Friday, June 13, 2014

Statins and Prostate Cancer - Don't Believe What You Read

Every few years, it seems, there is renewed interest in using statins (hydroxy-methyl-glutaryl CoA reductase inhibitors - drugs that lower cholesterol) to treat (or prevent) prostate cancer. WebMD reported on a 2009 study suggesting an almost 2/3 reduction in death rate with the use of statins:
Statins and Prostate Cancer Death

The new study involved 380 men ages 55 to 79 who died from prostate cancer between 1999 and 2001 and who had living spouses who could verify their medical histories. They were compared to 380 married men in the same age group who were still alive.

A total of 63 men who died from prostate cancer had taken statins, as had 109 of the men who were alive.

After taking into account other risk factors for dying from prostate cancer, men taking statins were 63% less likely to die from the disease than men not taking statins.

Stephen Marcella, MD, assistant professor of epidemiology at the University of Medicine and Dentistry of New Jersey in Piscataway, presented the findings at the 2009 Genitourinary Cancers Symposium.

Further analysis showed that high-potency statins like Lipitor, Zocor, and Crestor were linked to a lower risk of dying from prostate cancer even more than weaker statins like Mevacor, Pravachol, and Lescol.

"The high-potency statins were about 2.5 times more effective at preventing prostate cancer death than the weak statins," Marcella says.

"That makes sense," Klein says. "The more potent the drug, the bigger the biologic effect."

That doesn't mean high-potency statins are better than weaker statins, he stresses. "Their primary purpose is for cholesterol lowering and you typically want to use the least aggressive therapy you can to achieve the desired effect," Klein says.

While the studies were not designed to examine how statins might protect against dying from prostate cancer, Klein notes that they are potent anti-inflammatory drugs. "There's a lot of evidence that inflammation contributes to the development of prostate cancer." Alternately, statins may directly kill cancer cells, Klein says.
The anti-inflammatory model of the reduction of cancer severity in those who use statins may be true for some patients. We don't know. But we do that a diet rich vegetables, antioxidants, fruits (especially berries), and anti-inflammatory herbs (curcumin, olive leaf extract, oregano oil), combined with regular exercise and an avoidance of too much red meat (or, more precisely, flame-cooked meat) and too much sugar and other simple carbs, all work in synergism to reduce inflammation, which is the primary driver of cancer growth.

Why use statins when we can get the same benefit (and may others as well) from a proper diet?

In a 2010 paper (Di Stasi, MacLeod, Winters, and Binder-Macleod1) on how physical therapists can be useful for those taking statins, the authors outline some of the issues with statins and muscle damage:
Approximately 25 million Americans use statins,13 and 5% to 18% of these patients report some form of myalgia.14 Skeletal muscle side effects that are associated with statin use involve muscle cramping, soreness, fatigue, weakness, and, in rare cases, rapid muscle breakdown that can lead to death (ie, rhabdomyolysis).15,16 Side effects have been associated with all commonly used statins and are dose dependent.17,18
Other research has suggested the percentage of people who experience side effects (especially in muscle) is not really so tiny. Parker, Capizzi, Grimaldi, Clarkson, et al. (20132) found that even non-symptomatic patients express increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects.

However, this is not the most serious with statins and prostate cancer. 

Earlier this year, the research surfaces again. This is a lengthy article, and I am including all of it - it comes via the Prostate Cancer Foundation.

Statins and Prostate Cancer

As the science comes together, risk of aggressive disease may be abated with use, but little effect on indolent, early prostate cancers

March 4, 2014 -- Statins are a group of widely prescribed drugs used to lower cholesterol levels in the body. Common statin medications include well-known brands such as Zocar, Lipitor, and Crestor. Statins work by inhibiting an enzyme in our bodies (HMG-CoA reductase) that is used to manufacture cholesterol, and the drugs can also help clear already formed cholesterol from the bloodstream. High cholesterol is a known cause of cardiovascular disease, and it’s well-established that statins reduce the rate of death and illness caused by cardiovascular disease. And while statins can help prevent the risk of heart attack or stroke, some studies have also suggested that statins may have an effect on prostate cancer.

Whether the effect would be beneficial or harmful has been the subject of ongoing studies for some time. When statins first became widely available to the public in the 1980s, concerns erupted that these drugs might spur some cancers. Those fears are now widely dispelled, and this past year, a massive meta-analysis of 135 randomized studies that included over a quarter million study participants, found that statin use did not increase the risk of developing cancer.

