Sunday, September 9, 2018

Some New Prostate Cancer News Stories of Interest


Contents


The Next IPCSG Meeting

Saturday September 15, 2018 10:00 AM
Dr. Carl Rossi         Update on Proton Therapy

Dr. Rossi has personally treated more than 9,000 prostate cancer patients with proton radiation over the last 26 years—more than any other physician in the world.
Internationally recognized for his achievements in cancer treatment, Dr. Rossi is a radiation oncologist with a research focus on the quality of life and cure rate in prostate cancer and lymphoma. Specializing in proton beam therapy, he has been treating prostate cancer patients with proton therapy since 1991. Prior to serving as the Medical Director of California Protons, he was the Medical Director of the Scripps Proton Therapy Center and was an Associate Professor in the Department of Radiation Medicine at the Loma Linda University Medical Center.

--------------------------------------------------------------------------------------------------------------------------------------

Participation in a patient support group increases prostate cancer patient knowledge

Posted on August 15, 2018 by Sitemaster
A newly published study from a group of German researchers examined the degree to which participation in patient support group activities increased prostate cancer patients’ health literacy and, specifically, their prostate cancer‐specific and non‐cancer‐specific knowledge about health care.
Unlike a lot of studies in this area, which often enroll only small numbers of patients, this study [https://onlinelibrary.wiley.com/doi/abs/10.1002/pon.4854] by Haack et al., at Hannover and Hamburg in Germany, enrolled nearly 600 participants in total, so the results should be pretty reliable.
Here are the basic data from the study:
·         There were 576 participants in total
·         441 were prostate cancer support group members (Group A)
·         135 were prostate cancer patients who had not participated in a support group (Group B)
·         Compared to the patients in Group B, the patients in Group A had:
·         Greater knowledge about prostate cancer in general (odds ratio [ OR] = 2.2)
·         Heard about specific guidelines related to prostate cancer (OR = 3.7)
·         Actually read one or more guidelines (OR = 5.1)
·         Greater competence regarding navigation of heath services (OR = 1.8)
·         Patients in Group A and Group B had similar levels of knowledge about non-cancer-related health care knowledge.
We should emphasize, of course, that one can become very knowledgeable about prostate cancer and how health care systems work without every actually participating in a patient support group of any type (prostate cancer-specific or otherwise). However, on the other hand, the authors conclude that participation in a prostate cancer-specific support group seems to provide an important platform for information exchange in the field of [prostate cancer]. The potentially conflicting results on PC knowledge and the application‐skills may arise from the different forms of measurement — knowledge was tested, skills were self‐assessed.
What this study did not test, however, is whether the benefits of participation in “live” prostate cancer support groups that meet on a regular basis was any more beneficial than participation in the various (and evolving) forms of on-line and phone-based support groups, and the degree to which participation in support groups increased the probability that patients would choose forms of management (over time) most suited to their individual needs.

-------------------------------------------------------------------------------------------------------------------------------------

