Prostate Cancer and Tests: Is This Progress?

In a recent announcement from Dana Farber in Boston, a paper has been prepared that indicates that testing for four gene products significantly improves the ability to determine an indolent Prostate Cancer from an aggressive form. The results also hit the news including a WSJ release.

The release from DF states:

The four-gene signature — Pten, Smad4, SPP1, and CyclinD1 — showed its effectiveness as a predictive tool for survival when researchers drew on data from the Physicians' Health Study, which has been tracking the health of thousands of U.S. physicians for nearly 30 years. When the investigators screened prostate cancer samples from study participants for the four-gene/protein signature, it was more accurate in predicting the ultimate course of the illness than conventional methods were.

We show some of the pathway elements above. A more detailed version is below.

The loss of PTEN has been known for years to be a sign that metastasis may very well already started.  SMAD4, SPP1 and the Cyclin D1 are in pathways that also control the growth of the cell. PTEN is most often the one pathway element of most concern.

The driving factor in the result is:

The standard measure of prostate cancer's aggressiveness, known as the Gleason score (which is based on cancer cells' appearance under a microscope), is accurate about 60 to 70 percent of the time depending on the skill of the pathologist. The four-gene signature method alone was accurate 83 percent of the time. Combining the markers and Gleason methods produced an accuracy of approximately 90 percent.

Now the above result need some clarification. 

1. Gleason scores are score based upon the histological presentation of the cells. Gleason 1 for example is low grade and shows the cells as small gland like structures but lacking gland architecture. Gleason 5 is a mass of undifferentiated cells clustered about the stroma, internal part of the prostate, with no structure. Gleason scores are the sum of the most prevalent cell type plus the next most prevalent so a 7 is a 4+3 or a 3+4. Clearly a 4+3 is more sever than a 3+4. But Gleason alone tells one little about the metastatic potential.

2. Genetic pathway changes are often the sine qua non for determination. But what genes and in what cells. The problem is the existence of the cancer stem cell idea, namely that one of the many cancer like cells is pluripotent and if this is true in prostate cancer then it is that cell we want. So perhaps in a biopsy we missed the killer cell, or it may have already escaped.

3. This procedure statistically takes us a step forward, now we can test to see if we do have some very bad cells. However one may ask if we are finding out when the cow has already left the barn. Namely what we may have is a test which conforms the fact that the patient's cancer is one of those very bad types so nothing much can be done. On the other hand we may have a patient with an aggressive form which is just a threshold below the bad level. Thus one need significant clinical tests.

4. The question then is; are there other pathway constituents that are prognostic enough to have a meaningful result in mortality, namely how well do we know the PCa pathways. What are the pathway dynamics between these four, we know some, and many are available through NCI.

5. The results appear to have quite extensive, but causality and dynamics still need some filling in. What caused the change. In addition one may look at the HGPIN cases and see that we have HGPIN which all too often is considered as pre-malignant, but we know that HGPIN also regresses to a fully benign prostate. What happened..


As the WSJ states:

Dr. DePinho said the new study suggests a test based on the four genes, when added to current prediction protocols could improve the accuracy to about 90%....Charles Sawyers, a cancer expert and Howard Hughes Medical Institute Investigator at Memorial Sloan Kettering Cancer Center in New York, said if it turns out that such a test is that effective, "it would have a huge impact." He wasn't involved in this research.

Dr. Sawyers cautioned that such gene signatures have been proposed to predict cancer progression in the past and haven't panned out. He said the genes the new research focuses on appear to have a functional role in regulating cancer development, but that more research will be necessary to validate whether a test would have value for doctors and patients..."We'll have to wait and see," he said.

 Indeed one must wait and see. However this will be a challenge to Medicare, since so many of the patients are Medicare patients. How effective is this test? If the genes are all showing aggressive growth then we act? Or is it too late already. If the genes do not show aggressive growth do we deny the patient care even if the patient has strong family history of aggressive PCa? The issue is that all too often the family history dominates. Perhaps this creates more issues than it solves, however it is a step in a good direction, it may or may not be the right one.

Finally the WSJ states:

A test based on the findings is being developed and could be available within a couple of years to help determine how aggressively to treat early-stage cancer, said Ronald DePinho, director of the Belfer Institute of Applied Cancer Science at Dana Farber Cancer Institute, Boston, and senior author of the study...Closely held MetamarkDePinho said he has equity in the company.

 One wonders what research funds were used in the testing. But notwithstanding welcome to the entrepreneur.

We have written a more detailed analysis that the reader may have interest in in one our White Papers.