Tuesday, March 5, 2019

Prostate Cancer News of interest for 3/2019


Prostate Cancer News of interest for 3/2019

Contents



Next IPCSG Meeting Speaker

March 16, 2019

Rana R. McKay, MD, is a board-certified medical oncologist who specializes in treating people with genitourinary (urologic) cancers, including bladder cancer, kidney cancer, prostate cancer and testicular cancer. Dr. McKay is part of the urologic cancer unit at UC San Diego Health’s Moores Cancer Center, where she works alongside a multidisciplinary team to provide patients with highly specialized care.  Dr. McKay will be discussing the Evolving Management of Patients with Metastatic Cancer & will highlight upcoming clinical trials of interest.

Last IPCSG Meeting Summary

February 16, 2019   Member Panel 
Summary by Bill Lewis
1.  Tim D’Andrea is 60 years old, and an engineer who went into technical sales.  “My Journey.”  He is currently in remission, after 31 sessions of proton therapy and 18 ongoing months of Lupron.  His PSA is 0.24 and still dropping.
He was diagnosed in early 2018.  MRI-guided biopsy found one core of Gleason 4+5, and a subsequent Ultrasound-guided biopsy found Gleason 3+3 and 4+3 in one side of the prostate.
During the previous two years, his PSA was in the range of 6 to 7.  His FreePSA was 5%, suggesting a 49% chance of prostate cancer.  The PSA4K test gave 77% odds of high-risk prostate cancer.  His urologist pushed him to accept a random biopsy (not having the MRI-guided option there at Sharp Rees-Stealy), and had no knowledge of any support groups.  He declined the biopsy, joined the IPCSG (“best thing I ever did”), and dove into research on the disease and his options.
He tried a naturopathic approach, including lifestyle (diet and exercise), supplements (apple cider vinegar, flaxseed oil, ginger root, baking soda/molasses, pomegranate extract, curcumin, Maitake, etc.) and 100-g doses of IV vitamin C.  He also cut down on work-related stress – his company approved a four-day workweek for him.  A second naturopath tried two antibiotics to rule out infection, checked with Color Doppler ultrasound (“normal” result), and gave many more (unpleasant) supplements.  His PSA remained steady for about a year.
But then, his PSA rose to 9.5 in October 2017, so he put his IPCSG knowledge and network into high gear.  The MRI guided biopsy mentioned above was done in early 2018, with only four cores.  It was essentially painless, and gave hope for a focal treatment.  But he had a second biopsy with 12 cores (and no anaesthesia – ouch!), which found more widespread cancer within the prostate, eliminating his hope of a focal treatment.  In retrospect, he feels that more cores should have been taken in the MRI-guided session.
Dr. Scholz at Prostate Oncology Specialists recommended Radiation + ADT.  Tim changed his medical network to UCSD, where Dr. Mundt recommended proton therapy, not X-rays (That’s a sign of a great doctor – he recommended a treatment other than his in-house capability!).  So he went to California Protons, and was treated as noted above by Drs. Einck and Rossi.  Last September, he was declared by Dr. Einck (also of UCSD) to be in remission, and told that he needs no biopsy now – just ongoing PSA testing.
Overall, he’s very pleased with his outcome, with IPCSG, and with his wife’s full participation (appointments, IPCSG meetings and research help).  His regrets are having delayed the initial biopsy, and not having more tissue samples in the first biopsy.
2. Elliot Shev and his wife, Dr. Wendi Maurer (clinical psychologist in grief and loss), with “Our Prostate Cancer Journey.”  Elliot is 71 and managing a facility in Tijuana for a large Japanese company.  Current status:  PSA = 1.7, feeling great, with all functions working fine.
After 5 years with his annual PSA hovering around 3.0, it rose to 4.7 by December 2017.  After two weeks of antibiotics (to see if it was an infection), the PSA was 5.5, so they needed to make a decision.  They chose immediate action, and went to see a urologist.  This led to a biopsy (not pleasant!) and Gleason score of 4+3, with Stage = T2b (one side of prostate diseased).  He was given a bone scan and a “high contrast abdominal MRI.”
They were referred to a surgeon and radiologist.  They recorded every conversation, and had them transcribed.  They talked to family members (some are experts in medicine) and “everyone” they knew, despite this aggressive inquiring leading to occasional embarrassing moments (“What’s your PSA?”).  Surprisingly, very many of them “had a story,” and they always made notes.  They found that two friends had had HIFU (high intensity focused ultrasound) treatment. 