ww.medscape.com

MRI-Based PIRADS Score Aids in Diagnosis of Prostate Cancer

By Reuters Staff
August 16, 2018
NEW YORK (Reuters Health) - Higher PIRADS scores are associated with a higher likelihood of diagnosis of prostate cancer, according to a retrospective study.
The Prostate Imaging Reporting and Data System (PIRADS) score classifies MRI lesions on a scale from 1 to 5, which reflects their level of suspicion from least to most. PIRADS 3 lesions are considered equivocal.
Dr. Niranjan J. Sathianathen and colleagues from the University of Minnesota, in Minneapolis, investigated the correlation between PIRADS 3-5 scores and the diagnosis of clinically significant and all prostate cancer for three common biopsy indications: biopsy-naive patients, patients with previous negative transrectal ultrasound (TRUS) biopsy, and active-surveillance patients.
Prostate cancer of any grade was found in 51.9%, 26.5% and 43.8% of patients, respectively.
Overall cancer-detection rates were 7.7% for PIRADS scores 1-2, 29.7% for PIRADS 3, 42.3% for PIRADS 4 and 82.4% for PIRADS 5, the team reports in Prostate Cancer and Prostatic Diseases, online July 23.
The detection rate for clinically significant cancers was 30.1% among biopsy-naive men, 15.7% among those with a previous negative biopsy and 19.5% among those on active surveillance.
Clinically significant cancers were found in 0% of men with PIRADS scores between 1 and 2, in 8.9% of those with a PIRADS score of 3, in 21.4% of those with a PIRADS score of 4 and in 62.7% of men with a PIRADS score of 5.
The accuracy of PIRADS scores (as measured by area under the receiver operator curves) was 0.69 for the diagnosis of any cancer and 0.74 for the diagnosis of clinically significant cancer.
Men who had a previous negative biopsy had lower detection rates for any prostate cancer for PIRADS 3 and 4 lesions compared with men who were biopsy naive or on active surveillance.
"Overall and clinically significant cancer detection rates are correlated with PIRADS score on multiparametric MRI," the researchers conclude. "Biopsy yield is also dependent on the clinical setting and this should be considered in the decision-making process when determining the need for biopsy."
"Moreover, it is important for institutions to audit their own cancer detection rates due to the multiple confounders which impact cancer detection rates," they add. "Avoiding biopsy of PIRADS 3 lesions appears to be safest in men with prior negative biopsy as it risks missing diagnosis of the fewest significant cancers."
Dr. Sathianathen did not respond to a request for comments.
SOURCE: https://bit.ly/2MGe6nk
Prostate Cancer Prostatic Dis 2018.
Reuters Health Information © 2018
Cite this article: MRI-Based PIRADS Score Aids in Diagnosis of Prostate Cancer - Medscape - Aug 14, 2018.
--------------------------------------------------------------------------------------------------------------------------------------

What are the natural ways to prevent prostate cancer?

Last reviewed Thu 16 August 2018
By Scott Harris 
Reviewed by Daniel Murrell, MD        
    Can you prevent prostate cancer? Natural ways to lower risk What to avoid Risk factors Get regular testing Takeaway
There is no single best way to prevent prostate cancer, but several natural methods can help. These include maintaining a healthful weight, exercising, and eating plenty of fruits and vegetables.
After skin cancer, prostate cancer is the type most common among American men, according to the Centers for Disease Control and Prevention (CDC). For the majority, prostate cancer is not fatal.
The American Cancer Society estimate that males with prostate cancer have a 5-year survival rate of 99 percent.
Prostate cancer can still carry serious consequences for quality of life and may be life-threatening.
In this article, we describe several natural steps a person can take to reduce their risk of developing prostate cancer.
Can you prevent prostate cancer?
Adding soy products to the diet may reduce the risk of developing prostate cancer.
It is not possible to prevent prostate cancer, but it is possible to reduce a person's risk.
Most natural methods of reducing this risk are safe if a person follows a doctor's instructions and has no allergic response.
Incorporate these methods into a broader care plan, and speak with a doctor beforehand.
The best ways to reduce the risk of developing prostate cancer are to make positive changes involving diet and exercise, according to the American Cancer Society.
If a person tries to reduce their risk in other ways, these are less likely to be effective without a healthful diet and exercise program.
Natural ways to lower risk
Researchers continue to investigate the potential for medications and natural remedies to reduce the risk of prostate cancer.
The following drugs may be effective:
·         finasteride (Proscar)
·         dutasteride (Avodart)
·         aspirin
However, no study to date definitively demonstrates that any drugs can eliminate the risk.
In recent years, rigorous biomedical research has tested the effectiveness of natural remedies. For example, results of laboratory studies have suggested that saw palmetto has beneficial properties. However, it is not an effective treatment for prostate cancer.
Below are some natural remedies that are commonly used to lower the risk of prostate cancer.
Soy products
Isoflavones are a chemical compound with anti-inflammatory properties. The foods with the highest concentrations of isoflavones are soybean products, including:
·         tofu
·         soy milk
·         miso
Other foods that contain isoflavones include:
·         chickpeas
·         beans
·         alfalfa
A 2016 study concluded that isoflavones could benefit health in several ways, including helping to protect against prostate cancer.
The medical community currently holds that, while isoflavones cannot treat or prevent the disease, they can play a protective role.
Omega-3 fatty acids
Omega-3 fatty acids are present in fish and other types of seafood. Additional sources include:
·         walnuts
·         flax seeds
·         soybeans
There is some evidence that omega-3s fatty acids may reduce prostate cancer risk.
However, many experts no longer believe that the acids have significant cancer-fighting properties.
Tomatoes
variety of tomatoes on a board
Studies suggest that tomato consumption may lead to a reduced risk of prostate cancer.
Processed tomatoes, including all cooked and canned varieties, contain a compound called lycopene.
Some studies suggest that this compound may reduce the risk of cancers, especially those of the prostate, lung, and stomach.
A review from 2016 found that increased tomato consumption resulted in a reduced risk of prostate cancer, though the authors note that more research is needed.
Grapefruit, watermelon, and apricots also contain lycopene.
Coffee
In 2016, researchers published a review of 105 studies that considered the effects of coffee on cancer risk.
They concluded that coffee and its antioxidant capabilities may reduce the risk of developing prostate cancer and some other types of the disease.
What foods are good for an enlarged prostate?
A person can reduce inflammation by making changes to the diet. This can support the functioning of the prostate, and it may prevent cancer. If a person has an enlarged prostate, certain foods may help. Learn about these foods here.
What to avoid
Some compounds in foods may increase a person's risk of developing prostate cancer.
Consider avoiding the following:
Selenium and vitamin E
The medical community once considered selenium and vitamin E to be opponents of cancer.
However, more recent research suggests that these compounds, when taken together or in isolation, can increase the risk of prostate cancer in some people.
Anyone concerned about prostate cancer should avoid supplements containing vitamin E or selenium.
Vegetable oils
A diet excessively high in fat can increase the risk of many types of cancer, and the omega-6 fatty acids in vegetable oils may promote the growth of prostate cancer cells.
Oils derived from corn, sunflowers, safflowers, cottonseed, and soybeans, for example, can contain substantial amounts of omega-6 fatty acids.
Grilled or fried meats
The National Cancer Institute in the United States advises against eating meats cooked at high temperatures, typically by grilling or frying.
When a person cooks muscle meat, including beef, pork, and poultry, at high temperatures, the meat may form chemicals that cause changes in DNA, resulting in an increased risk of cancer.
Sugar and carbohydrates
The glycemic load and glycemic index measurements show how quickly carbohydrates and sugars affect a person's blood sugar and insulin.
Some studies have suggested that a diet with a high glycemic load may increase the risk of developing prostate cancer.
The Dana-Farber Cancer Institute report that, while the relationship between sugar and cancer remains complex, sugar may have the highest impact on the risk of prostate, colorectal and pancreatic cancers.
Risk factors
People aged 65 years of age or older account for many cases of prostate cancer.
Risk factors for prostate cancer include:
·         Age. Approximately 60 percent of all prostate cancer diagnoses occur in males aged 65 or older.
·         Genetics. The highest rates of prostate cancer in the U.S. occur in African-American men, followed by men who are Caucasian, Hispanic, American Indian/Alaska Native, and Asian/Pacific Islander, respectively.
·         Diet. A diet rich in fat and low in fruits and vegetables increases the risk of prostate cancer.
·         Environment. Exposure to some industrial chemicals also increases this risk.
·         Family history. If a father or brother has had prostate cancer, a person has more than twice the risk of developing it.
Get regular testing
A lifestyle that includes exercise and a healthful diet can help to reduce the risk of prostate cancer.
However, attending regular checkups and screenings is still the best way to handle this risk.
Speak with a doctor before trying natural or alternative ways to prevent cancer.
Takeaway
While it is not possible to prevent prostate cancer, some lifestyle changes and natural compounds may reduce a person's risk.
Anyone concerned about their prostate cancer risk should attend regular checkups and screenings.

