]. Although this Multiethnic Cohort study did not separate results by disease grade, the data from SELECT suggest that obesity should be positively linked to overall prostate cancer risk in black men, as obesity was linked to both low-grade and high-grade disease. However, in the Multiethnic Cohort, obesity was not linked to prostate cancer risk in black men, refuting the SELECT findings. Finally, another study examining men with prostate cancer also found that obesity was equally linked to recurrence after surgery, regardless of race [19].

In summary, over the last few years, multiple papers have suggested that either obesity or factors associated with obesity are more strongly linked to aggressive prostate cancer in black men. While these results are potentially very important, other studies found that obesity affects aggressive prostate cancer equally, regardless of race. Thus, further research is needed before firm conclusions can be drawn regarding whether associations between obesity and prostate cancer vary by race.

3.3. Obesity and prostate cancer as a function of the molecular subtype of prostate cancer

Separate from studies on obesity, it is increasingly clear that prostate cancer is molecularly heterogeneous. Thus, simply viewing “prostate cancer” as a single entity may not be appropriate. To this end, investigators have begun to ask whether the link between obesity and “prostate cancer” may vary depending on the molecular subtype of prostate cancer. One of the most common genetic mutations in prostate cancer is a gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor gene family [20]. Of all the ETS family members, ERG is the most common fusion partner for TMPRSS2 [20], and the TMPRSS2:ERG gene fusion occurs in approximately 50% of prostate cancers [21]. Determining their presence may identify not only the particular molecular subtype of prostate cancer [21] but also its influence on the effect of obesity on prostate cancer outcomes [22].

It has recently been reported that the association between obesity and prostate cancer is modified by TMPRSS2-ERG tumor subtype. Using data from a large prospective study of prostate cancer patients (n = 1243, 92% white) from the Physicians’ Health Study Professionals Follow-Up study, the authors found that obesity predicted poorer outcomes among men whose tumors had the TMPRSS2-ERG gene fusion, but not among men who did not have the gene fusion. [20]. Specifically, the authors found positive associations between both generalized obesity and central obesity and the risk of prostate cancer metastases and death (lethal disease) in men with TMPRSS2-ERG-positive tumors, but not among obese men with TMPRSS2-ERG-negative tumors [20]. Among 119 men who developed lethal disease during 12.8 yr of follow-up, each 5-unit increase in BMI before diagnosis in men with TMPRSS2-ERG-positive tumors was associated with a higher risk of lethal disease (HR 1.48, 95% CI 0.98–2.23). In addition, each 8-inch increase in waist circumference before diagnosis increased the risk of lethal disease (HR 2.51, 95% CI 1.26–4.99) among men with TMPRSS2-ERG-positive tumors. However, among men with TMPRSS2-ERG-negative tumors, obesity was unrelated to prostate cancer outcomes (HR 1.14, 95% CI 0.62–2.10 for BMI, p = 0.09 for interaction; HR 0.78, 95% CI 0.52–1.19 for waist circumference).

Furthermore, the study also found that TMPRSS2-ERG-positive tumors had higher expression levels of insulin receptor (IR), IGF-1R, and fatty acid synthase compared to TMPRSS2-ERG-negative tumors [20]. If confirmed, this may explain why obesity, which is associated with higher serum insulin and IGF-1 levels, correlated with poor outcomes for men with fusion-positive tumors in comparison to men with fusion-negative tumors.

Another recent analysis of two population-based case-control studies that included 2208 men investigated the relationship between obesity and prostate cancer risk by TMPRSS2-ERG subtype [22]. Although the authors found a differential association between obesity and risk of prostate cancer according to tumor TMPRSS2-ERG status, obesity (highest vs lowest BMI quartile) was inversely associated with prostate cancer risk among men with TMPRSS2-ERG-positive prostate cancer (odds ratio 0.66, 95% CI 0.45–0.97). Thus, the more obese a man was, the lower was his risk of TMPRSS2-ERG-positive prostate cancer. However, as in the above-mentioned study, among men with TMPRSS2-ERG-negative tumors, no association between obesity and prostate cancer risk was found [22]. It is worth noting that even though analyses in the latter study were not stratified by prostate cancer grade, the majority of the patients had low-grade prostate cancer (Gleason ≤6, ~44–55%) and pathologic stage T2 (~68–69%) [22]. Hence, these results are in accordance with findings that obesity is associated with lower risk of low-grade prostate cancer. Now we may have a biological explanation for why not all studies have agreed on these findings. The authors concluded that lower circulating levels of androgens in obese men may partly contribute to the lower risk of developing androgen-positive TMPRSS2-ERG tumors among men with the highest BMI.