HIFU is a “non-invasive” procedure which uses sound waves to image and destroy prostate cancers.  Using real-time imaging, precise, focused ultrasound energy is delivered to the diseased cells of the prostate.  Ideal candidates (per Stanford Healthcare) are men who hope to preserve continence and sexual function, currently have satisfactory sexual function, have cancer visible in MRI and confined to the prostate, and have a PSA below 20.  Some references:  “A Multicentre Study of 5-year Outcomes Following Focal Therapy in Treating Clinically Significant Nonmetastatic Prostate Cancer,” in europeanurology.com.  FDA approval -- Medscape.com/viewarticle/853120.  Doctors: Dr. Robert Pugach, Los Alamitos, CA, HIFUprostateservices.com and Dr. Steven Scionti, Sarasota, FL, sciontiprostatecenter.com.  Much more info is available from Elliot by email on request (via the IPCSG).
Only the half of Elliot’s prostate which contained the tumors was treated, so he still has half of his prostate.  Treatment took about 2.5 hours under total anesthesia, with 4 hours total at the clinic.  His PSA dropped in 90 days from 5.5 to 1.7.  He will be retested every 90 days for the first year, then get an MRI and a checkup with Dr. Scionti.
Lessons learned:  Be your own advocate and case manager!  Get an MRI prior to a biopsy, which should then be targeted.  Talk to everyone.  Don’t turn away loving support.  Be patient with yourself and others.  Doctors mean well, but they don’t know everything, and they are good salesmen for their specialty.  Always, be your own advocate and case manager.
3.  John Tassi is 63 years old, in satellite communications, and a 9-year survivor in remission.  “What to Do if Your Prostate Cancer Doesn’t Return. “  In retrospect, his gradually rising PSA in his 40’s, reaching 3.5 at age 49, was an indication of prostate cancer, though his DRE (rectal exam) was still normal.  The next year, he was incorrectly diagnosed with BPH (enlarged prostate).  Two years later, in 2007, his PSA reached 19, still with a normal DRE.  His doctor said, “You are too young for prostate cancer.”  In December 2007, a biopsy revealed Gleason 3+3 on the right side and 3+4 on the left side.  He chose Robotic-assisted Radical Prostatectomy, which was done in February 2008.  Pathology of the removed prostate showed both sides had Gleason = 4+5, and that the margins were positive (Bad!).  His PSA rose, doubling between August and October, so in December he started 37 sessions of IMRT (intensity modulated external radiation therapy), followed immediately in February 2009 with 5 sessions of Chemo using Taxotere, and in March 2009 with 12 months of ADT using Trelstar (equivalent to Lupron for testosterone suppression).  Since then, his PSA has been undetectable!
More retrospective thoughts:  He blindly accepted his urologist’s recommendation for surgery, which was “conveniently” available in two weeks.  Although at first it seemed the cancer was gone, he was surprised to find it returned.  He feels now that radiation should have promptly followed the surgery (common practice today, but not back then).  He did become his own case manager, found the IPCSG, and went to a prostate cancer specialist (late 2008).  Together with this doctor, his best course of action was mapped out: radiation, chemo, and ADT.  He researched the best doctors for the subsequent treatments (three doctors for each, always asking “if you had my problem, who would you go to?”), and is alive and healthy today.
Recommendations:  “Be your own case manager!”  Seek out the best doctors, and don’t be afraid to FIRE YOUR DOCTOR – John has fired three.  Request and keep copies of all your medical records.  Carry a condensed medical history, including a) Current medications, dosage, date started and doctor.  b) Discontinued medications c) Over-the-counter supplements (including list of ingredients) c) Any allergies. d) List of surgeries and procedures, dates, where performed, and doctor. e) List of your doctors with address and phone. f) Your pharmacy with address and phone.
Parting thoughts, regarding “yesterday” vs. today:  He doesn’t put off routine medical appointments and checkups.  He researches and understands his lab reports.  He asks the doctor questions.  He eats more moderately, and reduces consumption of sugar, salt and alcohol.  He uses a respirator around chemicals and in the attic.  He does still eat red meat and desserts.  He enjoys every day, not being hyper-focused on work.  He takes vacations.
Questions:
Why can’t we trust our doctor to give us good information – why do we need the IPCSG to be able to get it right?  It’s the specialization and fast-changing developments; the ordinary doctor can’t keep up.  Seeing an oncologist (rather than a urologist) is a help.
What did Elliot mean by “3D MRI”?  It’s the current advanced MRI, such as is available at Imaging Healthcare Specialists (more often referred to as mp-MRI, or 3T MRI, or nowadays, just “MRI.”)

More details are given in the video of these presentations, including the PowerPoint slides, which will be available for purchase via the website shortly before the next meeting, or at the March meeting on the 16th.

