Genetic Testing: The Future of Prostate Cancer Treatment

Genetic testing
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Five new life-extending treatments—Provenge, Zytiga, Xtandi, Xofigo and Jevtana—have become available for treating prostate cancer in the last five years. Fortunately, the old standby treatments like radiation, Lupron, and Taxotere remain effective as well. Generally, prostate cancer progresses fairly slowly, meaning that mortality can be postponed for a very long period of time.

Despite all these hopeful aspects, 28,000 men succumb to prostate cancer each year.

In most cases, mortality occurs because the cancer ultimately becomes resistant to all of the standard treatments listed above. If this occurs, the next logical step is to consider off-label treatments such as medicines that are FDA-approved for other types of cancer, say kidney cancer or lung cancer, for example. The problem is selection among so many options. If you are going to take a shot in the dark, which gun should you pick?

Off-Label Agents: A Patient's Story

The quest for an effective off-label agent can have a big payout if you get lucky. From the FDA's perspective, an approved drug may be used for an unapproved use when a healthcare provider feels that it is medically appropriate for their patient, whether it's because there is no approved drug to treat the given condition or because a patient has tried all approved treatments without seeing results.

Let me relate Bill’s story. He was first diagnosed in late 2010 with a PSA of 4.2 and a Gleason score of 3+4 and was treated with surgery to remove the prostate.

The first sign of further trouble was that his pathology report showed cancer outside the edge of the prostate. His Gleason score was also upgraded to 4 + 5 = 9, and his PSA never dropped to zero after the prostate was removed.

In March 2011, he underwent radiation directed to the area of the body where the prostate used to be, but the PSA only remained low for a brief period of time.

 He then started Lupron, but his tumor became resistant within a year. Over the next three years he was treated with the medicines listed above, Provenge, Zytiga, Xtandi, and Taxotere. By summer 2014, his cancer spread extensively throughout his bone marrow. Treatment with Xofigo was started in February 2014. Unfortunately, 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. When the Xofigo was stopped in August 2014, the PSA had risen to over 120. Bill's chance for living another six months were less than one in 10.

Up to this point, another doctor was managing his case. Right before he switched supervision of his medical care to my office his previous physician started Bill on an off-label medication called Mekinist.  Mekinist is a pill that is FDA-approved for metastatic melanoma. Since use for prostate cancer (off-label use) is not covered by insurance, Bill purchased the pill himself at a cost of $10,000 per month.

However, his investment paid off. By December 2014 the PSA dropped to 18.96, his bone marrow started functioning again, and he no longer needed any further blood transfusions.

Bill’s health improved so much that he returned to his job full time and even took frequent trips with his family to Europe and various places in the U.S. over the next two years. The Mekinist was well-tolerated without any notable side effects. Unfortunately, his prostate cancer eventually became resistant to Mekinist and the cancer began to progress. Our further intensive efforts to find another off-label magic bullet were unsuccessful and he succumbed to the disease in early 2016.

Bill’s Mekinist was an amazing lucky pick. After showing such a great cancer response, he was even able to convince his insurance company to cover the cost. The achievement of a cancer remission at such a late stage of disease is truly remarkable, a testament to the groundbreaking products being developed in the pharmaceutical industry. Given that many new agents are being developed, the odds for good fortune, like Bill’s case, to be repeated are improving.

Genetic Testing: A Means for Smart Selection

The problem now is that there is such a large number of new agents being approved in all the different types of cancer. How do you know which agent to pick? We have tried giving Mekinist to a few other patients, but without any visible anti-cancer benefit. This is not surprising considering that prostate cancer is not a single illness. We have long observed a wide variation in how patients respond to different agents. However, there is another area of rapid technological progress that may help us sort patients for specific therapies. The advent of genetic testing of tumor cells may finally bring an end to the era of picking treatments randomly.