--------------------------------------------------------------------------------------------------------------------------------------

New genetic marker could help diagnose aggressive prostate cancer

Date: August 30, 2018
Source: University of Turku
Summary: A new link has been found between certain genetic mutations, the aggressiveness of prostate cancer, risk of developing the disease and poorer survival rates of patients.
Scientists have discovered a link between certain genetic mutations, the aggressiveness of prostate cancer, risk of developing the disease and poorer survival rates of patients. The gene, called ANO7, could play a vital role in improving diagnosis of prostate cancer patients.
There is currently no clear way to diagnose aggressive prostate cancer at an early-stage. Genetic mutations, such as those revealed in this study, could lead to the development of accurate diagnostic tests that will ultimately mean patients receive the best possible treatment, sooner.
The researchers studied the DNA from over 1,700 prostate cancer patients and a comparable number of healthy men to look for genetic mutations that were associated with the disease. They were particularly interested in studying mutations to the ANO7 gene because their previous research suggested this could be a gene of interest for prostate cancer.
"We found that small genetic changes to the ANO7 gene increase a patient's risk of aggressive prostate cancer. One of the current biggest unmet needs in prostate cancer care is being able to diagnose aggressive cancers at an early stage. Genetic testing for ANO7 could help identify these patients sooner and may bring new opportunities for precision oncology in prostate cancer," says the leading author of the study, Professor Johanna Schleutker from the Institute of Biomedicine of the University of Turku, Finland.
The researchers found one particular genetic mutation that correlated with an increased risk of developing prostate cancer as well as the severity of the disease. They also found a separate mutation that correlated with shorter survival.
Analysis of tissue samples from prostate tumours revealed that mutations to ANO7 were associated with the gene being more active, suggesting that the biological function of ANO7 may play an important role in why these cancers are more aggressive. The function of ANO7 is not fully understood, but further research could lead to new ways to treat the disease.
Although the study involved a large population, it is limited by the fact that it is primarily a Caucasian population from Northern Europe. Further research involving other demographics is needed to validate the findings. The research was published in the International Journal of Cancer. The study was funded by the Worldwide Cancer Research in Britain, the Cancer Foundation, Academy of Finland, Sigrid Jusélius Foundation, and Government research funding granted by Turku University Hospital.
Story Source:
Materials provided by University of Turku. Note: Content may be edited for style and length.
Journal Reference:
·         Elina Kaikkonen, Tommi Rantapero, Qin Zhang, Pekka Taimen, Virpi Laitinen, Markku Kallajoki, Dhanaprakash Jambulingam, Otto Ettala, Juha Knaapila, Peter J. Boström, Gudrun Wahlström, Csilla Sipeky, Juha-Pekka Pursiheimo, Teuvo Tammela, Pirkko-Liisa Kellokumpu-Lehtinen, Vidal Fey, Lovise Maehle, Fredrik Wiklund, Gong-Hong Wei, Johanna Schleutker. ANO7 is associated with aggressive prostate cancer. International Journal of Cancer, 2018; DOI: 10.1002/ijc.31746

--------------------------------------------------------------------------------------------------------------------------------------

