The international death rates for PC are highly disparate. However, the phenomenon of latent ‘autopsy’ prostate cancers remains stable. Certainly, there is a baseline genetic determination for the overall prevalance of prostate cancer, but the factors driving the development of clinically significant prostate cancer are less understood. Indeed, migration studies (especially those involving Japanese and Chinese immigrants to the west) indicate that migrants who come from areas of low PC prevalence inherent the epidemiologic characteristics of their new environment with respect to incidence and clinical aggressiveness. Dr. Fleshner presented a graph showing the normal slope of disease progression from atypia to end-stage disease. Environment has the ability to influence this slope at any point along the timeline, and should not be ignored when understanding this disease from a birds-eye-view.
Because environment plays such a central role, many attempts have been made to identify vitamins, supplements, minerals, plant-based nutrition such as soy, and other health adjuncts that could reduce disease risk. Unfortunately, none of these have shown any meaningful beneficial effect. Obesity, however, is a definite “western civilization” problem that is the elephant in the room, especially when it comes to understanding migration studies. Along that concept, metabolic syndrome (MS) has been shown in a series of excellent investigations to impute higher PC risk. For example, it is estimated that for every 5 unit increase in BMI, PC progression risk increases by 5%.
PC has a unique metabolism that must be understood, especially with respect to its interaction with MS. Prostate cancer cells have a low rate of glucose metabolism and variations in aerobic glycolysis. They have a series of mitochondrial genetic anomalies (common mutations in prostate cancer), aberrant citrate metabolism, and mevalonate pathway upregulation, just to name a few of the abnormalities. Rodent studies of MS and PC have shown that rodents fed with high carb/high fat diets have more aggressive tumors than those fed low carb/high fat diets, indicating some sort of direct link between carbohydrate metabolism on PC risk.
Luckily, medicine has already addressed some of the central issues in MS and glucose-intolerance with a variety of metabolically active pharmaceuticals. One important such drug is metformin, a very common oral hypoglycemic. Dr. Fleshner and other groups have published research showing how metformin plays an active role in multiple pathways influencing PC metabolism and progression, including on cell-cycle regulators, aerobic glycolysis pathways, and electron-transport regulation. From a clinical outcomes perspective, metformin has been shown to associate with decreased PC mortality.
The potential utility of metformin is quite exciting. For example, androgen deprivation used for metastatic prostate cancer increases rates of MS. Studies of men receiving androgen deprivation who are also taking metformin demonstrate that metformin mitigates the progression of metabolic syndrome, and may be a good supplement to use in the appropriate patient population to subvert the effects of androgen deprivation in these men.
Another important class of pharmaceuticals are statins. Studies show that statins decrease PSA levels and associate with lower risk of recurrence and mortality following prostatectomy. They likely act along many of the same metabolic pathways responsible for metformin’s influence on PC progression. Luckily both of these drugs are highly tolerable, and combination studies of statins and metformin appear to have impressive anti-tumor properties in both in-vitro and in-vivo models. In fact, the combination is almost as effective as docetaxel in animal models!
The MAST study is a tertiary prevention, placebo-controlled, randomized study of metformin in PC aimed to evaluate some important questions as to the efficacy of the drug on PC outcomes. There are other trials underway involving statins, and certainly the combination of drugs will be the subject of further investigation.
In summary, PC metabolism is unique. The environmental factors that influence it are complex, but clearly play a central role in determining disease characteristics. MS is likely a pivotal reason there is higher PC aggressiveness in the west, and treating MS appears to also target PC metabolism. This is a very exciting time for research in this area, as effective drugs are already on the market and can have a major impact in some patients. As we learn more, these pathways should continue to be a target for exploitation.
Presented by: Robert Reiter, MD
Written By: Shreyas Joshi, MD, Fox Chase Cancer Center, Philadelphia, PA
at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA