By Mark Scholz, MD | PCRI Executive Director

Uncontrolled cancer cell growth results from misbehaving genes. An intriguing approach to cancer therapy is to identify the mutated genes and target treatment to specifically counteract the damaging effects of that gene.

Recently, five new life-extending treatments have become available: Provenge, Zytiga, Xtandi, Xofigo, and Jevtana. Older treatments like radia-tion, Lupron, and Taxotere are also still effective. Thankfully, mortality can be postponed for a long period of time. 

Still, roughly 28,000 men die of prostate cancer each year in the United States. Mortality results when all treatment options have been exhausted due to the prostate cancer becoming resistant. When resistance develops, it is reasonable to consider off-label treatments, usually treatment that is FDA-approved for other types of cancer. The question is, with so many treatment options, where does one begin? 

I had a patient, who we will call Paul, who was successful in finding a very effective “off-label” treatment. He was diagnosed in 2010 and initially things looked pretty optimistic. His Gleason score was 3+4=7 and PSA was 4.2. Paul had a prostatectomy, but the cancer was outside his prostate and PSA never dropped to zero.  He had radiation and Lupron but the PSA only remained low for a brief period of time. Over the following 3 years, Paul tried almost every possible treatment. By summer 2014, he developed progressive bone marrow failure, a common development in men with uncontrolled prostate cancer. His production of red blood cells was so impaired he could only be kept alive with monthly blood transfusions. The PSA was above 120 and he had a less than 10% chance of living 6 months.

At this point, Paul switched his med-ical care to my office. But just before he switched, his doctor started him on an off-label medication called Mekinist, a pill that is FDA-approved for metastatic melanoma. Within months, his PSA dropped to 18.96 and his bone marrow improved dramatically. Paul's health improved to the point he was able to return to work full time and travel inter-nationally with his family. He tolerated the drug very well, but after two years the cancer became resistant again, leading to his passing in 2016. 

Paul and his doctor were very fortunate in picking Mekinist as a treatment. Men have a better chance nowadays at prolonging life with advanced prostate cancer due to the achievements in the medical field and the growing number of available options. But that’s where the issue of choosing the the right treatment comes in.

It is difficult to know which agents to select with so many new agents be-ing approved for all the different types of cancer. We put several other patients on Mekinist after seeing Paul's success, but they showed no benefit. But prostate cancer is not a single disease, it is multiple diseases; it looks different for each man. So it is not surprising when one man shows anti-cancer benefit while many others show none with the same treatment. This is where genetic testing has the potential to make a big difference. 

METHODS OF GENETIC TESTING

We actually attempted a scandirected bone biopsy on Paul, in hope of obtaining cancer cells for genetic testing. Unfortunately, the biopsy was unsuccessful because no viable tumor cells were obtained. Our experience in doing bone biopsies in prostate cancer patients to obtain tumor cells for genetic testing has only been successful in about half of the patients in whom we have attempted to perform a biopsy. Until recently, bone biopsy was the only way to access the genetic material in tumor cells. But technological advancements in the medical field are growing quickly. The latest breakthrough is the discovery that tumor DNA released into the blood from dying cancer cells can be obtained with a blood test.

There are still many challenges to overcome in our attempts to use a genetically-guided approach. While we now have the ready ability to identify malfunctioning genes by name, we don’t always know the gene’s actual function. Also, in most cases, medicines to counteract the mutations we detect don’t yet exist. 

However, the fact that targeted therapy for specific mutations can be successful was most notably validated by the discovery that Olaparib, an FDA-approved drug for ovarian cancer, may also be beneficial in men with prostate cancer who have a specific mutation in the BRCA gene. It turns out that this BRCA mutation (or other related types of mutation related to DNA repair) occur fairly frequently in men with advanced metastatic prostate cancer. A study testing Olaparib for treatment of prostate cancer patients was published in the New England Journal of Medicine. It showed that Olaparib was very effective in 15 out of 16 men who had this type of mutation in their cancer cells. In men without this specific type of mutation, the response rate to Olaparib was less than 10 percent. Hopefully, genetic testing will lead to further such discoveries.

Because we were unable to obtain genetic information from Paul, we don’t know if his excellent response to Mekanist occurred due a malfunction of a specific gene called GNAS (which can predict that Mekanist will work), or to some other yet unknown gene. However, now with the easy access of genetic information through blood testing with blood-derived genetic tests, we should be able to learn which treatments are likely to induce a cancer response based on each patient’s specific g-netic profile. 


ABOUT DR. SCHOLZ:

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Mark Scholz, MD is the Executive Director of the Prostate Cancer Research Institute. He is also the Medical Director of Prostate Oncology Specialists Inc. He received his medical degree from Creighton University in Omaha, NE. Dr. Scholz completed his Internal Medicine internship and Medical Oncology fellowship at University of Southern California Medical Center. He is co-author of Invasion of the Prostate Snatchers.  He has authored over 20 scientific publications related to the treatment of prostate cancer.

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