Thursday, July 30, 2015

The Press and The Prostate

There are times when you have to say; "You cannot make this up!". In a WAPO piece today the reporter extols the work of some Brits who have on some work on a very small sample and have identified a few genes, mRNA, SNPs etc and from this have developed a staging type system. One should add this to the list of hundreds of others.

Now the researchers state:

We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions.

Frankly much of the above was known in some way shape or form. There are also quite a few commercial tests available already. Now WAPO states:

Through genomic profiling of 259 men with prostate cancer, scientists have identified five groups of prostate cancer with distinct DNA signatures. The discovery represents a major advance as researchers can now begin trying to tailor therapies to those subtypes. The approach has worked well in breast cancer and helped millions avoid the unnecessary cost, pain and time spent on treatments that are destined to fail. [Obama touts ‘lifesaving’ potential of personalized medicine] Such work is the backbone of President Obama's $215 million precision medicine initiative announced in January, which aims to pioneer a new approach to how we treat disease by moving away from a "one-size-fits-all" approach to medicine to one that takes into account things like a person’s genetic makeup, or the genetic profile of a tumor.

Now this is UK, Sweden, and Norway work.  It also is at best personalized but not precise. One can be "precise" but inaccurate. I can tell you precisely where something is but it may not be there. But alas I guess English is no longer used "good" uh well.

Now if the WAPO author had understood where the work in this area is going perhaps they would have had a better view. In fact we have detailed work by Gundem et al in Nature just a short while back. They noted:

Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.

 Namely they noted that prostate metastatic cells in the body had a disparate set of genetic changes. In fact the profiles were quite complex. Thus any small sample as in this article is in my opinion suspect.

As Cancer UK notes:

First, the researchers looked at copy-number alterations in tumour samples from 156 men who had undergone surgery in Cambridge to remove their prostate after being diagnosed with cancer. They then analysed the levels of thousands of mRNAs in these same samples. Next, they compared the two sets of results. Could they find regions of genetic disruption that, by altering gene activity – the level at which they are switched on or off – could be driving the growth of tumours? The answer was yes – they spotted around 1,000 genes where changes in the copy-number – that is, they were deleted or repeated – also changed gene activity. The researchers then homed in on 100 genes with the greatest change compared with healthy samples and which seemed to be crucial to prostate cancer growth, and looked to see how their activities varied across the 156 men. They found that by using this group of 100 genes – or gene signature – prostate cancer patients who’d had surgery to remove their prostate could be divided into five distinct sub-groups.
  • One group had lots of DNA deletions and consequently low activity of certain genes
  • Another had high amounts of DNA repetition which resulted in increased activity of specific genes.
  • Two more groups had very few copy-number alterations, or changes in activity.
  • The fifth and final group had some – but not too many – copy-number alterations.

But one may ask; how do these compare with all the others? Also the sample size is quite small. As Science Daily states:

"This research could be game-changing if the results hold up in larger clinical trials and could give us better information to guide each man's treatment -- even helping us to choose between treatments for men with aggressive cancers. Ultimately this could mean more effective treatment for the men who need it, helping to save more lives and improve the quality of life for many thousands of men with prostate cancer."

Namely the authors themselves seem to readily admit the small sample size issue.

But there are two points to be made:

1. All too frequently authors extend the significance of their results. This is the equivalent of "shingling the roof in the fog". Be careful.

2. The Press, especially WAPO, uses this as some adulation of the Obama Administration. It was NOT in the US and IT IS NOT CONCLUSIVE!

It is truly amazing in my opinion how political even basic medicine has become, especially in reporting.