One of the big question remaining about lethal, advancer prostate cancer is It is whether a single clone metastasizes and remains dominant over the course of the cancer or if each clone is independent.
Researchers have described the clonal architectural heterogeneity (internal differences in the tumor) at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive prostate cancer survivors.
They found that by characterizing the cancer of commonly occurring deletions at 21q22, 8p21, and 10q23 (mutations in these three specific genes), they were able to identify multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. They showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of men progressing on abiraterone (Zytiga) and prednisolone or dexamethasone. These resistant clones showed a complex dynamic with temporal and spatial heterogeneity, which strongly suggests that there are distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure (what treatments were used).
This finding provides a management paradigm requiring constant monitoring of men with advanced prostate cancer using both plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.
Failure to monitor plasma and tissue tumors leading to the continuation of treatments when these mutations occur actually will drive the problem genetic mutations causing your disease to progress and become lethal much more quickly than it might otherwise. Most doctors do not adequately monitor the genetic mutations that are caused by treatment and eventually drive the disease to become lethal.
Tumor Clone Dynamics in Lethal Prostate Cancer; Sci Transl Med 17 September 2014: Vol. 6, Issue 254, p. 254ra125 ; DOI: 10.1126/scitranslmed.3009448, S. Carreira, A. Romanel, J. Goodall, E. Grist, R. Ferraldeschi, S. Miranda, D. Prandi, D. Lorente, J.-S. Frenel, C. Pezaro, A. Omlin, D. N. Rodrigues, P. Flohr, N. Tunariu, J. S. de Bono, F. Demichelis, G. Attard,
Joel T. Nowak, M.A., M.S.W.
Yesterday I wrote about the cognitive effects of hormone therapy (ADT), today’s topic is about depression in men on ADT. It is commonly known that men on ADT often experience many physical and psychological side effects of the treatment. One of these side effects to ADT may be associated with increased risk for depression, but the relationship between ADT and depression is not fully understood.
In a longitudinal study designed to assess depression in men receiving hormone therapy (ADT) researchers compared two study groups of men with prostate cancer against a matched control group of men without a prostate cancer diagnosis.
Participants in the study were men diagnosed with prostate cancer who were initiating ADT treatment (ADT + group support) and ADT without group support and their matched no prostate cancer controls.
Depressive symptomatology was assessed using the Center for Epidemiological Studies Depression Scale at ADT initiation and again at 6 months. Differences in depressive symptomatology and rates of clinically significant depressive symptomatology were analyzed between groups at each time point and within groups over time.
Rates of clinically significant depressive symptomatology were higher in the ADT+ group support than the ADT without support and the non cancer control without support at both time points. Although exhibiting less depressive symptomatology than the ADT+ group the ADT without support group also exhibited more depression than the non-cancer control group. This finding leads to our asking if the depression comes from having a cancer diagnosis and it group support encourages feelings of depression.
Despite these questions, the most important finding supports the general hypothesis that men diagnosed with cancer and possibly those receiving ADT are subject to increases in depression.
This leads us to conclude that the mechanism behind receiving a cancer diagnosis and ADT’s association with depression should be further explored. Prostate cancer survivors, including those who are being treated with ADT should receive particular focus in depression screening and intervention. P
Joel T. Nowak, M.A., M.S.W.
When I went on my first round of hormone therapy (ADT) I experienced severe cognitive side effects. I found it impossible to concentrate, read and remember anything. I lost the ability to navigate the New York City subways no less drive my car to a destination. Occasionally, when I was attempting to navigate the subway I found it necessary to get off the train, go upstairs (losing my fare) and call my wife Wendy so that I could describe what I saw so she could remind me where I was headed and how to get there from where I described.
Remembering what I had read from day to day was impossible. I finally went to a bookstore and bought a boy’s adolescent sailing novel about cannons and pirates, etc. Then, each night I went to bed and read the same first few chapters of the book. It was always new, exciting and I was able to follow the characters. Even though I had read the same chapters night after night it was always brand new and exciting!
When I reported this to my doctors they universally scoffed and told me that I was exaggerating. I was not it was this difficult for me.
Finally, the concept that chemo brain might exist for men on ADT has had some traction. Researchers from the University of South Florida have taken to heart this issue and decided to examine it from a scientific perspective. They have systematically reviewed the existing literature to determine the effect of ADT on performance across seven cognitive domains using a meta-analysis.
Through a search of PubMed Medline, PsycINFO, Cochrane Library, and Web of Knowledge/Science databases they found 157 unique abstracts reviewed by independent pairs of raters. Fourteen studies with a total of 417 men treated with ADT were included in the meta-analysis. Objective neuropsychological tests were categorized into seven cognitive domains: attention/working memory, executive functioning, language, verbal memory, visual memory, visuomotor ability, and visuospatial ability.
They found that men treated with ADT performed worse than controls or their own baseline only on visuomotor tasks (g?=?-0.67, p?=?.008; n?=?193). The magnitude of the deficits was larger in studies with a shorter time to follow-up (p?=?.04). No significant effect sizes were observed for the other six cognitive domains (p?=?.08-.98)
They concluded that prostate cancer survivors who received ADT performed significantly worse only on visuomotor tasks compared to non-cancer control groups. These findings are consistent with the known effects of testosterone on cognitive functioning in healthy men.
I guess I am truly an outlier. Are there any other outliers out there?
Support Care Cancer. 2014 May 25. Epub ahead of print. doi: 10.1007/s00520-014-2285-1; McGinty HL, Phillips KM, Jim HS, Cessna JM, Asvat Y, Cases MG, Small BJ, Jacobsen PB.
Joel T. Nowak, M.A., M.S.W.
As I shared on this blog earlier thanks to many of you I was awarded the 2014 Harry Pinchot award. This prestigious award is made annually by the Prostate Cancer Research Institute (PCRI) and is given at their annual gala dinner which was this past Saturday night. I was joined at my table by my wife Dr. Wendy Lebowitz, my son Dov Lebowitz-Nowak, his girlfriend Amber Bloom, and Malecare’s Executive Director, Darryl Mitteldorf, as well as a number of friends who live in the Los Angeles area.
I was allowed to deliver an acceptance speech which I had written in anticipation. When I accepted the award, I went off script, but still wish to share what I had written as these are my sentiments.
My Speech as Written:
I would like to point out to everyone here this evening that during the 3 hours we are here having this celebration, 105 men worldwide will have died from advanced prostate cancer. I say advanced prostate cancer because men do not die from prostate cancer; they die from advanced prostate cancer.
This is in essence why I am here this evening, or more accurately why I do what I do.
I am a survivor of four separate primary cancers, including advanced prostate cancer. Unlike the other cancer diagnoses I have received, when I found out I had a PC recurrence I was put into a tailspin. I searched for support and good, reliable education about my disease, which I knew, would be ultimately terminal. Despite my living in New York City, with all of its hospitals and educational institutions, I was shockingly unable to locate any support or educational program specific to my diagnosis, metastatic prostate cancer.
My search went on, but it constantly came to a dead end causing me increasing levels of anger. Darryl Mitteldorf, the Founding Executive Director of Malecare, responding to my anger after a Malecare support group that again did not respond to my personal needs, gave me a simple challenge: he told me to stop complaining and do something about it.
I went home, even madder and angrier. I discussed the experience with Wendy, my loving and supportive wife. She responded, “So Joel, why don’t you do something about it?”
So, with Wendy and Darryl’s support I picked up the gauntlet and decided to go out and make a difference in the lives of the men with advanced PC as well as their families.
I started out small as Darryl set up a blog dedicated to advanced PC with the simple directive that I write everyday and write about anything I wish as long as it pertained to advanced PC. Currently, I have written over fifteen hundred posts on this blog, although I do confess I no longer write a post every day; I now take off the weekends.
Over time the blog has changed, today I mostly use it to translate and to inform survivors about cutting edge, translational PC research that could make a difference in their life as well as issues of advocacy, treatment options and public policy that directly affect our advanced prostate cancer community.
Since starting the blog I have expanded my activities to writing a book, A Survivors Guide to Advanced and Recurrent PC, downloadable for free on the Malecare web site.
I have conducted multiple teleconferences also available online, conducted with the experts on issues surrounding advanced PC.
Darryl and I started the world’s first, and I believe only, crowd funding site for prostate cancer research (StartACure.com) which has already funded a project at John’s Hopkins University.
