International group creates better gene map for men with mCRPC

A new article in the journal Cell is being said to “clarify the genetic backgrounds of men with metastatic, castration-resistant prostate cancer” (mCRPC). It also suggests that most cases of prostate cancer are “sensitive to drugs already available or under development.”

The article by Robinson et al. has already gained extensive media coverage and involves an international consortium of contributors from eight major centers involved in the study of the underlying genetics of progressive prostate cancer. The various teams have been working together to develop what they describe as “a precision medicine framework” for management of men with mCRPC. To do this, they collaborated on the prospective whole-exome and transcriptome sequencing of tumors from 150 patients with mCRPC that had spread to the bones, soft tissues, lymph nodes, and livers.

Here’s a link to the media release issued by Cancer Research UK.  … And here are some of the key findings from this important study:

  • 89 percent of the 150 patients were found to carry a “clinically actionable” genetic aberration in their cancer cells.
  • Aberrations of AR, ETS genes, TP53, and PTEN were frequent — occurring in 40 to 60 percent of the cases.
  • Aberrations in TP53 and AR occurred more often in men with mCRPC than in primary prostate cancer.
  • Aberrations in BRCA2, BRCA1, and ATM were also observed at higher frequencies than in primary prostate cancer — occurring in 19.3 percent of cases overall.

Two study authors are being widely quoted on the importance of this work. According to Dr. Eliezer Van Allen of the Dana-Farber Cancer Institute in Boston, these data provide

a strong argument that the genomics driving advanced prostate cancer is fundamentally different than primary prostate cancer.

And Dr. Johann de Bono (based at the Institute for Cancer Research and the Royal Marsden Hospital in England) states that:

This map will guide our future treatment and trials for this group of different lethal disease. … We’re describing this study as prostate cancer’s Rosetta stone — because of the ability it gives us to decode the complexity of the disease, and to translate the results into personalized treatment plans for patients.

Now we should be very clear that, although this study is certainly going to help to move clinical research forward over time, and it is gratifying to know that most cases of mCRPC are now “sensitive” to the many new drugs either on the market or in development, this does not mean that we are necessarily close to finding treatments that will stop advanced prostate cancer in its tracks and put these patients into long-term remissions. It does mean, however, that we may be able to get a lot better at defining who needs treatment with newer drugs (like abiraterone acetate and enzalutamide and the newer PARP inhibitors) early in the development of their disease so that they can be treated more efficiently and effectively early on.

The other thing that this study makes abundantly clear (if it wasn’t already) is that the genetics of progressive prostate cancer are complex and multi-faceted. We are not going to be able to find one or probably even two forms of therapy that can stop prostate cancer in its tracks once it is metastatic and castrate resistant. From a clinical point of view, what is going to be needed are therapies that can stop the progression of the cancer earlier in the development of metastasis, so that we can break that chain of progression before we see the diversity of evolution of all the genetic aberrations that are now evident in men with mCRPC.

One Response

  1. For men who have failed the new second-line anti-androgens, who have, or are suspected to have, the AR V7 mutation, and who do not harbor a BRCA gene, there are still woefully few options … even if we have a good genomic map of their tumors.

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