Articles of Interest

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Low-Dose Aspirin Doesn't Prolong Survival in Prostate Cancer

By Steven Reinberg HealthDay Reporter
TUESDAY, March 5, 2019 (HealthDay News) -- Will an aspirin a day keep prostate cancer at bay?
Not necessarily, according to new research.
Danish scientists say low-dose aspirin doesn't seem to reduce a man's risk of death from prostate cancer, but it may slow down the disease in some cases.
For patients with slow-growing, non-aggressive cancer, aspirin did appear to stop the cancer from progressing. A slight benefit was also seen among men who took aspirin for more than five years, the researchers found.
"Aspirin is widely used due to its established protection against cardiovascular diseases," said lead researcher Charlotte Skriver, from the Danish Cancer Society Research Center in Copenhagen. "Our results, however, do not suggest an overall protective effect of low-dose aspirin used in the year after prostate cancer diagnosis on mortality from prostate cancer."
But growing evidence suggests aspirin might reduce the risk of developing and dying from colon and other cancers, Skriver said. It was thought that prostate cancer could be added to that list.
Researchers did see a small reduction in prostate cancer deaths among patients who took low-dose aspirin for an extended time, she said. More study is needed to confirm that finding.
Skriver said any potential benefit from low-dose aspirin needs to be weighed against the risk of gastrointestinal bleeding linked with its use.
For the study, her team collected data on more than 29,000 men, average age 70, who were diagnosed with prostate cancer between 2000 and 2011.
During nearly five years of follow-up, more than 7,600 men died of prostate cancer and more than 5,500 died from other causes, the study found.
The findings were published March 4 in the Annals of Internal Medicine.
Dr. Teemu Murtola, a professor of surgery at the University of Tampere in Finland, wrote an editorial that accompanied the study.
"Aspirin may have other benefits, but it is probably not helpful against prostate cancer," he said.
Murtola noted that aspirin was not associated in this large study with a lower risk of death from prostate cancer, despite promising previous laboratory studies.
Still, the risk was reduced among aspirin users in a subgroup of men with lowest-risk prostate cancer, he said.
"Future studies should aim to evaluate effects of very long-term, at least 10 years, of aspirin use on risk of prostate cancer death," Murtola said.
Dr. Anthony D'Amico, a professor of radiation oncology at Harvard Medical School in Boston, said the study doesn't take into account the treatment patients received -- an important point, because treatment directly affects survival.
Variables such as surgery, radiation and hormone treatment are essential to tease out the real effect of aspirin on survival, he said.
It's not only the treatments themselves, but the combinations used and the duration that can make a difference, D'Amico said.
"This is not definitive, because there is too much lacking in terms of treatment specifics," he said. "It's interesting, but it doesn't mean you should take an aspirin."
More information
The American Cancer Society has more about prostate cancer.
SOURCES: Charlotte Skriver, M.Sc., Danish Cancer Society Research Center, Copenhagen; Teemu Murtola, M.D., Ph.D., professor, surgery, University of Tampere, Finland; Anthony D'Amico, M.D., Ph.D., professor, radiation oncology, Harvard Medical School, Boston; Annals of Internal Medicine, March 4, 2019
Last Updated: Mar 5, 2019
Copyright © 2019 HealthDay. All rights reserved.

Personalized Medicine Is Next Step in Castration-Resistant Prostate Cancer

https://www.onclive.com/web-exclusives/personalized-medicine-is-next-step-in-castrationresistant-prostate-cancer
Brandon Scalea
Raoul S. Concepcion, MD, FACS