I also have started face-to-face support groups including a group for men with advanced PC; as well as an online support group for advanced PC, which now has participants from all over the world.
Recently, we set up an innovative email based educational program that presents timely, curated translational information to men based specifically on their individual disease stage.
Information in these Prostate Flashes is designed to inform men about cutting edge research that could have an immediate and direct effect on them and their families. Our goal is to have the survivors bring this information to their doctor’s attention and engage in a conversation about its relevance to their individual healthcare plan.
One of my proudest moments was when the DOD Prostate Cancer Research Program elevated me from being a scientific reviewer to the Integration Panel where I have had the great experience, although way too short time period, to work with our own Dr. Maha Hussein, who is a medical participant here at this conference.
Now, I want to challenge all of you like I was challenged nine years ago. I challenge you, the leaders of the prostate cancer community to develop better programing for our community.
Many of us, both individuals and organizations have become lazy and only do the things we have always done.
We sit on the laurels of our prior accomplishments.
We assume the success of our programs based on quantity and not quality.
What we need is programing that is innovative, not more from our traditional mold, its time to dump the regular and mundane.
We need programing that truly speaks to our individual constituents needs and we need to confirm that we are doing this job.
We need programing that responds to the most vulnerable among us, the constituent populations that has not received adequate attention.
Malecare recently began a program, Living Alone with Cancer that seeks to understand and then respond to the special needs of men who must fight cancer while living alone. This program just completed a Quality of Life Survey. It was open for just 2 months, received 1,800 responses and generated over 125,000 data points that will be publicly available in early 2015.
Our program, Twice As Many, is responding to the great disparity we see in the African American Community where twice as many African Americans die from prostate cancer than their European counterparts.
We need to increase our support for other, less known disparate populations, like Malecare’s National LGBT Cancer Project that recognizes and supports gay and bisexual men and transgender women who have prostate cancer.
The reason I quoted worldwide death statistics when I first came up here is because prostate cancer is a worldwide problem. We need to strengthen our ties with our counterparts in other countries by utilizing organizations like The Global Prostate Cancer Alliance, which currently has 34 members coming from every continent in the world.
Now we as the prostate cancer community leaders need to let our minds go free, find the issues that plague our community and figure out ways to respond to and eliminate these issues.
It is time to think out of the box. As we do in the DOD and at Malecare, we need to support high risk, but high potential gain programing to serve the individual needs of men with prostate cancer.
I have learned so much from clinicians and researchers, who’ve shared their expertise and their time participating in workshops and teleconferences, and to explain, teach and encourage me personally.
I’ve received a tremendous amount of support and encouragement from many individuals, from Darryl, and especially my family, specifically Wendy, and my boys Dov and Max.
I thank them all, but the support that has had the most meaning for me is the support from the men with advanced, metastatic Prostate Cancer and their families.
Thank You Wendy, Darryl, all you survivors and to PCRI for this honor.
I want to leave you this evening with the wisdom of the great 20th century philosopher Lily Tomlin who said:
“I always wondered why somebody doesn’t do something about that. Then I realized I was somebody.”
Expected and extraordinary news today on the new treatment front. Medivation and Astellas’ Xtandi (enzalutamide) was approved for use in men with castrate resistant prostate cancer.
The new FDA approved label for Xtandi says that it is for the treatment of men with metastatic castration-resistant prostate cancer. This label is basically the same as for Zytiga. Both encompass the pre-chemo and post-chemo stages in castrate resistant prostate cancer. However, in the clinical section of the Xtandi label says that there is statistically significant improvement in overall survival when compared to Zytiga.
I must remind you that this seeming advantage to Xtandi comes from a statistical conundrum stemming from the way the Xtandi and Zytiga clinical trials were conducted. Zytiga never showed a statistical survival advantage because the trial was stopped early (before the data matured) as a result of the drug demonstrating so much promise that it was felt that it was unethical to continue the trial. We do not know and we will never know the statistical survival advantage that Zytiga might provide.
What is important and worthy of celebration is that Xtandi is now FDA approved in the pre-chemotherapy stage of castrate resistant prostate cancer. It joins Zytiga and Provenge in the pre-chemotherapy stage.
Approval Based on Improved Overall Survival, Delayed Time to Radiographic Progression and an Overall Positive Benefit-Risk Profile
Joel T. Nowak, M.A., M.S.W.