23 & You – Genetic tests for pca


The genetics of prostate cancer are daunting, but there are now a range of tests available that could be used at almost every stage of the disease IF you can deal with the answers you are likely to receive. Generally these tests are the product of science that goes something like this: A complete molecular picture is taken of all the mutations or all the genes expressed in a series of prostate cancer patients diagnosed years ago. For these patients “all you need to do” is go back to the paraffin blocks that were saved for each patient, extract the DNA/RNA and quantify gene expression and any mutations that can be detected. A decade ago, the technology for doing this was daunting, but now it is relatively easy. Once you have the gene expression profile, you can ask a computer to look for gene expressions that correlate with a certain outcome. For example, you take 500 patients from one center for whom the outcome is known…50 patients are dead, 32 from prostate cancer…70 patients developed metastases by 5 years…these 315 patients are alive and well with no evidence of recurrence…etc. Let’s say there are 50 genes that show changes in expression or mutation. Do we need all 50 to forecast what happened to the patients in that group? No. A computer algorithm can keep testing combinations and permutations of genes and reduce the 50 to a smaller number. We can either let the computer pick the final genes, or we could start with genes we think are related to tumor progression and then do the reduction. In the end, we have a small number of genes with characteristics that accurately separate the patients into “good” and “bad” groups and everything in between. We now take our gene panel, reduced to something like a computer chip and apply the test to 500 patients at another institution blinded from what actually happened to those patients. If our algorithm works, we should be able to accurately predict what happened to those patients in the next 5 or 10 years. If it works, our testing system has been validated, and we can begin offering the test to newly diagnosed patients at some stage of illness. For example, a Gleason 3+4=7 patient might fall into a group where surgery produced a 90% chance of being cured at 10 years, or a 40% chance depending on the gene expression. BUT…and this is key…what to do about the result is still a complex decision for both patient and physician. If you are a Gleason 3+3=6 patient and with no treatment at all you have an 85% chance of “cure” at ten years, is that good enough? What if it is a 95% chance? Will that make you more comfortable choosing no treatment, or do you want to be cured at any cost (impotence, incontinence, other side effects of radiation or surgery)?

As none of these tests has been proven in a prospective study – that is, using the tests to do something like even more aggressive therapy in a group of high risk patients, we are still in the early stages of understanding how and when to use them. Fortunately, my colleague, Dave Crawford and some colleagues have put together an excellent website to help patients/doctors understand the tests. http://www.pcmarkers.com has a list of most of the available tests and you can see what results might look like before you and your physician decide to send one off. This is a rapidly evolving field however, and not every test that is being commercialized is listed, and at big centers, there are always new tests being developed.

Finally, as with all of medicine, the payment systems/insurance coverage is crazily complex. Only today, I received an email with the “news” that a cardiologist/congressman, Rep. Buchson has introduced a bill called the “Prostate Cancer Misdiagnosis Elimination Act of 2017” that uses DNA profiling to make sure the tissue being tested is yours. You could theoretically apply this test to ANY cancer biopsy of course, so why prostate cancer? Then there is the motivation…call me cynical, but I suspected that the good congressman, meddling in medicine, might have a local connection, and sure enough, the company that markets the test is from his home state, Indiana. Not to say it isn’t important to know that tissue being tested comes from the correct patient or that the test isn’t a nice application of the kind of technology that identified OJ’s blood, just that we live in interesting times where medical technology is rapidly consuming more and more of our tax/insurance/personal dollars. Personalized medicine will depend totally on this type of technology and can be incredibly expensive. Whether it saves money or consumes it may depend on how many “worthless” (for that patient…and is a treatment with only a 5% chance of working really worthless??…not if you are in the 5% group) treatments are avoided and at what cost. I don’t have the answers. Hopefully this blog at least helps you begin to understand the current molecular diagnostic landscape.

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Today’s the day! Grow a Mo


Movember is here! I urge you to join our team and raise money for helping men fight prostate cancer.  We have, once again, organized a University of Colorado Cancer Center Team.  The MOVEMBER Foundation raises money to fund projects related to men’s health – specifically prostate cancer, testicular cancer, and mental health.  Since 2003, this grass roots project has gathered 5 million participants across 21 countries raising more than $710 million and funding over 1,200 projects.  We, The University of Colorado Cancer Center,  are actively involved in the Prostate Cancer projects which include translational research, clinical registries, and the Global True NTH program.  True NTH is aimed at catalyzing innovative health outcomes programs, through supportive care services, in an effort to improve the lived experience of men with prostate cancer, as well as their partners and caregivers.  

 Your action required is quite simple.

 1)      click HERE to register with the CU Cancer Center Team

2)    get your friends and family to join the conversation and support your efforts

3)    grow (or inspire others to grow) an incredible mustache for 30 days, starting TODAY

I cannot emphasize strongly enough the difference Movember has made in the fight against prostate cancer. Through multiple initiatives they are doing for this disease what Susan G Koman for the Cure has done for breast cancer research. I always used to say, “In breast cancer, they RACE for the cure, while in prostate cancer we CRAWL for the cure.” No longer! This an initiative by men and for men, although just as we have seen the NFL football players sporting pink shoelaces, there are a lot of women who support Movember as “Mo Sisters” as well. 

If you don’t want to join the team and “grow your own”, you can sponsor my feeble attempt at a moustache by clicking HERE.  Many thanks for your consideration. 

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A statin a day??


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I remember when the statins first came out in the late 1980’s. I had a mildly elevated cholesterol that didn’t respond much to the dietary changes (admittedly few) I was willing to make, so taking a statin seemed like a great step forward. But… were they safe? Of course the same could be asked of aspirin, bike riding, eating meat, or skiing. It’s really about risk/benefit in the end. In the years that followed, I ended up taking statins with the permission of my doctor and they work far better than dietary manipulation for my cholesterol and I combine their use with exercise for all of the other benefits (read here). I previously posted about statin use here, but there are new data all the time worth keeping up with.

In a recent JCO article, a large group (31,790) of Danish men were evaluated for prostate cancer specific and overall mortality depending on their use of statins. Even though there was a higher mortality from prostate cancer than is usually seen in such studies (23% – potentially because there is lower use of screening in Denmark), the prostate cancer specific death rate and overall death rate was 15-20% lower in the men who took statins after diagnosis. This was regardless of their treatment (surgery, radiation, hormones). Since I mentioned aspirin, other studies have suggested that men with high Gleason scores (≥8) may benefit from aspirin use as well. Statins have also been shown to inhibit a long list of other cancer causes of death that you can read about in Wikipedia, so the benefits to prostate cancer patients, who often die of other cancers or cardiovascular disease is not limited to their concerns about prostate cancer itself.

In an editorial accompanying the JCO article by Mucci and Kantoff, there is a thoughtful review of whether statins should be recommended for all men with prostate cancer. The article also discusses how they might work to slow down prostate cancer, so be sure to read it for the excellent summary. They conclude that the evidence is still not there, although certainly the large number of studies and meta-analyses they provide make a strong case. My question would be “what is the risk?”, and it seems to be minimal. Statins are cheap and widely available. They provide risk-lowering effects on cholesterol/heart disease, and the only side effect that is a problem in general is the muscle pain that occurs in some patients, which almost always goes away when you stop the drug. I can’t disagree with the thought that a prospective randomized trial in a subgroup of prostate cancer patients is desirable, but in the absence of such a trial to invite patients’ participation, I personally encourage patients to take statins unless their primary care physician disagrees. For that matter, I would almost encourage their presence in the water supply like fluorides given all their other benefits (just kidding, but they really do have a long list of benefits and very favorable risk profile in my view).

An apple a day is a good idea. Statins should maybe join that, and keep exercising!

 

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Rising PSA – When to start therapy


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One of the most frequent situations I encounter in my small “prostate cancer only” practice is a man who has had treatment (usually surgery or radiation) several years ago and now has a rising PSA. He feels absolutely fine, may be exercising daily, and his PSA is often so low that a routine scan won’t show anything. What to do?

The options in this situation are changing. Treating oligometastatic disease (few metastases) is somewhat of a new frontier in this situation. In the “old days” when I wrote about this subject, we reviewed the non-randomized data that suggested no advantage to starting ADT earlier. More recently, the idea of treating some men with radiation or surgery directed at the mets if they have only a few has become more popular. Added to this is the increased sensitivity of the newer PET scans (choline, acetate, PSMA targeted) that may reveal metastases even with PSA values less than 1.0. While it is hoped that some men could be cured by this approach, it is also possible that one could delay the implementation of ADT and its side effects. There are multiple ongoing clinical trials looking at this issue. With such rapidly changing technology, it will be difficult to come up with a “right choice” in every situation. What may have been considered “non-metastatic rising PSA” last year could become “oligometastatic” simply by the implementation of the new scans.