The field of castration-resistant prostate cancer (CRPC) is moving forward with the development of several new treatment options, and the next steps for clinicians will be tailoring treatment strategies to each individual patient, said Raoul S. Concepcion, MD, FACS.
The phase III ARAMIS trial introduced a third androgen receptor inhibitor that may shake up the treatment paradigm for patients with nonmetastatic CRPC. In this study, the addition of darolutamide to androgen deprivation therapy (ADT) was found to significantly improve metastasis-free survival (MFS) versus ADT alone, with comparable tolerability to enzalutamide (Xtandi) and apalutamide (Erleada).
The findings, which were presented at the 2019 Genitourinary Cancers Symposium, showed the median MFS was 40.4 months for patients treated with darolutamide compared with 18.4 months in those who received ADT alone (HR, 0.41; 95% CI, 0.34-0.50; P <.0001). At a median follow-up of 17.9 months, the median time to pain progression also favored darolutamide at 40.3 months compared with 25.4 months with placebo, which translated to a 35% risk reduction (HR, 0.65; 95% CI, 0.53-0.79; P <.0001).
Although additional data will be critical in determining where darolutamide will fit into the nonmetastatic CRPC space, Concepcion, director of the Comprehensive Prostate Center, and clinical associate professor of urology, Vanderbilt University School of Medicine, said that cost could be the biggest deciding factor.
Beyond this approach, immunotherapy in the form of PD-1/L1 inhibitors could soon have a more significant role in the treatment of patients with metastatic disease, Concepcion predicts. As the space continues to move away from traditional approaches, the ability to interpret and utilize predictive biomarkers will become all the more important, as they will help inform which treatment will result in the greatest clinical benefit.
In an interview with OncLive, Concepcion, who is also the editor-in-chief of Urologists in Cancer Care, discussed the clinical implications of the findings from the ARAMIS trial and highlighted other therapies that are coming down the pike for the treatment of patients with CRPC.
OncLive: How has the results from the ARAMIS trial impacted the nonmetastatic CRPC landscape?
Concepcion: ARAMIS was a highly anticipated trial mostly because the drug itself, darolutamide, is structurally different than apalutamide and enzalutamide. In this trial, investigators were looking at patients with nonmetastatic CRPC, a very similar population to [those evaluated] in the SPARTAN and PROSPER trials. In other words, these patients had a diagnosis of prostate cancer, were on ADT, had testosterone levels in the castration range, and had rising prostate-specific antigen (PSA). They were imaged and showed no evidence of metastatic disease by traditional imaging, which includes a bone scan and a computerized tomography scan. Enzalutamide and apalutamide are FDA approved for these patients. The inclusion criteria for these patients was to have a PSA doubling time <10 a="" doubling="" has="" in="" less="" months.="" months="" patient="" population="" reality="" span="" this="" time="" when="">
The theory of darolutamide being structurally different is that there may, in fact, be less toxicity relative to central nervous system (CNS) adverse events. What they reported out [at the 2019 Genitourinary Cancers Symposium] was what many people anticipated: the time to metastases was delayed versus placebo. But what would be the side effect profile? This [question] was specific to fatigue, because enzalutamide and apalutamide have a very significant fatigue factor somewhere in the order of 20% to 30%. What they reported at the symposium was that in the darolutamide arm, the incidence of fatigue was approximately 15%; in the placebo arm, it was 12%. Therefore, there is definitely a reduction in the incidence of fatigue. Again, the delay to MFS was pretty much similar to what we saw with enzalutamide and apalutamide in this nonmetastatic CRPC population.
These data are significant, and there will be more data coming out on this. [The questions of] how this is going to translate into practice and how we are going to use darolutamide versus the other 2 agents still need to be flushed out. Cost will be a big factor, and it will be interesting to see how long it will take for an approval.
Where do you see darolutamide fitting in this treatment paradigm?
This is going to be an interesting question. Now, we have potentially 3 agents that have been studied with positive trials in this setting. The challenge for clinicians is going to be: which drug do we use? For urologists in particular, our experience with enzalutamide going back to 2012 means that we are very comfortable with using it. Because apalutamide has recently been approved [by the FDA] and it is a very similar product, the urology world is getting used to this. With darolutamide, once investigators start looking at the side effect profile, what is going to be the willingness for the provider to use this drug? It will probably be related to how they view individual patients. If you have a patient who already has a lot of central nervous system toxicity and fatigue, darolutamide may be a more preferable option. However, like anything else, when you look at the primary endpoints, these drugs are very similar in their results. It may ultimately just come down to cost.
What is the importance of evaluating quality of life (QoL) in clinical trials?
We know there are so many agents that prolong survival. What many people do not realize is that in many of these patients with CRPC—especially if they are nonmetastatic—their ECOG performance status is 0; they are highly functional and active. These are not patients who are walking around in significant pain. The issue with some of these agents is that their side effect profiles may set these patients back. If therapy is going to slow down what patients are able to do on a daily basis, that becomes significant. I'm glad we are emphasizing QoL into the equation here. It is happening across the board with all of these targeted therapies, and it should become the standard in clinical trials moving forward.
What does the future hold for immunotherapy in prostate cancer?
Over the years, the utilization of ipilimumab (Yervoy) had minimal efficacy in CRPC. However, we know that mCRPC tumors are “cold” tumors—they are not that immunogenic. There are a lot of data now, especially in men with mCRPC who have moved through several lines of therapy, where we do see this mutational burden. There are [biomarkers] that come as a result of treatment pressure selection. The 2 that come to mind are microsatellite instability (MSI) and CDK12. If you take these 2 groups, a percentage of patients will actually respond to a PD-1/PD-L1 inhibitor. Therefore, there is going to be a place for our newer immunotherapies, but what [this will depend on] is the clinicians understanding which testing they need to order.
As we move from our traditional therapies, the ability to interpret these predictive markers becomes really important. Testing for MSI and CDK12 biallelic loss with anticipation that we will also see [FDA] approvals for PARP inhibitors—understanding where these factors lie, how to process the results, and make them actionable is crucial. The challenge is going to be utilizing these biomarkers and next-generation imaging.
What are biggest challenges moving forward?
If we start from initiation of disease, for newly diagnosed prostate cancer, the question is going to be, “How can we determine who most needs treatment? Who needs active surveillance?” Urologists are looking at that appropriately. We are even taking that one step further in asking who we need to biopsy. Just because a patient's PSA is elevated doesn't necessarily mean that they need to undergo a biopsy. We are [working on developing] a better understanding of how to utilize PSA in conjunction with some of this adjuvant testing—whether it be blood-based, urine-based, or now, imaging-based with magnetic resonance imaging.
With definitive therapy, some of the challenges are in patients with high-grade prostate cancer who we know are going to progress. Who are the patients who will benefit from adjuvant radiotherapy? We also know there are ongoing trials in patients who have been definitively treated and have a biochemical recurrence. We know these patients are at a higher risk of developing metastatic disease. The EMBARK trial is looking at these patients and giving them ADT alone, enzalutamide alone, or the 2 modalities combined; that will be a significant trial. Getting back to localized prostate cancer, we know that there is a trial looking at sipuleucel-T (Provenge) in patients who are candidates for active surveillance.
The point here is, for the practicing urologists, to really look at prostate cancer and try to isolate patients into these individual buckets. It does become a mastery of the clinical trials and the particular phenotype we are dealing with, as well as the drugs that are approved [by the FDA] or not. There is no doubt it is becoming complex. We are going to see more agents, and we can guess that immunotherapy will play a bigger role. We know some other mechanistic drugs will come to the table. For urologists, it used to be operating, putting the patient on ADT, then seeing what happens. Now, we have to critically look at these patients.
Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7S, abstr 140). meetinglibrary.asco.org/record/170190/abstract.
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www.medscape.com

