Tag Archives: genome

Improving our focus


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I have had two life changing experiences in focusing. The first was when my wife discovered the Myers-Briggs personality classification system and found I am a “strong P”. This meant I couldn’t help it when I was on my way to take out the garbage, noticed a light had burned out, put the garbage down and went to get a light bulb, but found that there was a spot on the carpet that needed cleaning and finally found the carpet cleaner but an hour later wondered why there was a garbage sack in the hall. Prior to her discovery, she just thought I was an idiot, but she became [somewhat] more tolerant of the foibles when she could “classify” me. The second was when I had my congenital cataracts removed and new lenses inserted in my eyes. It was a whole new world of color. I had been living in a fish tank with scum on the glass and “wow, the world is really pretty!” was my response when I took the patches off the next morning. “Trees have LEAVES!”

Focus in understanding prostate cancer is becoming clearer as well. For several decades we have known that the Gleason scoring system is pretty darn good at predicting the cancer’s behavior, adding a lot to what we knew when there was only the digital rectal exam… “Oh, oh, that feels like a really big tumor” or “Maybe I’m feeling something but I can’t be sure”.  Then came the number of biopsies positive, the percentage of each core, differentiating 3+4 vs 4+3, and now an avalanche of new molecular markers, briefly reviewed here. Combining the old standby risk categories with the newer methodologies has been challenging.

A recent paper in the JCO provides us with one way of integrating the old risk categories with the newer molecular classifications. Using the widely adopted risk categories of the NCCN, the authors added to this, one of the more mature molecular classifiers, the 22 gene Decipher™ scoring system to reclassify (focus) a new model to predict outcomes. As I explained previously, these genetic tests are typically developed looking at the level of gene expression in biopsies or in removed prostates in a group of patients for whom an outcome is known (examples include prostate cancer free survival at 10 years or freedom from metastases at 5 years). The investigators (or companies) then go to a different institution or collection of biopsy material and see if their gene expression model developed from the first group accurately predicts the outcome in the second group. This is called “validation” of the test. Decipher has done all of this. The question is how it might change the risk classification of the “old” system.

This figure illustrates how it plays out when a large number of institutions collaborate to study the information gained and develop a new model.Screen Shot 2018-04-28 at 10.16.05 AM

As an example of how this can be used in the “real life” clinic, we are often faced with a patient who has a “favorable intermediate” prostate cancer. Let’s say this is a 75 year old man with excellent health. Should we advise that he adopt a “watchful waiting” strategy, given his age and the relatively low risk? By adding the genomic test, you can see that 27% of the time, this might be a bad recommendation. Similarly, in the unfavorable intermediate group, 40% of patients are moved into a high risk category. Such a patient might be well advised to “do more” (example: more prolonged ADT with radiation, or use of brachytherapy in addition to external beam radiation if they had chosen radiation therapy as their preferred treatment modality).

These kinds of improved focus will allow investigators to do better studies prospectively as well. In breast cancer it is already a standard of care to do molecular classification of certain stages and types of tumors, allowing women to make far better decisions on whether (for example) to take chemotherapy in addition to surgery/radiation. In prostate cancer, where I have been concerned that we aren’t “racing for the cure“, rather we are “crawling for the cure”, it looks like we may be catching up. Research is the answer – sign up and contribute!

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Filed under General Prostate Cancer Issues, Prostate cancer therapy

3 Articles and a forth


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OK, I admit to a sleazy, seemingly misspelled word to attract attention. At least I didn’t tweet it at 3AM. So what about the “forth”? I’m using it to remind you to sally forth in your search for information about prostate cancer. I previously wrote a blog giving some practical instructions on how to find the latest research publications on prostate cancer that you can find here. Another possibility, if you want to be overwhelmed is to subscribe to the Prostate Cancer Daily, published by Uro Today. So far as I can tell it is open to all, presents the original abstracts, and links via PubMed to the article itself. I now realize that the prediction of patients knowing more than their doctors about a given condition is glaringly obvious, something I discussed when I first wrote about the Internet and Oncology two decades ago.

So, on to the 3 articles: Typically, the most important articles in medicine are published in high profile journals. The premier one for medical oncology is the Journal of Clinical Oncology, JCO. The editors recently published a “best of genitourinary cancer, 2017” edition in coordination with what we medical oncologists call “GU ASCO” (actually co-sponsored by ASCO, ASTRO, and SUO). I thought it would be of interest to briefly re-cap the 3 prostate articles chosen for that edition.

ARTICLE 1: Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. This study compared the more potent anti-androgen, enzalutamide (Xtandi™) to the older drug, bicalutamide (Casodex™) in patients who had become resistant to initial hormonal therapy. About 2/3 of the men had positive scans, while in 1/3 the resistance was detected only by a rising PSA without a positive scan. As we might have expected from the way enzalutamide was developed, it was clearly superior, with progression free survival of 19 months for enzalutamide vs. 6 months for bicalutamide. In an ideal world, we would use enzalutamide instead of bicalutamide in almost all cases where an antiandrogen is indicated. However, the increased cost of this drug is dramatic, and there may be other options or confounding issues with interpretation of the study.

ARTICLE 2: Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. This article reports on one of many studies looking at whether radiation therapy treatment times can be safely shortened by increasing the dose of radiation given with each treatment and giving fewer treatments (fractions). The underlying principles are that tumor cells cannot repair DNA damage from radiation as quickly as normal cells, so giving radiation in small fractions daily allows killing of the tumor while normal cells repair most of the damage. Giving all of the radiation at once would kill every cell (and the patient).  Experimentally, prostate cancer cells may be more susceptible to larger fractions, and this study demonstrated that a radiation therapy course could be safely shortened from 41 sessions to 28 sessions with similar “cure” rates at 5.8 years of followup. This is a general trend in radiation therapy for prostate cancer. Using newer radiation focusing technologies (IMRT, IGRT, Stereotactic radiosurgery, etc.) it is possible to treat prostate cancer with as few as 5 treatments, although the long term efficacy is still unknown, and the addition of androgen deprivation to radiation treatment at any dose also improves efficacy. How to combine these approaches, the optimal duration of ADT, and which patients should stay with the older methods is still uncertain.

ARTICLE 3: Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer. Proudly, many of the authors on this article are from the University of Colorado Cancer Center. The authors used the National Cancer Database to determine whether patients with metastatic prostate cancer, traditionally treated with hormone therapy (ADT) only (although more recently with hormone therapy plus chemotherapy) benefit from also radiatiScreen Shot 2015-10-30 at 11.02.16 AMng the prostate itself. The analogy would be burning down the barn after the horse has left (with apologies to my radiation therapy colleagues who never like to compare radiation
treatments to burning). The patients who had their prostates radiated
had a 5 year survival of 49% compared to 33% for those receiving ADT alone. Removing the prostate surgically also worked. The prostate may also be a site where metastatic cells from another location return, as illustrated in this picture and discussed here. The take home message is that the cancerous prostate may continue to “seed” cancer cells to the rest of the body, or be a home for circulating tumor cells and getting rid of it, even though not curative, may be a good idea (toxicities and costs aside).

Consider yourselves updated! (sort of…)

 

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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Uncategorized