The idea is to select treatment by identifying the genetic profile of the cancer cells by gene sequencing. Uncontrolled cellular growth, “cancer,” results from misbehaving genes. Specific mutated genes that are related to cellular growth can get locked in the “on” position. These mutations can be identified by gene sequencing. Over 50 genes have been identified that malfunction in prostate cancer.  Genetic analysis of tumor tissue shows that in the average cancer cell about four genes are found to be mutated. However, the number of bad genes detected can range from as few as one to more than 10.

As exciting as the promise of this sort of “smart” selection sounds, there are still a number of challenges to overcome. Gene sequencing can consistently identify malfunctioning genes by name, but not always the gene’s actual function. When we do know the function, we frequently don’t have a specific medication to counteract the problem the gene creates. Even when an active medication exists to treat a specific malfunctioning gene in another type of cancer, there is no guarantee that its administration will also be effective in prostate cancer. For example, Mekinist is thought to be effective in counteracting the misbehavior of a gene called GNAS in patients with melanoma. However, as of yet we don’t have data showing that Mekinist will be effective for prostate cancer patients with GNAS.

Methods of Genetic Testing

We actually attempted to obtain cancer cells for genetic testing in Bill via a scan-directed bone biopsy.  Unfortunately, the biopsy was unsuccessful because no viable tumor cells were obtained. Our experience with biopsy to obtain tumor cells from the bone for genetic testing in prostate cancer patients 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. Bone biopsy, however, is cumbersome and uncomfortable requiring a large-bore needle. Fortunately, technology continues to progress at an ever accelerating pace. The latest breakthrough is the discovery that tumor DNA released into the blood from dying cancer cells can be detected and tested with a blood test.

Testing blood DNA is much easier than doing a bone biopsy. Besides the convenience factor, DNA in the blood is a composite of DNA released from all the tumors throughout the body. The genetic material derived from biopsy of a single tumor will often not tell the whole story because cancer is so genetically unstable that different cancer sites from the same patient may be genetically different.

Blood assay for tumor DNA is now commercially available. The company that performs the assay is called Guardant Health. They call their blood assay that tests for cancer genes Guardant360. The assay tests for 70 of the most common mutations seen in cancer. Studies have been done to test if the abnormal genes detected in the blood match the abnormal genes detected by a traditional tumor biopsy in the same patient.  The blood assay appears to perform extremely well. 

After an Abnormal Gene Is Detected

So let’s return to our main theme of using genetically-derived information to select off-label cancer treatments in men with prostate cancer who have exhausted their FDA-approved treatment options. When an abnormal gene is detected there are basically four possible outcomes:

  1. No known therapy is associated with this particular abnormal cancer gene.
  2. There is a FDA-approved treatment for prostate cancer available for this specific gene
  3. There is a FDA-approved treatment available that works for another type of cancer (lung, kidney, melanoma, etc.) that may have anticancer activity in prostate cancer with this specific gene abnormality.
  4. There are new agents being evaluated for this specific genetic abnormality in clinical trials either in prostate cancer or another type of cancer.  Patients who have this type of mutation may be more likely to respond to this particular agent considering the agent’s known mode of action. 

Referencing the above in practical terms, the first two outcomes are not going to be much help to patients. Specifically, in regards to the second outcome, most patients who undergo genetic testing for prostate cancer have already exhausted the prostate-cancer-related FDA-approved treatment options anyway. The third and fourth outcomes are the ones that may point to a type of therapy that would otherwise be lost in the background of the multitude of off-label options to be considered.

It’s unfortunate that Bill’s gene profile could never be obtained despite our best efforts. The impact of Mekinist on his longevity and quality of life was truly stupendous. At this point we don’t know if his excellent response occurred due his having a malfunction of GNAS, another gene or to a specific combination of genes. However, now with the easy access of genetic information through blood testing with Guardant360, we will be able to learn which treatments are likely to induce a cancer response based on each patient’s specific genetic profile.  

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