Obesity, height, and advanced prostate cancer: Extending current evidence toward precision prevention

Growing evidence suggests that the risk of advanced or fatal prostate cancer is higher among men who are taller or have greater body fat, usually assessed by body mass index (BMI) as a measure of total adiposity or waist circumference as a measure of central adiposity.[1–3] However, relative risk estimates have been inconsistent across studies, possibly due to differences in assessments of anthropometry, definitions of aggressive disease, or analytic approaches. Further, the precision of estimates is limited when the goal is to evaluate these associations within subgroups of men or tease apart independent associations for adiposity measures.

In this issue of Annals of Oncology, Genkinger et al. undertook a pooled analysis to address these limitations.[4] Using individual-level data from 15 cohorts within The Pooling Project of Prospective Studies of Diet and Cancer, the investigators harmonized exposures, outcomes, covariates, and analytic approaches, minimizing these potential sources of variation across studies. The global cohorts included participants from the U.S., Europe, Japan, and Australia, providing an opportunity to investigate anthropometry and prostate cancer across diverse populations. The authors identified that taller height and greater baseline BMI and waist circumference (primarily in mid-to-late life), but not early adulthood BMI, were positively associated with risk of advanced, high-grade, and/or fatal prostate tumors. The associations between waist circumference and clinically relevant prostate cancer persisted with additional adjustment for BMI, providing support for central obesity as an independent risk factor. A unique feature of the study was the large number of men with advanced and fatal prostate cancer, which is a considerable strength over prostate cancer epidemiological studies to date.

While the study highlights the value of harmonizing and integrating evidence across settings, it is important to consider three challenges. First, there was a wide range of age at baseline across the cohorts (18–97 years), although the investigators report that most participants were in mid-to-late life. Baseline BMI may have varying utility as a measure of adiposity across this spectrum of age (due to the loss of lean body mass with age),[5] and the measure of BMI change from early adulthood (age 18–21) to baseline (age 18–97) spans different time periods for different participants. Second, early adulthood BMI was evaluated as a pre-baseline exposure. Unhitching exposure assignment from baseline in this way may contribute to a selection of men who were overweight before baseline and remained at risk and under follow-up at baseline. Third, the authors were unable to directly evaluate associations of anthropometry independent of prostate-specific antigen (PSA) screening, a key predictor of advanced and fatal disease, although they conducted sensitivity analyses to partially address this.

The findings from Genkinger et al., together with existing evidence on anthropometric measures and clinically relevant prostate cancer, serve as a solid foundation for further research aimed at driving a precision approach to prostate cancer prevention. First, emerging evidence suggests that the specific distribution of body fat may help to improve the identification of men at high risk of aggressive disease over measures of BMI alone. In a cohort of 1,832 Icelandic men with measured body fat distribution on computed tomography imaging, the accumulation of fat in specific body regions, such as the visceral and thigh subcutaneous depots, was associated with risk of advanced and fatal prostate cancer.[6] Moreover, the associations for visceral fat were stronger among men with a lower BMI. These findings, coupled with Genkinger et al.’s identification of waist circumference as a risk factor for aggressive disease independent of BMI, may help to direct further research on whether a man’s unique pattern of body fat distribution can be used to better define his risk.

Second, it is unclear whether these anthropometric measures mark factors that may act locally to “seed” an aggressive tumor or systemically to fuel the “soil” for metastatic growth.[7] For example, obesity is associated with unique somatic alterations in prostate tumors, and men with these alterations are at a higher risk of lethal disease.[8] Moreover, bone is the primary site of prostate cancer metastasis, and adipocytes, which accumulate in the bone marrow, may prime this metastatic niche for enhanced growth.[9] A deeper understanding of these biological processes could help to identify appropriate targets for the prevention of prostate carcinogenesis and progression.

Third, a key question is how men can best act on knowledge of their higher risk to prevent prostate cancers that are potentially fatal. The observed associations between anthropometric measures and aggressive disease may help to identify men at a higher risk, but they do not support any specific intervention to reduce risk.[10] Attained height is not modifiable, but marks genetic and early life environmental, hormonal, and nutritional factors affecting growth that may also play a role in the etiology of advanced disease.[3, 11] Obesity is potentially modifiable, but there are many ways to intervene on BMI (e.g., physical activity, diet, or a combination of the two) that may each have a different effect on prostate cancer outcomes. This is the case even for interventions that lead to the same BMI in a given person, because each intervention may have direct effects on prostate cancer not mediated through body weight. Given the accumulation of evidence flagging men with obesity as a high-risk group, future research efforts may shift to identifying the optimal type, intensity, and timing of energy balance strategies to reduce the risk of clinically relevant prostate cancer. These studies will require high-quality repeated measures of lifestyle and clinical features, a long duration of follow-up given the long natural history of prostate cancer, and rigorous consideration of causality, including potential confounding by subclinical disease (i.e., reverse causation).[12]

In summary, strong evidence has accumulated for height and measures of body fat as risk factors for aggressive prostate cancer. Building on this, further predictive analyses of directly measured fat distribution may sharpen our view of who is at the highest risk, and causal analyses of precisely defined energy balance strategies may help to identify targeted prevention strategies that minimize risk by getting the right interventions to the right men at the right time.