The androgen-sensitive to androgen-resistant transition: an hypothesis

Posted on September 5, 2018
A media release issued on Tuesday this week by a usually highly respected medical center in the Los Angeles area is misleadingly entitled, “Hormone therapy can make prostate cancer worse, study finds”.
The fact that men treated with androgen deprivation therapy (ADT) can and do progress, quickly or much less quickly, by becoming androgen resistant, and that, in some of those cases, this occurs because of the development of neuroendocrine forms of prostate cancer, is not news, by any manner of means, and the implied suggestion that researchers at Cedars-Sinai Medical Center have just made this discovery is unfortunate at best. (See here for the actual media release.)
What the research team at Cedars-Sinai actually have done is propose a possible mechanism explaining why and how ADT can induce the transformation of androgen-sensitive prostate adenocarcinoma cells into androgen-resistant neuroendocrine cancer cells. And the title of the paper by Mishra et al. (just published in the Journal of Clinical Investigation) that reports their findings and their hypothesis is [Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming]. The paper itself is very clear that transition from androgen-sensitive to androgen-resistant forms of prostate cancer is a common and well-known effect of ADT.
MIshra et al. report detailed findings — based on studies in laboratory mice — about how certain epigenetic effects on prostatic cancer-associated fibroblasts (PCAFs, a specific type of cell found in men with prostate cancer) can lead to secretion of abnormal levels of glutamine, and that there is a clearly higher level of serum glutamine in mice that are resistant to ADT than in those which are responsive to ADT (with an odds ratio [OR] = 7.45). They further postulate that epigenetic regulation of Ras activity in PCAFs is associated with a gene identified as RASAL3, and that expression of this gene and the consequent rise in serum glutamine levels is or at least may be a biomarker for metabolic and neuroendocrine reprogramming in some prostate cancer patients who become resistant to standard forms of ADT. This hypothesis is still to be validated in actual prostate cancer patients (as far as we can tell).
We wish to be very clear that the work reported by Mishra et al. is of considerable interest since it may help us to develop new and better forms of test for the onset of neuroendocrine prostate cancer and for treatment for at least a subset of men who start to become castration-resistant after either orchiectomy or other standard forms of medical castration. However, we also wish to point out that the media release issued by Cedars-Sinai spends four paragraphs implying that no one knew about the transition from androgen-sensitive adenocarcinona to androgen-resistant neuroendocrine carcinoma, which has been well understood for years based on research at centers like the University of California, San Francisco (UCSF), the Johns Hopkins Medical Center in Baltimore, and others.

--------------------------------------------------------------------------------------------------------------------------------------

Why does hormone therapy worsen some prostate cancers?