Novel Radiotherapy Shows Promise in Heavily Pretreated mCRPC

Roxanne Nelson, RN, BSN
February 14, 2019
A novel targeted radionuclide therapy has shown promising clinical activity and low toxicity in a group of heavily pretreated men with metastatic castration-resistant prostate cancer (mCRPC).
The novel product is Lutetium-177 (177Lu)-PSMA-617 (under development by Endocyte) is a radiolabeled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA), enabling tumor-targeted delivery of beta-radiation. PSMA is over-expressed 100-1000 times in prostate cancers, and expression is further increased in metastatic and castration-resistant carcinomas.
The new results come from an updated report on 50 patients with PSMA-positive mCRPC who had progressed on standard therapies and were treated with the new product. The results show a median overall survival of 13.3 months, which is longer than the average 9-month survival time for men with this stage of disease, noted lead author Michael Hofman, MBBS, a professor of nuclear medicine at the Peter MacCallum Cancer Centre, Melbourne, Australia.
While he believes that this may be a life-prolonging therapy, "this is not a claim that we can make yet, because there's no comparator arm," he said.
Hofman was speaking at a press briefing for this week's Genitourinary Cancers Symposium (GUCS) 2019 in San Francisco, California. The study was presented today at the conference.
"Metastatic castration-resistant prostate cancer is a fatal disease and there is an urgent need for new effective therapies," said Hofman, adding that based on the results of this trial, two randomized trials were now underway.
One is the TheraP trial, which compares LuPSMA with cabazitaxel (Jevtana, sanofi-aventis) and the other is the VISION trial, which is comparing LuPSMA to best standard of care; both trials are being conducted in men with PSMA-positive, progressive mCRPC.
"This is a very intriguing agent, and the VISION study is open in the US," commented briefing moderator Robert Dreicer, MD, of the University of Virginia in Charlottesville and an American Society of Clinical Oncology (ASCO)-designated expert.
"For this group of patients in dire need of new options, using an entirely new approach, this study provides hope that we can start to change their outcomes," he added.
Prolonged Survival, Decreased PSA
Hofman noted that in an earlier study his team found favorable activity and low toxicity in 30 patients with mCRPC. The current study is an updated report on the safety and efficacy, and with a larger cohort and a median follow-up of 23.5 months.
In this updated phase 2 study, the 50 patients received up to four cycles of 177Lu-PSMA-617 intravenously every 6 weeks. All patients had progressed on standard therapies, and 90% of the men had been treated with abiraterone (Zytiga, Janssen) or enzalutamide (Xtandi, Astellas) or both. The median PSA was 190 and the median PSA doubling time was 2.6 months.
Eight patients received fewer than 4 cycles owing to an exceptional response, Hofman said, while 10 patients did not complete all planned cycles owing to disease progression. The mean administered radioactivity was 7.5 GBq/cycle.
A prostate-specific antigen (PSA) decline of ≥50% was achieved in 32 (64%) of 50 patients, including 22 patients (44%) who achieved a PSA decline ≥80%.
The median overall survival was significantly longer among patients who achieved a greater drop in their PSA levels: 18 months for those with a PSA decline of ≥50% vs 8.7 months for those with a decline <50 .001="" span="">
In addition, 14 patients who progressed with PSMA-avid disease after the study was completed received additional treatment with Lu-PSMA. In this patient subset, 64% had a PSA decline ≥50% and the median overall survival was 33 months.
The most common toxicities associated with Lu-PSMA treatment were transient grade 1 to 2 dry mouth in 68%, grade 1 to 2 nausea in 48%, and grade 1 to 2 fatigue in 36%. Grade 3 to 4 toxicities were infrequent and included thrombocytopenia in 10% and anemia in 10% of patients.
The study was sponsored by the Peter MacCallum Cancer Centre, Melbourne, Australia. PSMA-617 was supplied by Endocyte and Lutetium-177 by ANSTO. Hofman disclosed relevant relationships with Endocyte, Ipsen, and Sanofi. Coauthors disclosed multiple relevant relationships with industry. Dreicer disclosed relationships with Astellas Pharma, AstraZeneca, Genentech/Roche, EMD Serono, Incyte, Pfizer, Seattle Genetics, Rainier Therapeutics, Janssen, and Merck.
Genitourinary Cancer Symposium: Abstract 228. Presented February 14, 2019.
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Cite this article: Novel Radiotherapy Shows Promise in Heavily Pretreated mCRPC - Medscape - Feb 14, 2019.
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Diet and exercise limit heart disease risk in men undergoing hormonal treatments for advanced prostate cancer

