To view this on my website, sign up for future posts, and search for previous topics, please click here.
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:
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.