Statins and Prostate Cancer

However, whether or not statins had a positive impact on cancer risk remained an open question. Research has suggested that statins can slow cancer cell growth in certain cancer types such as breast, colorectal, and skin cancers, and may lower the risk for the latter two. And some research has also suggested that statins might lower the overall risk for prostate cancer, but because of inconsistent findings, it was clear more research was needed. From such ongoing research, what is emerging is that statins may indeed reduce the risk of death from prostate cancer, but likely have little effect on whether or not a man develops prostate cancer in the first place.

Statins and Advanced Prostate Cancer

Dr. Elizabeth A. Platz of the Johns Hopkins Bloomberg School of Public Health and a Prostate Cancer Foundation-funded researcher.

Dr. Platz and colleagues have twice found that individuals with lower levels of cholesterol (within the normal ranges, not the super low ranges) had a lower risk of developing more aggressive disease, as defined by high Gleason scores. This is yet another reason for men to put aside that plate of fried chicken and head for the salad bar, in order to naturally lower their cholesterol levels.

This January, research out of Canada published in the Journal of Clinical Oncology found that men who used statins after a diagnosis of prostate cancer had a 24% decreased risk of death from the disease compared to men who did not take statins. The longer the men took statins, the greater the protective effect. For example, men who took statins for less than one year post-diagnosis had a 1% lower risk of death from prostate cancer compared to non-users. But men who had taken statins for three or more years post-diagnosis lowered their risk of death from their cancer by 39%.

Interestingly, the study also found that statin use prior to a diagnosis of prostate cancer was even more protective to the men, in terms of both mortality specifically from prostate cancer, or from any other cause. Pre-diagnostic statin use reduced the men’s risk of death from prostate cancer by 45%, and conferred a 34% reduced risk of death from any cause, compared to men not taking statins.

All the men in the study had been newly diagnosed with non-metastatic prostate cancer at the time of their enrollment into the study; men who used statins after their diagnosis were 23% less likely to develop distant metastatic cancer spread during the study period.

This study adds to other recent research showing reduced prostate cancer-specific mortality among men who used statins. Dr. Janet Stanford, of the Fred Hutchinson Cancer Research Center in Seattle and a Prostate Cancer Foundation-funded researcher, and colleagues published a study this past summer in The Prostate demonstrating that men who took statins prior to their diagnosis of prostate cancer experienced an 81% reduced risk of prostate cancer-specific mortality compared to men who did not take statins. At 10 years of follow-up, only 1% of statin users had succumbed to prostate cancer, compared to 5% of non-users. However, that study also found that statin use prior to prostate cancer diagnosis did not affect whether or not prostate cancer recurred or progressed. At the time the study was published, Stanford called for confirmation study to validate her findings, and suggested that such research could pave the way for a large, randomized, placebo-controlled study that will yield the most definitive results on whether or not men with prostate cancer should or should not be prescribed statins to lessen their risk of death from the disease.

In response to last month’s study in the Journal of Clinical Oncology (JCO), Drs. Lorelei A. Mucci and Meir J. Stampfer from the Harvard School of Public Health and both Prostate Cancer Foundation-funded researchers, penned an editorial on the subject: Mounting Evidence for Prediagnostic Use of Statins in Reducing Risk of Lethal Prostate Cancer. In this article, Mucci and Stampfer point out that much of the inconsistency among studies on statins and prostate cancer “disappears" when the research distinguishes between risk of overall incidence of prostate cancer and risk of advanced or lethal disease. In reviewing the current “mounting" evidence, Mucci and Stampfer pointed to Stanford and colleagues findings of lower risk of death from prostate cancer in statin users, as well as a Danish study showing lower rates of death for statin users, and a Norwegian study finding that risk of lethal prostate cancer also dropped with statin use.

The authors noted that Prostate Cancer Foundation researchers were the first to focus on risk of lethal disease and statin use in a prospective, observational study published in the Journal of the National Cancer Institute (JNCI) , in 2006. (Men at risk for prostate cancer were observed over the course of several years; their use of statins was recorded, as was their incidence of prostate cancer.) That study, with first author Dr. Elizabeth A. Platz of the Johns Hopkins Bloomberg School of Public Health and a PCF-funded researcher, found that men diagnosed with prostate cancer who used statins halved their risk of developing advanced disease during the study period, and lowered their risk of lethal disease (having metastatic disease at time of diagnosis or succumbing to prostate cancer during the study’s follow up period) by 61 percent. Furthermore, the study found that the risk of developing advanced prostate cancer was lower with longer durations of statin use.

