Body Fat Distribution Points to Prostate Cancer Aggressiveness

Liam Davenport

June 13, 2019

Body fat distribution may be related to prostate cancer aggressiveness. Men with high levels of visceral fat have an increased risk of developing advanced prostate cancer, while those with increased subcutaneous fat in the thigh are more likely to die from the disease, suggests an analysis of prospective data from Iceland.

Barbra A. Dickerman, PhD, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, and colleagues studied more than 1800 Icelandic men who were followed up for up to 13 years after a comprehensive medical exam.

While increases in body mass index (BMI) and waist circumference were, as expected, associated with a significant increased risk of both advanced and fatal prostate cancer, the accumulation of fat in specific areas also influenced the risk.

The researchers found that each unit increase in visceral fat was associated with a 31% increased risk of advanced prostate cancer, while a unit increase in subcutaneous thigh fat increased the risk of fatal prostate cancer by 37%.

Notably, the association between visceral fat and advanced and fatal prostate cancer was significant only in men with a lower BMI.

The findings, which were published in Cancer on June 10, underline the imprecise nature of BMI and waist circumference when examining the relationship between adiposity and disease risk, say the authors.

"Studies of BMI or waist circumference alone may not capture important subphenotypes, and this may explain the heterogeneity of previous findings for obesity and prostate cancer," they write.

Calling for prospective studies of fat distribution and prostate cancer outcomes, they say that identifying "the adiposity phenotypes at highest risk of clinically relevant prostate cancer may help to elucidate the mechanisms linking obesity with aggressive disease and target intervention strategies."

Dickerman told Medscape Medical News that, although the study has a number of strengths, including the complete and reliable data and the long follow-up, the participants being exclusively older, white men means that the results "may not be generalizable to younger, more diverse groups."

Nevertheless, the findings highlight that measuring BMI alone may "miss" high-risk patients, and they "open up new directions for future research to investigate how measures of fat distribution can be integrated clinically to inform targeted prevention and treatment strategies."

Dickerman added that the finding of a stronger association between visceral fat and advanced prostate cancer in men with a lower BMI requires "further investigation."

She said: "It is possible that higher visceral fat may be a marker for an underlying physical activity pattern or hormonal milieu that influences both fat distribution and risk of advanced disease. For example, fat may be preferentially deposited in the visceral depot among leaner men in the presence of a particular hormonal milieu."

Dickerman continued: "If this hormonal milieu is also a risk factor for advanced prostate cancer, this may partially explain the results of our analyses stratified by BMI."

Analyzing Body Fat Distribution

Obesity measures such as BMI and waist circumference have been consistently associated with an increased risk of advanced prostate cancer and a poorer prognosis.

However, there is increasing evidence that body fat distribution may be an important prognostic risk factor for prostate cancer outcomes.

The authors note that this may reflect differences in metabolic, hormonal, and inflammatory markers between fat locations.

For example, visceral fat is associated with proinflammatory cytokines and inversely associated with bioavailable testosterone, while intramuscular fat in the thigh is linked to worse glucose tolerance.

To examine the role of body fat distribution in prostate cancer risk, the researchers studied data from the Age, Gene/Environment Susceptibility-Reykjavik study, wherein a random sample of participants underwent comprehensive medical examinations between 2002 and 2006.

Excluding participants with a history of cancer, those without complete computed tomography data, and those with a BMI < 18.5 kg/m2, the team were left with 1832 men.

The Icelandic Cancer Registry was then used to identify prostate cancer cases diagnosed up to the end of 2015, with cases categorized as high-grade, advanced, or fatal,based on Gleason grade and stage.

The mean age of the men at study entry was approximately 67 years, and the mean BMI was between 24.5 kg/m2 and 29.3 kg/m2. The mean percentage body fat lay between 18.8% and 25.1%.

Men with higher visceral fat had, unsurprisingly, a higher BMI and waist circumference than men with less visceral fat. They also had less physical activity during youth and midlife and were less likely to be current smokers.

Over the study period, there were 172 prostate cancer diagnoses and 31 prostate cancer-specific deaths. Forty one cases were advanced and 43 were high-grade.