Published 9/6/18
By Catharine Paddock PhD         
Fact checked by Jasmin Collier    
Hormone therapy for prostate cancer does not always work; the tumor can become resistant and continue to spread. Now, new research reveals how the therapy alters the environment of tumor cells to make this happen.
Hormone therapy can actually make some prostate cancers worse, but how?
Scientists at the Cedars-Sinai Medical Center in Los Angeles, CA, suggest that their study could lead to a "simple blood test" to identify prostate cancer cases that are likely to become resistant and aggressive if they are treated with hormone therapy.
They report their findings in a study paper that now features in the Journal of Clinical Investigation.
Prostate cancer starts in the prostate, which is a gland that lies between a man's bladder and his penis, next to the rectum. The gland surrounds the urethra, which is the tube that carries urine from the bladder to the penis. It makes and adds fluid to semen as it passes through this tube.
The cancer begins when cells in the prostate grow out of control and form a tumor. It arises mostly in men aged 65 and older and rarely before the age of 40.
In the United States, prostate cancer is the most common cancer in men after skin cancer. The American Cancer Society (ACS) estimate that the U.S. will see around 164,690 new cases of prostate cancer and 29,430 deaths to the disease in 2018.
Hormone therapy for prostate cancer
Although it can be serious, most men diagnosed with prostate cancer will not die of it. This is why today in the U.S., there are 2.9 million men living with or who have survived the disease.
In general, prostate cancer survival rates are higher the earlier the cancer is detected and treated. However, many other factors can also affect a man's outlook, including how well his cancer reacts to treatment.
A research project lasting 6 years has identified dozens of genes that could help identify men at higher risk of prostate cancer.
The male sex hormone androgen stimulates tumor growth in prostate cancer. Hormone therapy — also known as androgen deprivation or androgen-targeting therapy — aims to halt tumor growth by reducing androgen levels or by blocking its effect on tumor cells.
The treatment can be used, for example, to shrink tumors before radiation therapy, or to treat men in whom surgery or radiation therapy has been ruled out.
Hormone therapy can be successful, but there are cases when the tumor develops resistance to the treatment and then comes back or spreads.
Transforms cancer into more aggressive type
In their study paper, the Cedars-Sinai researchers reveal that a possible reason for this is that the hormone therapy triggers a fundamental change in the tumor.
It causes some cancer cells, which are mainly of the common adenocarcinoma type, to transform into a much rarer type called neuroendocrine, which occurs in less than 1 percent of cases.
"This transformation is a problem," says senior study author Neil A. Bhowmick, who is the co-director of the Cancer Biology Program at Cedars-Sinai, "because neuroendocrine prostate cancer is especially aggressive, metastasizes more readily, and is more resistant to both androgen-targeted therapy and chemotherapy."
He explains that there is evidence to suggest that around a quarter of men treated with hormone therapy can experience a return of their cancer in which the tumors look like neuroendocrine prostate cancer and become treatment resistant.
So, working mainly with mice, he and his colleagues decided to focus on the interaction between prostate cancer cells and their microenvironment inside the tumor. The microenvironment is supported by cells called stromal cells.
The team found that androgen deprivation therapy can influence genetic programs in the stromal cells to cause prostate cancer to progress to "a more aggressive differentiation state."
Rise in glutamine
They also observed that the cell transformation was accompanied by a rise in glutamine, an amino acid that is known to hasten the growth of cancer.
The glutamine was being produced in the genetically altered stromal cells and "served as a source of energy" for the cancer cells, as well as helping transform the adenocarcinoma cells into neuroendocrine ones.
Finally, the scientists confirmed the glutamine finding in humans. In a small group of men who had prostate cancer, they found that those whose cancer was resistant to treatment had higher levels of glutamine in their blood than those whose cancer responded to treatment.
They suggest that this means that it should be possible to develop a simple blood test to detect those prostate cancers that are not responding to hormone therapy and perhaps even predict resistance.
    "To our surprise, we found this type of therapy further changed the cellular environment in a way that caused adenocarcinoma cells in the prostate to transform into neuroendocrine cancer-type cells."

--------------------------------------------------------------------------------------------------------------------------------------

Roswell Park Team Identifies Possible Cause of Resistance to Prostate Cancer Treatment