Dr. Mucci says that the Canadian study was a particularly good study for a number of reasons. “It is one of the larger studies to date with the ability to study lethal cancer during the follow-up period," says Mucci, referring to the fact that a large number of men in the study developed lethal disease during the study’s follow-up. Because smaller studies may pick up outcomes that happen just by chance rather than due to the effect of the drug, this study allows far greater confidence in the findings that statin use did have a positive effect on risk of dying from prostate cancer. Also, says Mucci, “A really unique feature of this study is that the researchers looked at statin use both before and after diagnosis." That may be important in helping to determine the mechanism of action statins have on prostate cancer. “One can think about statin use after a diagnosis, and that the drug will probably influence tumor cells after they’ve left the prostate, whereas, statin use before diagnosis could influence the tumor itself," says Mucci.

Knowing when and where statins act on prostate cancer can help determine which patients are most likely to benefit, as well as lead to new drug development specific to prostate cancer once the cellular pathways of action are determined.

Dr. Mucci and colleagues are now working out how statins may affect genes and other molecular pathways for better or worse in prostate cancer patients. They will examine prostate tissue samples taken from men who’ve just undergone radical prostatectomy. “We want to determine if there are differences in gene expression between men who use statins and those who don’t," says Mucci. They examine both tumor tissue samples and normal tissue samples taken from the prostate of each man in their study.

Statins and Overall Risk of Prostate Cancer – unlikely to work as chemopreventive agent

While statin use may have an effect on survivability of prostate cancer in some men, the evidence to date does not point to a protective effect from the drug in terms of overall risk of prostate cancer. In the 2006 JNCI study by Platz and colleagues, while risk of lethal disease was lowered among statin users, there was no risk reduction for the overall occurrence of prostate cancer in men who were taking statins.

On the heels of that study, Platz and colleagues decided to further investigate overall risk of prostate cancer and statin use. “Most of overall prostate cancer is early stage disease, and we did not see an association between statin use and prostate cancer overall" says Platz, “and we were worried maybe we might be missing an association because of a particular study bias—detection bias." Men who regularly seek care through their primary-care doctor are more likely to be screened for both high cholesterol and PSA levels. “If a man has high cholesterol he may well be prescribed a statin to lower his cholesterol levels, and if his PSA levels are elevated, his doctor might recommend a biopsy," says Platz. Regular screening can lead to both a high incidence of statin use and prostate biopsy. And because biopsy if quite sensitive to picking up early prostate cancer, this can create a false association between statin use and prostate cancer, says Platz.

“We wanted to study early prostate cancer in a setting where such detection bias is very unlikely to be operating," said Platz.

To that end, her group studied statin use in a group of men enrolled in the Prostate Cancer Prevention Trial, a study that called for annual PSA screening and digital rectal exams for prostate cancer. This eliminated the variability in screening that likely colored other studies. And, because Platz wanted to focus on early cases of prostate cancer, a setting where all men are screened equally also favored early disease detection that gave the researchers a more homogenous group of diagnosed men, weeding out most cases of late stage disease. In a study just published online in the Journal of Urology, Platz and colleagues again found no association between statin use and early prostate cancer among some 10,000 men enrolled in the Prostate Cancer Prevention Trial who were followed for a period of seven years.

“Overall," says Platz, “if you take all of the literature together, it appears as though statin drugs may be inversely associated with aggressive disease—meaning the cancer progresses to the point of distant metastatic spread, or death of the patient—but not associated with the development of the most common form of prostate cancer in men, which is very early disease."

Why and how might statin use affect development of aggressive prostate cancer?

Clearly this needs to be better understood, but there are several likely avenues of action statins can exert on cancer cells. Pre-clinical research has shown that these cholesterol-lowering drugs can inhibit prostate cancer cell growth, and may encourage cancer cell death and prevent tumor blood vessel growth as well as modulate immune system factors. Additionally, it has been suggested that statins may tamp down the activity of certain oncoproteins. Dr. Mucci’s team, in their work just beginning on tumor tissue samples and statin use, will help suss out such molecular activity and pathways involved.

Dr. Platz and colleagues have now twice found, in two different study groups of men, that individuals with lower levels of cholesterol (within the normal ranges, not the super low ranges) had a lower risk of developing more aggressive disease, as defined by high Gleason scores. (This is yet another reason for men to put aside that plate of fried chicken and head for the salad bar, in order to naturally lower their cholesterol levels.)

Moving forward to better answers

And while the indications are fairly ripe for an interventional randomized clinical study of statins as one agent in the treatment of men with advanced prostate cancer, it is very important to do the groundwork to best determine which subset of men and at what time in their treatment scope, statin use may yield the best results, says Dr. Howard Soule, chief science officer at PCF. Large randomized studies are very costly and if not properly set up, may not bring forth the best information.

From a public health standpoint, it doesn’t make sense to give healthy men, who do not have elevated cholesterol levels, statins for prevention of cancer, says Platz. “Even though these drugs are quite safe, they are not without side effects," she says.