The median time to prostate cancer diagnosis was 10.1 years, and the median time to prostate cancer death was 10.4 years.

Visceral fat was associated with an increased risk of advanced prostate cancer, at a hazard ratio of 1.31 per standard deviation (SD) increase, while thigh subcutaneous fat increased the risk of fatal prostate cancer at a hazard ratio of 1.37 per SD increase.

Interestingly, the strength of the association was modulated by BMI, with the link between visceral fat and advanced and fatal prostate cancer significant among men with BMI < 27 kg/m2 but not significant for men with a greater BMI.

The results for total fat mass and percent fat were similar to those for visceral and thigh subcutaneous fat.

The researchers also calculated that each 5 kg/m2 increase in BMI increased the risk of both advanced and fatal prostate cancer, at hazard ratios of 1.52 and 1.56, respectively.

Compared with men with a healthy BMI, those with BMI ≥ 30 kg/m2 had a significantly increased risk of advanced prostate cancer, at a hazard ratio of 2.54, and an increased risk of fatal cancer, at a hazard ratio of 2.59.

Similarly, each SD increase in waist circumference was associated with an increased risk of advanced and fatal prostate cancer, at hazard ratios of 1.40 and 1.45, respectively.

In an accompanying editorial, Celina H. Shirazipour, PhD, and Stephen J. Freedland, MD, from Cedars-Sinai Medical Center, Los Angeles, California, argue that looking at the current results in the context of the evidence around diet and exercise offers "new opportunities" for researchers and clinicians alike.

"First, researchers could benefit from including measures that assess visceral fat as outcomes in interventions, whereas clinicians would benefit from collecting knowledge of fat location in addition to the total weight."

They also make the intriguing suggestion that the results underline the importance of timing lifestyle interventions, as "optimal benefits may be experienced prior to diagnosis through early preventative interventions."

Shirazipour and Freedland write: "Although a direct association was not made, through knowledge of the importance of diet and physical activity in targeting fat, interventions should potentially prioritize targeting these lifestyle factors during youth or emerging adulthood in order to decrease the risk of prostate cancer."

Responding to these comments, Dickerman said that the study's findings "alone do not provide evidence for a specific intervention for prostate cancer risk reduction."

"However, they can, as the editorial suggests, help to generate hypotheses for future research on specific interventions," which may include, for example, physical activity, she added. "These interventions may target fat loss and regional fat distribution and benefit clinically significant prostate cancer outcomes."

Speaking to Medscape Medical News, Shirazipour said that, in any case, one of the issues around lifestyle interventions that target diet and physical activity is the messaging.

She pointed out that it is not simply a question of underlining the importance of lifestyle interventions and whether that is framed as being "at risk of if you do this behavior or not."

What may be more important is whether a particular disease or condition is salient to an individual, which is often related to their age.

Shirazipour explained: "If you go to youths and you say you should be active because you might be at risk for prostate cancer, that's not a very salient message if you're 15 and you're talking about a condition that might be some 50-60 years away. But if you are talking, for example, to someone at midlife that might be a much more salient message."

More broadly, she agreed with the researchers that the findings show that "we can't just focus on a BMI number; that we need to look more deeply," which is "very important" when talking to patients in the clinic.

She said that it is up to clinicians to decide whether, for example, computed tomography would be an effective method for assessing fat distribution, but the current findings at least "add to the knowledge that clinicians can use."

For Shirazipour, the research emphasizes the need to consider how measures such as fat distribution and lifestyle interventions "feed into each other."

"Our hope is that not only does this help with within the clinic but this also points out that there might be lifestyle approaches that can be beneficial either early on in life or [around] diagnosis that might be really effective in targeting some of these key risk factors."

The study was funded by the National Cancer Institute of the National Institutes of Health, an ASISA Fellowship, and the Prostate Cancer Foundation. The AGES-Reykjavik study was supported by the Intramural Research Program of the National Institute on Aging, the Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). In addition, this study was supported by funding from the Harvard Catalyst Award and the Icelandic Cancer Society. The authors have disclosed no relevant financial conflicts.

Cancer. Published online June 10, 2019. Abstract, Editorial

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