Beyond this is the issue of treatment-related side effects. In an article this week in Lancet Oncology, the side effects of treating men with asymptomatic, non-curable prostate cancer (TOAD and TROG studies) was reported. This study is one of the few randomized studies in this setting. The men were about 70 years old with rising PSA’s, most having been previously treated. They were randomized 1:1 to starting ADT immediately or waiting until at least 2 years later unless “symptoms or metastases developed or PSA doubling times decreased to 6 months or less”. Earlier, the investigators published the survival data in this study, indicating some advantage to starting earlier, as shown in this graph. Screen Shot 2017-09-12 at 9.14.48 PM

However, keep in mind that the men who were in the immediate ADT arm also experienced the ADT side effects sooner according to the new report. The most important areas of symptoms were the hot flashes and decreases in sexual activity (reported only in the men who were sexually active) which were significantly worse with the immediate treatment, as might be expected. In a “global quality of life” measurement there was also worse quality of life, although it was not significant (the score number was 72.39 for delayed therapy vs. 70.83 for the immediate group). Further, the type of ADT used varied, and included both intermittent and continuous therapy (usually intermittent therapy has at least some improvement in quality of life). Finally, none of the men in these studies received the newer (and vastly more expensive -but probably more effective) ADT agents, abiraterone or enzalutamide which have been shown to improve survival when used “up front” in the metastatic setting.

Thus, a rising PSA is obviously a reason for concern, but choosing a management strategy is quite complicated at the present time. The best news to come out of this study is that prostate cancer is a slow disease. “Overall, 18 (6%) men died from prostate cancer, 12 (8%) in the delayed treatment arm and six (4%) in the immediate arm…” This is not to say that as time goes on there will not be more prostate cancer deaths, and there was earlier metastatic progression in the delayed group, but it is equally important to realize that at age 70 there will be significant competing causes of mortality. Something will get us eventually, so the key is to not let prostate cancer (or the PSA) dominate our thinking. What other things can you work on? Stop smoking. Exercise. Improve your diet. And most of all, enjoy each day as a gift and live it to the fullest regardless of how you decide to deal with a rising PSA.

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Abiraterone (Zytiga™) earlier makes a big difference in outcomes


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The big news at the ASCO annual meeting this year included two “practice changing” presentations for prostate cancer that have been widely covered in the medical press. The basic finding is that adding abiraterone to ADT in the “up front” setting (i.e. when initially starting ADT for high risk disease, a rising psa or in someone who has newly diagnosed metastatic disease) results in markedly improved overall survival and time to progression of disease. I encourage you to read the link above which reviews the presentations and commentaries in detail. Reflecting our amazing digital age, the New England Journal published the detailed, peer-reviewed articles on the two studies simultaneously with the ASCO presentations.

In the Latitude trial, 1199 men who were newly diagnosed with metastatic disease and who “… were considered to have at least two high-risk prognostic features (e.g., a Gleason score of ≥8, the presence of ≥3 bone lesions, or the presence of measurable visceral metastasis)” were randomized to receive a GnRH analog plus abi/prednisone vs GnRH analog plus dual placebos. The science behind this is that with surgical (orchiectomy) or medical (GnRH analog) castration, testosterone synthesized by the testicles is mostly eliminated. But there is still stimulation of the prostate cancer androgen receptors (AR) by other testosterone, coming from the adrenal glands, the tumor cells making testosterone themselves,  other steroids, or even changes in the androgen receptor itself. Abiraterone or its metabolites can block most of these pathways. Thus the question is whether nearly complete shutdown of AR stimulation from the onset of treatment can achieve more than waiting to use Abi after resistance to AR directed treatment with a GnRH analog develops. The results were remarkable:

A second trial, from the STAMPEDE group used a similar approach in a different, more heterogeneous group of 1917 patients with high risk localized disease, metastatic disease, or PSA relapsing disease after local therapy. The randomization to standard ADT alone vs ADT plus Abi/prednisone was similar as were the remarkably positive outcomes.

Screen Shot 2017-06-05 at 10.16.58 AM

The P-values for some of the endpoints in this trial were eye-popping. “Time to failure improved by 71% in the abiraterone group (HR 0.29, 95% CI [0.25, 0.34]; p = 0.377×10-61)” The discussants at ASCO pointed out that future trials may need to consider comparison of abiraterone early addition to the early addition of chemotherapy as was done in the CHAARTED trial. Generally, however, the toxicities of docetaxel are certainly greater than abiraterone and such a trial would be complicated. It is even possible that one of the ways docetaxel works is “simply” blockade of AR translocation and that it is just a more toxic way of hitting the same pathway. In addition, the cost considerations of abiraterone, particularly when it must be taken for years, are a real concern, and in keeping with the very keen worries we have regarding new cancer drugs in general.

