Nex Gen Diagnostics and Treatment

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When I was a fellow in Dr. David Livingston’s lab 40+ years ago, DNA sequencing had just become “widely” available, developed by Maxam and Gilbert. There was a brilliant MIT student, 16 years old as I recall, who visited the lab that summer and brought his TI calculator to the lab, assigning a number (1,2,3,4) to each of the bases and would go into David’s office with a string of numbers to look at. The evolution of that technology to what goes on today when you send in a saliva sample to 23 and Me is shown in the following video:

This video explains next generation DNA sequencing

With what seems (to an old guy like me) shocking speed, the human genome was unraveled and with it, all (most?) of the genes that control cellular processes including cancer. As I have recommended before in this blog, for a fabulous review of the story, I recommend you read “The Emperor of All Maladies” by Siddhartha Mukherjee.

Due to the power of DNA sequencing it is now possible to obtain DNA that originates in tumors and do sequencing of cancer causing genes directly from the blood stream or from the urine or other body fluids. This is a so-called “liquid biopsy“.

The entry of this technology into caring for cancer patients has also been incredibly rapid. At the present time, for prostate cancer, the NCCN patient guidelines are a great place to start learning about pca in general if you are new to the topic, but the physician NCCN guidelines are much more specific regarding what you need to know about your genetics. Here are the recommendations for “germline” testing, i.e. what you have inherited that may have pre-disposed you to develop prostate cancer and what might affect other members of your family including children or siblings:

The guidelines are also very informative about this testing being done with the help of professional genetic counsellors:

Genetic testing in the absence of family history or clinical features (eg, high- or very-high-risk prostate cancer) may be of low yield.
• The prevalence of inherited (germline) DNA repair gene mutations in men with metastatic prostate cancer, unselected for family history (n = 692), was found to be 11.8% (BRCA2 5.3%, ATM 1.6%, CHEK2 1.9%, BRCA1 0.9%, RAD51D 0.4%, and PALB2 0.4%). The prevalence was 6% in the localized high-risk population in the TCGA cohort (Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015;163:1011-1025; Pritchard CC,Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443- 453).

• Genetic counseling resources and support is critical and pre-test counseling is preferred when feasible, especially if family history is positive.

• Post-test genetic counseling is recommended if a germline mutation (pathogenic variant) is identified. Cascade testing for relatives is critical to inform the risk for familial cancers in male and female relatives.

https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

However, as noted above, we can also sequence the tumor itself or look for mutations in tumor DNA that is circulating. The most important thing that may show up in these analyses is a mutation that can be specifically targeted with one of the newer drugs. Examples include the finding of a DNA repair gene mutation such as BRCA1 or BRCA2 in which case the use of a category of drugs called PARP inhibitors or platinum based chemotherapy might be an important consideration for patients who have failed hormone therapy. Thus, we now utilize DNA sequencing both in patients who have family histories for certain cancers, patients with metastatic disease, high risk disease, and again when there is progression of the cancer after hormone treatment stops working. Beyond these impacts of DNA sequencing are the many gene-based tests that have evolved that can help determine risk for finding prostate cancer on a biopsy, or predicting whether someone is at high or low risk for metastatic disease after a positive biopsy and Gleason score is known.

I tried to help understand the complexities of integrating all of these new tests and therapies in this blog. Although it may be difficult to keep up with this rapidly evolving landscape for both patients and physicians, there is no doubt that we have entered the “next gen” era of prostate cancer management. Finding an expert who focuses on pca and discussing some of the issues raised in this blog is key to taking advantage of what is being learned. Hopefully this blog will help you become a better informed member of your team in terms of the underlying technology. For a more erudite discussion of cancer precision medicine, you might read this newly posted discussion.

5 Comments

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5 responses to “Nex Gen Diagnostics and Treatment

  1. David Stevens

    Sir: with regard to your advice, ” Finding an expert who focuses on pca and discussing some of the issues raised in this blog is key to taking advantage of what is being learned.” Is there a resource available where one can search for PCa-focused physicians? Just trying to avoid a haphazard approach to finding such expertise. Thanks.

  2. Hi David, That is and excellent question. I confess that with my background in academic medicine, my first response will be viewed as “elitist” by many. Those of us who spend the most time in our careers narrowly focused in one area tend to “publish or parish”. If you find a physician who has continued to publish on prostate cancer in academic journals, he/she is most likely to be following the advances closely. A related way might be to look for clinical trials in your area at http://www.clinicaltrials.gov and enter “prostate cancer” and then restrict geographically. Again, most experts or centers of excellence in the disease are often participating in the research that advances the field. Finally, if those methods fail, I would try to find an oncology group that is large enough so that one or two of the practitioners focuses on GU oncology and doesn’t try to take care of “everything”. I’m well aware that there are some outstanding oncologists in solo practice who may be able to keep up in all areas, and when they don’t feel sufficiently confident, will call a colleague with more expertise for advice, but there is no substitute for seeing 100’s or 1000’s of patients over time with the same disease in terms of building up hands on expertise.

  3. Bob Lederer

    So incredibly helpful for us as patients to sort all of this out. I forgot some risk factors that I have and it dovetails perfectly. Though practicing Christian, I am by heritage 98.7% Ashkenazi Jewish so I have to add that to my huge family history of cancer from my father’s side. I am fortunate to have a young oncologist who quickly did testing on my tumor and we will definitely be moving on to a PARP inhibitor when my current treatment fails. Since you and I are close in age-this is another wonder of modern medicine. I knew why I needed to retire when I couldn’t understand some articles I read. Thanks again for providing us clarity. Hope Fall fishing has been good.

  4. Bob Louthan

    Dr. Glode, Thanks for writing this blog which I’ve read, including all reference links and books. It has been helpful to me as I struggle (somewhat, not a lot) with not yet knowing the outcome or efficacy of my 41 radiation treatments. During this “wait and see” period I try, mostly successfully, to focus on enjoying life and not looking back nor looking to the future. Think in the present is my goal. However, I remember you saying that statistically the efficacy of radiation treatments such as mine was 80%. I hope that applies to patients like me whose Gleason scores were 4+4 and 3+4.

    You may be interested in how I finally decided to get a biopsy: For 3-4 years I was told by my GP and urologist doctors to “wait and see, monitor PSA” as my PSA hovered between 3.5 and a high of 5. Then back to

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