Dr. Jonathan Simons, president and CEO of the Prostate Cancer Foundation, says, “This tantalizing possibility that statins may be used in conjunction with other therapeutics to lower a man’s risk of death from aggressive prostate cancer is well worth further exploration." Simons adds: “Finding that subset of men who might most benefit from statin use in order to hold their cancer in check, or discovering what genes and molecular pathways might be targeted with other new drugs, is a definite goal." And with the recent advent of blood tests that use genetic signatures to help separate out risk of less aggressive from risk of more aggressive disease, and the discovery of constellations of single point mutations—changes in DNA sequence called SNPs—that add up to a higher risk of lethal disease , it may be that evaluating statin use in men who are deemed at higher risk of aggressive disease may be ideal candidates in whom to study statin use as a treatment option. In fact, says Platz, such a research strategy would be feasible because in a high-risk group of men the likelihood of having an event of aggressive prostate cancer is higher, so the study would be more manageable in term of size and duration—fewer men would need to be enrolled and follow up time could be shorter in order to get actionable data.
If you noticed in the article, these studies were conducted on non-metastatic cancer patients, and the studies did not progress far enough to see if any of the patients did suffer from metastasis. Although in one of the studies mentioned, "men who used statins after their diagnosis were 23% less likely to develop distant metastatic cancer spread during the study period." But how long was the study period?

Statins, Metastasis, and Red Blood Cells

One of the emerging theories for the metastasis of prostate cancer is that the cancer stem cells have found a way to "hijack" red blood cells, which allows them to move through the body undetected by the immune system and to eventually hide out in bone morrow, where they are safe from radiation and chemotherapies, and where they also have a steady blood flow to keep them alive.

So the question, then, is how do they get into the red blood cells?

Research (Honda, Yamada, Endo, Ino, Gotoh, et al., 19983) demonstrates that regulation of the actin cytoskeleton of erythrocytes (red blood cells) likely plays a central role in cell motility and cancer invasion. These authors believe that nonmuscle actinin-1 associates with cell adhesion molecules, such as integrin β1 and α-catenin, and is plays an important role in stabilizing cell adhesion and regulating cell shape and cell motility (Otey et al., 1990, 1993; Glück et al., 1993; Glück and Ben-Ze'ev, 1994; Knudsen et al., 1995).

Their research found that cytoplasmic actinin-4 (a novel isoform of nonmuscle α-actinin) regulates the actin cytoskeleton and increases cellular motility. However, it becomes inactivated when it is transferred to the cell nucleus, which "abolishes the metastatic potential of human cancers." So, in essence, activation of actinin-4 increases cell motility. But how?

It's long been known that inflammatory substances in the immune system can damage erthrocytes, which creates an opening for cancer stem cells to enter. The above study showed that actinin-4 was markedly induced in cells along the edges of a wound to the cytoskeleton.  
Actinin-4 was expressed in a limited population of normal cells, including erythrocytes, endothelial cells, and epithelial cells in various tissues at their border with stromal connective tissue.
So where I am going with all of this?

Simvastatin (Zocor), one of the more common statins, has been shown (Clapp, Ellsworth, Sprague, and Stephenson, 20134) to increase erythrocyte deformability, which means red blood cells are more easily deformed, as in the research above. It is highly likely that other statins produce the same risks.

Deformed erthrocyes, whether from cytokines or statins, increase the risk that cancer cells, including prostate cancer, can invade the damaged blood cells and metastasize throughout the body.

So when you read that statins might be an effective treatment for prostate cancer, please keep this in mind.


1. Di Stasi, SL, MacLeod, TD, Winters, JD, and Binder-Macleod, SA. (2010, Oct). Effects of Statins on Skeletal Muscle: A Perspective for Physical Therapists. Physical Therapy; 90(10): 1530–1542.
2. Parker, BA, Capizzi, JA, Grimaldi, AS, Clarkson, PM, Cole, SM, et al. (2013). Effect of Statins on Skeletal Muscle Function. Circulation127: 96-103.
Honda, K, Yamada, T, Endo, R, Ino, Y, Gotoh, M, Tsuda, H, Yamada, Y, Chiba, H, and Hirohashi, S. (1998, Mar 23). Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. Journal of Cell Biology; 140(6):1383-93.
4. Clapp, KM, Ellsworth, ML, Sprague, RS, and Stephenson, AH. (2013, Mar 1). Simvastatin and GGTI-2133, a geranylgeranyl transferase inhibitor, increase erythrocyte deformability but reduce low O2 tension-induced ATP release. Am J Physiol Heart Circ Physiol.; 304(5): H660–H666.

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