“Targeted therapies” along with the immune checkpoint blockade drugs are changing the landscape for cancer patients. To me, the somewhat surprising thing about these two studies is how great the advantage seems to be when you can truly effectively hit a target early and hard, in this case the AR signaling pathway. It is all the more remarkable that this is a pathway we have now been targeting for over 70 years and there is still more to come. If we can find the right combination of AR targeting and immune modulation, I see no reason why metastatic prostate cancer can’t be added to the “curable neoplasm” list in the near future. Then the question of whether, and how we need to screen will become even more complex. Good news !!

Disclaimer: I am a consultant for Janssen, the pharmaceutical company that sponsored the Latitude trial discussed above.

 

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To Watch or Not to Watch


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Active surveillance (active monitoring, watch and wait, etc. – each with slightly different definitions) means you know you have a low risk prostate cancer (typically defined by a small amount of cancer in only a few of the biopsy cores and usually with a Gleason 3+3 score (some studies also include low volume Gleason 3+4 patients). Knowing this, you decide to not have treatment but just “keep an eye on things”. It all sounds so simple until you try to project what that means for YOU, and here is where the decision making becomes complex. Risk tolerance and rewards of decisions are psychological issues, not so much medical ones. Some people feel the thrill of jumping out of an airplane or off a bridge with a bungee cord more than compensates for the relatively small risk. Others don’t. For some men, ANY decrease in their sexual function or chance of incontinence is not worth the risks of treatment. For others, ANY risk of dying from prostate cancer is unthinkable. And, I would add – having counseled many couples – that the spouse’s feelings about sexual intimacy and survival vary considerably. For the record, the most common comment I hear from the wife is “We don’t care so much about sex, I just want George to be here” or similar, sometimes paired with the comment (regarding surgery vs. radiation) “I just want it out of him.”

With that background, Anthony D’Amico, one of the most prolific researchers and best analytic minds in our field, has written an editorial worth reading. In it he posits the question of whether the development of metastases, not death from prostate cancer, should be the better way of evaluating active surveillance. His primary analysis comes from looking at the ProtecT study, published last year in the NEJM. In that study, “82,429 men had a PSA test; 2664 received a diagnosis of localized prostate cancer (including 146 men from the feasibility study), and 1643 agreed to undergo randomization to active monitoring, radical prostatectomy, or radiotherapy.” There were about 550 men in each arm of the study and at the end of 10 years, there was no difference in the death rates from prostate cancer. 291/545 of the men in the surveillance arm had gone on to receive treatment within 10 years. However, as D’Amico points out, “the occurrence of metastasis, defined as the spread of PC to bone, viscera, or lymph nodes or a PSA level > 100 ng/mL, occurred in 62 men and was more than two-fold higher in men randomly assigned to [active surveillance] versus a treatment protocol.” In absolute terms, this meant that 32/545 surveillance vs 13/553 surgically treated vs 16/545 radiotherapy patients developed metastases and would need to suffer the side effects of hormonal treatment during their last decade or so of life. D’Amico argues that these men with metastases should be a better measure of the outcome for the active surveillance approach. What he does not deal with, however, is the benefit the men without metastases experienced by taking the approach. By 10 years, nearly half of the surveillance group had not had the side effects of definitive treatment, and even those who “fell off the wagon” and were treated enjoyed some additional time without side effects.

In a companion article to the ProtecT cancer outcomes article, we learn more about the side effects of treatment. These graphics from that article show that surgery (red line) and radiation therapy (gold line) produce significantly more side effects than the slower problems that develop over time with both urinary and sexual function in the surveillance (and all aging men) group (blue line). The PIVOT trial (also worth reading to gain perspective on the relative advantages of treatment or not) demonstrated that virtually all patients who receive treatment experience some decrement in sexual function.

Not shown, but an important part of the overall picture, is that the surveillance protocols involve biopsies every 1-2 years, or MRI exams (or increasingly both), following the PSA values which can and does produce anxiety (see my blog on the “PSA Clock”), and the psychologic burden of “knowing you have cancer”. These side effects of surveillance are often under-appreciated, and some men who elect for surveillance eventually change their mind and opt for treatment because of them.

Finally, age makes a big difference in psychology. Older men are generally less sexually active and focused than younger. There is good evidence that it is just as safe to do active surveillance in younger men, if sexual function is an overriding consideration. In the end, the decisions about what to do if you have been diagnosed with a low grade prostate cancer are not easy, and highly personal – just like sky-diving and bungee jumping!

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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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