Wednesday, June 12, 2013

Prostate Cancer Testing

I noticed a piece which gives prices for various prostate cancer gene tests. The article in Spectrum Online states:

The newest test was developed by Genomic Health Inc., which has sold a similar one for breast cancer since 2004. Doctors at first were leery of it until studies in more groups of women proved its value, and the same may happen with the prostate test, said Dr. Len Lichtenfeld, the American Cancer Society’s deputy chief medical officer.

The company will charge $3,820 for the prostate test and says it can save money by avoiding costlier, unnecessary treatment. Another test for assessing prostate cancer risk that came out last summer — Prolaris by Myriad Genetics Inc. — sells for $3,400.

We discussed the CCP test in a detailed White Paper  and expressed our concerns, based not upon any deficiency but due to in our opinion a lack of reproducibility. We do not have any data on the second test. But if our understanding of the CCP test is correct it is used after a biopsy and tests 31 genes in the cancer ridden prostate. The test then provides some statistical measure of death in some period of time given some scalar metric based upon what appears to be an undisclosed process of gene expression. 

The the test allegedly tells a patient who has undergone a biopsy with some level of Gleason score that the have a good or bad chance of survival.

Thus the patient is charged for the biopsy, the path study, the test, and then gets to decide what? That is where I would have the problem.

The article continues: 

About 240,000 men in the U.S. are diagnosed with prostate cancer each year, and about half are classified as low risk using current methods. Doctors now base risk estimates on factors such as a man’s age and how aggressive cells look from biopsies that give 12 to 14 tissue samples. But tumors often are spread out and vary from one spot to the other.

The NY Times says: 

The test looks at the activity level of 17 genes in the biopsy sample and computes a score from 0 to 100 showing the risk that cancer is aggressive.To see how well the test worked, testing was performed on archived biopsy samples from 412 patients who had what was considered low or intermediate-risk cancer but then underwent surgery.In many such cases, the tumor, which can be closely studied after it is surgically removed, turns out to be more aggressive than thought based on the biopsy, which looks at only a tiny sample of the tumor.

We have shown that if one uses 24 or more cores, depending on prostate volume, that one can reduce the risk of missing the diseased segments. We have moved from six cores, to 12, to 24, and some are as high as 36. With a highly competent urologist and 24 cores one should managed to have a high detection probability. Furthermore we know that if upon detection we have a Gleason of 7 or more than most likely we have a serious problem. Yes, many of Gleason 7 progress slowly, and yes it would be good to know which do not, yet the above tests in my opinion have a way to go. Just my opinion.

Yet one of my major concerns is the possibility that a prostate cancer stem cell may have migrated to a distant site, say the bone, and that the test would miss that event and provide a false sens of security. Furthermore, even in the biopsy samples the stem cell may have been missed and the cells detected may be considered indolent but the ore aggressive cells have remained in place.

Just grossly testing for the presence of certain genes is interesting but in my opinion far from conclusive.One need just look at the paper by Navin and Hicks and examine the various problems with the approaches mentioned above. As Navin and Hicks state:

Defining the pathways through which tumors progress is critical to our understanding and treatment of cancer. We do not routinely sample patients at multiple time points during the progression of their disease, and thus our research is limited to inferring progression a posteriori from the examination of a single tumor sample. Despite this limitation, inferring progression is possible because the tumor genome contains a natural history of the mutations that occur during the formation of the tumor  mass.

There are two approaches to reconstructing a lineage of progression: (1) inter-tumor comparisons, and (2) intra-tumor comparisons. The inter-tumor approach consists of taking single samples from large collections of tumors and comparing the complexity of the genomes to identify early and late mutations. The intra-tumor approach involves taking multiple samples from individual heterogeneous tumors to compare divergent clones and reconstruct a phylogenetic lineage. Here we discuss how these approaches can be used to interpret the current models for tumor progression. 

We also compare data from primary and metastatic copy number profiles to shed light on the final steps of breast cancer progression. Finally, we discuss how recent technical advances in single cell genomics will herald a new era in understanding the fundamental basis of tumor heterogeneity and progression.

Thus the multiplicity of ways tumors progress means that taking samples at one time and place most likely will not reflect upon the true status of the systemic disease.