Posted By Charlie Schmidt On February 25, 2019 @ 3:39 pm In Health,Living With Prostate Cancer,Prostate Knowledge,Treatments | No Comments
Men with advanced prostate cancer are typically treated with drugs that prevent the body from making or using testosterone. A hormone (or an androgen, as it’s known), testosterone drives prostate cancer cells to grow faster, so shutting it down is essential to keeping the illness in check. About 600,000 men with advanced prostate cancer in the United States today are undergoing this type of anti-hormonal treatment, which is called androgen deprivation therapy (ADT). But even as ADT helps men live longer, it exerts a toll on the body. Men can lose muscle and bone mass, gain weight, and they face higher risks for heart disease and type 2 diabetes.
The good news is that a few helpful strategies can lessen these metabolic side effects. Engaging in aerobic exercise and resistance training, for instance, has been shown to drop levels of inflammation in the body that might otherwise lead to heart disease. Quitting smoking is similarly beneficial, since tobacco smoke’s toxic effects on the heart are more pronounced in the absence of testosterone.
In a new study, researchers have shown that taking daily walks and eating a low-carbohydrate diet can also lessen ADT’s harms. During the investigation, 42 men who were just starting on ADT were split into two groups: Half the men took daily walks lasting at least half an hour five days a week, and were instructed to limit their carbohydrate intake to no more than 20 grams per day. The other half of the men (the control group) maintained their usual diet and exercise patterns.
After six months, typical weight loss among men in the walking/low-carbohydrate group was about 20 pounds, compared to a nearly 3-pound weight gain among men who stuck to their usual dietary and exercise routines. Men in the walking/low-carbohydrate group also had significantly higher blood levels of high-density lipoprotein (HDL), which removes cholesterol and lessens risks of atherosclerosis and heart disease. And they also had significant improvements in insulin resistance (a pre-diabetic condition), but only at three months and not when the levels were checked again three months later.
The study’s lead author, Dr. Stephen Freedland from Cedars-Sinai Medical Center in Los Angeles, California, says exercise combined with low-carbohydrate diets appears to be a promising strategy in men undergoing ADT that should be studied further. Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of HarvardProstateKnowledge.org, agreed, pointing out that weight gain can be a real problem for men that endures even after ADT is discontinued. “The weight loss in the experimental group is encouraging and should be validated in larger studies,” he said. “In the meantime, combining exercise with low-carbohydrate diets is a common-sense strategy that clinicians should recommend to their patients.”
Article printed from Harvard Health Blog: https://www.health.harvard.edu/blog
URL to article: https://www.health.harvard.edu/blog/diet-and-exercise-limit-heart-disease-risk-in-men-undergoing-hormonal-treatments-for-advanced-prostate-cancer-2019022516083
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How prostate cancer becomes treatment resistant