Even though more studies are needed to confirm both results, what is interesting is that although the two studies have apparently discrepant findings (lower risk of low-grade cancer, but more lethal cancers), it should be noted that this is generally the association between obesity and prostate cancer: fewer low-grade lesions and more high-grade lesions [1]. Thus, it is very interesting that both studies found that (1) these associations were limited to TMPRSS2-ERG-positive tumors and (2) the associations between lower risk of low-grade disease and greater risk of prostate cancer death among men with TMPRSS2-ERG-positive tumors were stronger than the associations seen among all men (ie, regardless of TMPRSS2-ERG fusion status). In other words, the lack of association between obesity and the risk of developing prostate cancer or outcomes among men with TMPRSS2-ERG-negative tumors dilutes the quite strong associations between obesity and TMPRSS2-ERG-positive tumors. Beyond TMPRSS2-ERG fusion, another common genetic finding in prostate cancers is silencing of PTEN [23]. From a clinical perspective, loss of PTEN predicts poor outcome [24–26]. From a biological standpoint, PTEN loss leads to constitutive activation of PI3 kinase. This is important because this is the same kinase that is activated by insulin and IGF-1. Thus, if PI3 kinase is always activated, it stands to reason that alterations in insulin levels (ie, those accompanying obesity or weight loss) would have no effect on tumor growth. In fact, a recent study found that caloric restriction (ie, weight loss, or reversing obesity) slowed tumor growth across multiple animal models, but not tumors in which PTEN was lost [27]. Whether obesity directly influences PTEN-negative tumors is not known; however, on the basis of the one animal study, we would predict that obesity (or weight loss) does not affect tumor outcomes in men harboring a prostate cancer with PTEN loss, although this requires further study.

4. Conclusions

Over the past few years, three new questions have been addressed regarding the link between obesity and prostate cancer. (1) Is active surveillance safe for obese men? (2) Does the association between obesity and prostate cancer differ by race? (3) Does the association between obesity and prostate cancer differ by the molecular subtype of prostate cancer? Despite a suggestion that their oncologic outcomes may be slightly worse, obese men with prostate cancer should continue to be offered active surveillance as a management option, given that the risk of competing mortality is higher in obese men than in men of normal weight. Although one study suggested that the link between obesity and prostate cancer risk is stronger among black men, given contradictory data, more studies are needed to better assess this intriguing suggestion. Finally, as the molecular heterogeneity of prostate cancer is being better understood, early studies suggest that obesity may only affect TMPRSS2-ERG-positive tumors. If confirmed in other studies, this provides exciting novel insights into not only the link between obesity and prostate cancer but also prostate cancer biology in general. Collectively, these studies, although early, suggest that obesity may be more strongly linked to prostate cancer in certain subsets of patients (ie, black men and those with TMPRSS2-ERG-positive tumors).

Obese men with localized prostate cancer should not be discouraged from active surveillance management. TMPRSS2-ERG-positive prostate cancer tumors in obese men predicting higher risk of aggressive disease provide novel insights into the link between obesity and prostate cancer.

Acknowledgments

Funding/Support and role of the sponsor: This work was supported by the National Institutes of Health. The sponsor played no direct role in the study.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Author contributions: Adriana C. Vidal had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Vidal, Freedland.

Acquisition of data: Vidal, Freedland.

Analysis and interpretation of data: Vidal, Freedland.

Drafting of the manuscript: Vidal, Freedland.

Critical revision of the manuscript for important intellectual content: Vidal, Freedland.

Statistical analysis: None.

Obtaining funding: Freedland.

Administrative, technical, or material support: None.

Supervision: Vidal, Freedland.

Other: None.

Financial disclosures: Adriana C. Vidal certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

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