Saturday, November 16, 2013

iwCLL 2013: Pharmacogenetics and Dr. Jeff Sharman Discusses New Prognostic Factors

In this interview from iwCLL 2013 with Dr. Jeff Sharman, a very clear teacher and community based cancer researcher, we learn about what I call the coming third generation of prognostic testing.

The first generation was staging, Rai in the USA, Binet in Europe, plus describing how the bone marrow looked liked under a microscope (degree and pattern of CLL infiltration), and some simple blood tests such as monitoring the rate of the rise in the lymphocyte count (doubling time), and B2M, a marker of disease burden.

Then we got more sophisticated (and expensive) with FISH testing, ZAP 70, CD38, and mutation status.

Dr. Sharman tells us what is coming next. An abstract of the Blood article that reviews some of this topic can be found here.

And the progress is not stopping.

Here's a new word we should all learn: pharmacogenetics or our unique genetic nature or phenotype that is concerned with how we metabolize medications. As we might easily infer, our individual pharmacogenetics has significant consequences on how well we respond to some therapies.

An article published last month in Blood, describes for the first time how this aspect of our genetic make up, specifically the subtype or allele of CYP2B6 that we carry, determines how well we convert a certain chemotherapeutic agent, in this case cyclophosphamide into its active form which in turn influences our response to that chemo. Not unexpectedly, those who have a low conversion rate not only do more poorly, but also have less adverse toxic events.

This  whole new area of medicine, pharmacogenomics is already important in cardiac disease where we can measure markers that tells us how and when we doctors should, but sadly too often are not, properly using certain blood thinners based on the patient's measurable genetic make-up.

UPDATE: More on the  gathering importance of pharmacogenetics from today's (11/19/13) New England Journal of Medicine (NEJM) here and here and here with an editorial here.

When the conservative and prestigious NEJM devotes most of an entire issue to a topic, we know that is an emerging hot topic. I am certain that this ill become an increasingly important arena in research in oncology precisely because so many drugs have such a narrow range of safety, and how we metabolize them might just determine the difference between toxicity or efficacy or no activity.

Let us return to listen to Dr. Sharman clearly explain some of these new prognostic tests that are emerging. I am particularly interested in his discussion of directly measuring the functionality of p53, rather than just look for a deletion. What matters to us patients is not the presence or absence of part of a single chromosome , but whether the anti--cancer gene is working or not.

Here's Dr. Sharman:

Part 2 soon.

ASH is coming so I want to be get most of the iwCLL posted here before.

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Blogger Unknown said...

Thank you for a lucid explanation of what I'm thinking of as 3G prognostics. I've been ignoring prognostics recently because they seem to lag behind drug breakthroughs like ibrutinib. I'll start paying attention.

November 17, 2013 at 7:49 AM  
Anonymous Anonymous said...

Some time back I was interested in p450 testing because of medications I was taking. At that time, it was difficult to get it done and covered under health plans. It seems the coverage has not improved as is evident from a recent survey (J. Personalized Med. 2012 #2 pp 201-216). There are online tabulations of known drug interactions with cytochromes (cyclophosphamide and 2B6 for example at as well as large research groups studying these for cancer drug applications (Univ Chicago at It is difficult to identify major effects of the research and present knowledge for CLL so continued efforts along the lines just presented are always welcomed. Be well! TomD

November 17, 2013 at 11:47 AM  
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