Date:    February 28, 2019           Source:    Sanford Burnham Prebys Medical Discovery Institute
Summary:
    Scientists have identified how prostate cancer transforms into a deadly treatment-resistant prostate cancer subtype called neuroendocrine prostate cancer (NEPC) following treatment with anti-androgen therapy. Their findings -- which include the metabolic rewiring and the epigenetic alteration that drives this switch -- reveal that an FDA-approved drug holds potential as a NEPC treatment.
The development of effective anti-androgen therapies for prostate cancer is a major scientific advance. However, some men who receive these targeted treatments are more likely to develop a deadly treatment-resistant prostate cancer subtype called neuroendocrine prostate cancer (NEPC). No effective treatment for NEPC exists.
Now, scientists from Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified how prostate cancer transforms into aggressive NEPC following treatment with anti-androgen therapy. Their findings -- which include the metabolic rewiring and the epigenetic alteration that drives this switch -- reveal that an FDA-approved drug holds potential as a NEPC treatment. The research also uncovers new therapeutic avenues that could prevent this transformation from occurring. The study was published in Cancer Cell.
"Acquired treatment resistance is a major concern for every oncologist. Eventually, over enough time, cancer patients who receive a targeted therapy can become resistant to treatment," says Darren Sigal, M.D., an oncologist at Scripps Clinic and Scripps MD Anderson Cancer Center who worked with the scientists on the study. "This study is an important advance that helps us understand why targeted treatments for prostate cancer may promote the development of a more aggressive tumor. These insights could lead to better treatments that help fathers, sons and grandfathers around the world who are fighting prostate cancer."
Prostate cancer is the second-leading cause of cancer death for American men, according to the American Cancer Society. The cancer grows in response to hormones called androgens. Targeted therapies that block these hormones have extended survival for many patients. However, nearly all men eventually develop resistance to these treatments. In 2019, more than 30,000 men in the U.S. are expected to die from prostate cancer.
"Similar to bacteria that gain resistance to antibiotics, tumors can become resistant to anti-cancer drugs by 'remodeling' their environment and developing strategies to evade targeted therapies. As targeted therapies become more potent, putting more stress on tumors, we expect to see drug resistance become more common," says Maria Diaz-Meco, Ph.D., the senior author of the paper and a professor in the Cancer Metabolism and Signaling Networks Program at SBP. "Our study shows that in a form of treatment-resistant prostate cancer, a tumor suppressor gene called protein kinase C lambda/iota is downregulated. We subsequently identified metabolic and epigenetic vulnerabilities which are possible routes to prevent treatment resistance from arising."
In the study, the scientists analyzed tissue samples from men with metastatic NEPC, prostate cancer cell lines and a new mouse model of NEPC, created by the researchers, to identify the molecular switch that triggers prostate cancer to become treatment-resistant NEPC following targeted treatment. In addition to detecting the downregulation of protein kinase C lambda/iota, the scientists found that the NEPC cells upregulate the synthesis of a metabolite called serine. Because serine is a non-essential amino acid, treatments aimed at blocking serine production may be devised that could impact the tumor with minimal or no effect on the normal cells, thereby reducing potential toxicities. Additionally, the researchers discovered that the cancer cells used a communication pathway called mTORC1/ATF4 to accelerate the synthesis of serine, allowing the tumor to grow faster and to epigenetically switch to the NEPC mode. A protein that regulates the positions of lysosomes, the cell's degradation machinery, was also involved in the tumor's transformation. Together, these tumor characteristics represent novel approaches that could prevent prostate cancer from transforming into NEPC.
A new identity
"NEPC is essentially a new cancer. From what it 'eats' to how it looks, the tumor cells are completely reprogrammed. The tumor even loses the receptor that is targeted by current treatments, which is why it is so difficult to treat," says Jorge Moscat, Ph.D., a study author and director and professor in SBP's Cancer Metabolism and Signaling Networks Program. "Identifying the switch that drives the transformation from prostate cancer to NEPC is a critical first step toward developing treatments that prevent treatment resistance in men with prostate cancer before it begins."
The scientists also identified epigenetic patterns -- molecular tags that modify our DNA -- associated with NEPC, linked to the expression of an enzyme, phosphoglycerate dehydrogenase (PHGDH), which could be a treatment target for NEPC. Next, the scientists plan to work with SBP's drug discovery center, the Conrad Prebys Center for Chemical Genomics (Prebys Center), to try to identify a drug that can block PHGDH. The findings also indicated that an FDA-approved drug that inhibits epigenetic changes, called decitabine, could hold promise as a treatment for NEPC.
"Luckily, prostate cancer is a cancer type that is well characterized, which helps us better understand the mechanisms behind treatment resistance," says Diaz-Meco. "With more research, one day we hope that no man dies of prostate cancer."
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Materials provided by Sanford Burnham Prebys Medical Discovery Institute. Note: Content may be edited for style and length.
Journal Reference:
    Miguel Reina-Campos, Juan F. Linares, Angeles Duran, Thekla Cordes, Antoine L'Hermitte, Mehmet G. Badur, Munveer S. Bhangoo, Phataraporn K. Thorson, Alicia Richards, Tarmo Rooslid, Dolores C. Garcia-Olmo, Syongh Y. Nam-Cha, Antonio S. Salinas-Sanchez, Ken Eng, Himisha Beltran, David A. Scott, Christian M. Metallo, Jorge Moscat, Maria T. Diaz-Meco. Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer. Cancer Cell, 2019; DOI: 10.1016/j.ccell.2019.01.018
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Sanford Burnham Prebys Medical Discovery Institute. "How prostate cancer becomes treatment resistant." ScienceDaily. ScienceDaily, 28 February 2019. .
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Links to Further Reading:

