In an attempt to identify younger men who are at risk for prostate cancer, researchers at Johns Hopkins in Baltimore, MD studied 94 men who had been diagnosed with prostate cancer when they were 55 years old or younger or who had close blood relatives with prostate cancer. Past research led the investigators to suspect that one particular region of the human chromosome, known as 17q21-22, might be the location of one or more prostate cancer susceptibility genes. The team analyzed 200 genes located in this region. They found that four of the 94 men had a mutation on a gene known as HOXB13, which plays an important role in the development of the prostate. These four men were also found to have a total of 18 close male relatives with prostate cancer. Blood tests revealed that every one of these men had the HOXB13 gene mutation — powerful evidence that it might be linked to hereditary prostate cancer. In a larger study of 5,100 men who had been treated for prostate cancer, it was found that 72 of them had the same mutation on the HOXB13 gene. In addition, these men were highly likely to have been diagnosed with prostate cancer at a young age or to have one or more relatives with the disease. For comparison, the team studied 1,400 men who didn’t have prostate cancer. Just one man had the HOXB13 mutation. “This study, which was published in the New England Journal of Medicine, found that men who carry the HOXB13 mutation are up to 20 times more likely than non-carriers to develop prostate cancer. It is important to keep in mind that the mutation discovered on the HOBX13 gene is rare and explains only a small number (between 2%-5%) of prostate cancer patients but it is an excellent example of the use of an individual’s personalized genomic information as a predictor of future health issues.
Genomic Health Inc., a cancer diagnostics company, recently announced they are now marketing a genomic test for men diagnosed with prostate cancer that will provide better information on how likely it is that their prostate cancer is an aggressive form of the disease needing immediate treatment, or a slow-growing, low-risk form of prostate cancer that can safely be monitored over time for signs of progression. The new assay, Oncotype DX Prostate Cancer Test, will potentially give tens of thousands of men increased confidence that they can safely forego aggressive treatment and instead enter a program of active surveillance, where their tumor is monitored over time, deferring surgery or radiation and potentially avoiding the sexual and/or bowel and bladder dysfunction side-effects that can result from those treatments. The new test—a 17-gene predictive “signature”, measures the amount of ribonucleic acids (RNA) expressed by these various genes, with some genes making large amounts of RNA and others making little. Seven separate studies by Genomic Health Inc., involving over 1,000 men diagnosed at biopsy with prostate cancer have shown that in men whose tumors turned out to be high-risk, those men tended to test positive for this 17-gene “signature.” The Oncotype DX Prostate Cancer Test currently costs about $3,800 and is not covered by insurances at this time. For further information, please see the May 9th and May 31st issues of the Prostate Cancer Foundation (PCF) NewsPulse.
On May 15th, 2013, the U.S. Food and Drug Administration approved Xofigo (previously known as Alpharadin) for use in men with treatment-resistant prostate cancer that had metastasized to bones but not to other organs. Xofigo, administered by injection, will be marketed by Bayer Healthcare Pharmaceuticals who developed the therapy jointly with Algeta, ASA, a Norwegian pharmaceutical company. The drug works by delivering radioactive alpha particles directly to prostate cancer cells that have formed tumors in bone. The radioactive alpha particles from radium-223 dichloride are relatively “heavy” and therefore do not penetrate very far in the body thus limiting the effect of the drug to about a 10-cell radius thereby limiting its toxicity. The drug binds with minerals in the bone to deliver radiation directly to the bones limiting damage to surrounding tissues. In Phase III clinical trials, men given Xofigo experienced a six-month longer timeframe to first complications (fractures or spinal cord compression) occurring as a result of bone tumors, a survival advantage of about 3 months and a higher quality of life. Xofigo also produced a 50% reduction in the risk of spinal cord compression caused by tumors—a complication that can result in paralysis, severe pain, and other loss of functions.
I recently learned of a good friend who has asymptomatic but metastatic prostate cancer which was being controlled by intermittent androgen deprivation (hormonal) therapy. One of the potential side effects of such therapy is the risk of osteopenia and the more serious condition, osteoporosis. Osteoporosis and the processes involved in breaking down bone (resorption) by cells called osteoclasts and generating new bone from osteoblasts are described clearly and briefly in the April 6th, 2013 issue of the Johns Hopkins Hospital Health Alerts. Patients on hormonal therapy are advised to have annual bone density tests known as dexa scans wherein bone density is measured in the lumbar spine and the hip femoral neck. Such patients also usually take bisphosphonates such as Boniva or Fosamax among others to minimize the bone depletion which often accompanies hormonal therapy. Since bisphosphonates also have some potential side effects coinciding with their long term use, my friend was advised not to take bisphosphonates (specifically Boniva) for a year and observe any effect on his bone density. After one year, the dexa scan showed a dramatic and very significant reduction in his bone density especially in the lumbar spine. He was then placed on a relatively new medication called Prolia (formerly called denosumab) which had been approved in 2011 by the U.S. Food and Drug Administration for use in prostate cancer patients whose cancer had not yet metastasized to bone in addition to other cancer patients.
Prolia works differently from the class of bisphosphonates such as Boniva by specifically binding to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Prolia thereby prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of this RANKL/RANK interaction thereby inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength. Prolia is administered as a 6-month. sub-cutaneous injection.
The moral of this anecdote is that prostate cancer patients undergoing androgen deprivation (hormonal) therapy need to consistently monitor and maintain their bone densities using appropriate medications such as bisphosphonates or Prolia and should also engage in regular exercise regimens to maintain bone strength.