1.      How prostate cancer becomes treatment resistant -- ScienceDaily: Scientists have identified how prostate cancer transforms into a deadly treatment-resistant prostate cancer subtype called neuroendocrine prostate cancer (NEPC) following treatment with anti-androgen therapy. Their findings -- which include the metabolic rewiring and the epigenetic alteration that drives this switch -- reveal that an FDA-approved drug holds potential as a NEPC treatment.
2.      Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer - ScienceDirect: Summary -Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.
3.      Volume 10.07 | Mar 1 - Prostate Cell News: Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer
4.      Misinformation on the Internet regarding Ablative Therapies for Prostate Cancer - Urology: To evaluate the quality of web-based information on ablative therapies for prostate cancer
5.      Prostatepedia Weekly
6.      First Data Release from The Metastatic Prostate Cancer Project — Cancer ABCs: The project’s goal is to have thousands and thousands of men with metastatic prostate cancer share their medical records, their DNA and their tumor tissue so that we can understand the genomics of this disease, learn how it progresses and how resistance to treatments develop.
7.      Cardiovascular history, abiraterone acetate, and 6-month mortality rates | THE "NEW" PROSTATE CANCER INFOLINK: In a not entirely surprising set of findings, data from a relatively large registry study — to be presented at an upcoming meeting of the American Association of Cancer Research (AACR)
8.      Re-Irradiation of Locally Recurrent Prostate Cancer with Volumetric Modulated Arc Therapy (Vmat) - ScienceDirect: This study explores the efficacy and safety of re-irradiation with modern radiotherapy technique in patients previously irradiated for prostate cancer…
9.      When Living With Prostate Cancer Is the Goal | Medpage Today: Men like me aren't dealing with effects of treatment -- we need our own support groups
10.  Technetium Based Radioguided Surgery for Prostate Cancer (TRACE) Study - Full Text View - ClinicalTrials.gov: Technetium Based Radioguided Surgery for Prostate Cancer (TRACE) Study - Full Text View.
11.  Modern prostate cancer imaging: application of the right scan at the right time | THE "NEW" PROSTATE CANCER INFOLINK: A new “opinion” article in the Journal of Clinical Oncology this week has addressed the complex issue of how best to think about (a) how we are regulating use of and (b) how we are app
13.  Zytiga May Up Mortality Risk in Prostate Cancer Patients With CVD | Medpage Today: Increased hospitalizations seen among all abiraterone-treated patients
15.  Diet and exercise limit heart disease risk in men undergoing hormonal treatments for advanced prostate cancer - Harvard Health Blog - Harvard Health Publishing: Men with advanced prostate cancer are typically treated with drugs that prevent the body from making or using testosterone. A hormone (or an androgen, as it’s known), testosterone drives prostate cancer cells to grow faster, so shutting it down is essential to keeping the illness in check. About 600,000 men with advanced prostate cancer i
16.  Germline DNA-repair Gene Mutations and Efficacy of Abiraterone or Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer - European Urology Focus: 1. mCRPC patients with gDDRm exhibit a good response to first abiraterone/enzalutamide treatments, despite this was not statistically significant.2. The different detections of gDDRm and treatments (abiraterone or enzalutamide), indeed, are influential factors.