A Roswell Park-led research team has linked the development of castration-resistant prostate cancer and resistance to treatment to a lack of androgen receptor expression in prostate cancer cells, identifying a new therapeutic target.
BUFFALO, N.Y. (PRWEB) September 06, 2018
A collaborative research team has linked the development of castration-resistant prostate cancer and resistance to treatment to a lack of androgen receptor (AR) expression in prostate cancer cells, identifying a new therapeutic target for one of the deadliest forms of cancer among men. Results of this research, which was led by scientists at Roswell Park Comprehensive Cancer Center, were published today in the journal Nature Communications.
Prostate cancer is one of the most common and treatable types of cancer in men. Most patients respond well to hormone therapy or chemotherapy, and five-year survival rates have reached nearly 100% thanks to advances in detection and treatment. However, prostate cancer remains the second-leading cause of male cancer deaths, because those with more advanced or aggressive forms of the disease eventually experience progression or recurrence despite treatment.
For men with advanced disease and tumors that cannot be surgically removed, standard therapy involves drugs that target and block AR, a protein that binds to androgens (male hormones). AR-targeted therapies stop or inhibit the growth of prostate cancer cells, but for unknown reasons, their effectiveness is usually short-lived. Within a year or two of antiandrogen therapy, many patients will develop castration-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.
In an effort to uncover the mechanisms of treatment resistance and progression in prostate cancer, a team of scientists led by Dean Tang, PhD, Chair of Pharmacology and Therapeutics at Roswell Park Comprehensive Cancer Center, in collaboration with scientists at other cancer centers and research institutions in the United States and China, examined AR expression patterns in 89 patients with castration-resistant prostate cancer and found three distinct types: AR in the nucleus of the cancer cell, AR in both the nucleus and cytoplasm, and near or complete absence of AR from all parts of the cell.
Further research confirmed that cells lacking AR did not respond to treatment with enzalutamide (brand name Xtandi), an AR blocker commonly used to treat patients with castration-resistant prostate cancer. These prostate cancer cells were also more likely than AR-containing cells to grow, regenerate and proliferate. Through deep RNA-Seq analysis, the team identified BCL-2, a stem-cell-enriched prosurvival molecule, as a critical regulator and important therapeutic target in castration-resistant prostate cancer cells.
“In order to survive the pressure of chemical castration and antiandrogen therapy, prostate cancer cells overexpress, redistribute or lose androgen receptor,” explains Dr. Tang, the senior author of the study. “Our study offers new proof-of-principle therapeutic strategies to not only treat advanced and metastatic prostate cancer but also prevent castration resistance.”
The research team also reports new evidence that combination treatment with enzalutamide and ABT-199 (brand name Venetoclax), a newly FDA-approved BCL-2 inhibitor, markedly inhibits experimental castrate-resistant prostate cancer. Dr. Tang has initiated a phase Ib/II clinical trial based on these findings, in collaboration three Roswell Park clinical colleagues: Gurkamal Chatta, MD, James Mohler, MD, and Igor Puzanov, MD, MSCI, FACP, who are also co-authors on the new published research.
The study, “Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses,” is available at https://www.nature.com/articles/s41467-018-06067-7. This research was supported by grants from the National Cancer Institute (project numbers R01CA155693, P30CA016056 and P01CA77739) and the U.S. Department of Defense (W81XWH-13-1-0352, W81XWH-14-1-0575 and W81XWH-16-1- 0575), as well as the Cancer Prevention Research Institute of Texas, Chinese Ministry of Science and Technology and National Natural Science Foundation of China.
For an online version of this release, please visit: https://www.roswellpark.org/media/news/roswell-park-team-identifies-possible-cause-resistance-prostate-cancer-treatment
Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer’s grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at http://www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@roswellpark.org.

--------------------------------------------------------------------------------------------------------------------------------------

Is regular screening for prostate cancer really necessary?

Published Friday 7 September 2018
By Maria Cohut
Fact checked by Jasmin Collier
A BMJ commission considered whether or not regular screening for prostate cancer using the prostate-specific antigen test is truly necessary, despite the possible risks it carries.
PSA test sample
Should men opt for routine screening for prostate cancer?
According to an official statement released by the United States Preventive Services Task Force in JAMA, men in the U.S. face an 11 percent lifetime risk of being diagnosed with prostate cancer and a lifetime risk of prostate cancer-related death of 2.5 percent.
Previous studies suggested that one effective way of catching this type of cancer early is screening.
This involves prostate-specific antigen (PSA) testing, which is a blood test that can help establish a diagnosis.
However, PSA testing is not always accurate and might lead to the prescription of unnecessary — and invasive — biopsies, which may harm a person's quality of life.
False positive PSA results can also result in overdiagnosis and overtreatment, which may affect a person both mentally and physically, thus impacting their overall health.
So, a commission of international experts — both clinicians and research methodologists — and men at high risk of prostate cancer has reviewed and analyzed the results of existing studies weighing up the benefits and risks involved in routine prostate cancer screening.
The results of this complex analysis are now reported in The BMJ.
More harm than good?
The panel analyzed data collected from 721,718 men enrolled in various trials, and it assessed the evidence that emerged from these studies.
Following a detailed analysis, the members of the panel concluded that routine screening for prostate cancer should not be recommended to most men as it may end up doing them more harm than good.
New technique treats prostate cancer in just five radiotherapy sessions
New technique treats prostate cancer in just five radiotherapy sessions
Have researchers finally found a quick way to treat prostate cancer?
Read now
"Based on moderate- and low-quality evidence, PSA screening seems to increase the detection of prostate cancer of any stage, increases the detection of stage 1 and 2 prostate cancer, and slightly decreases the detection of stage 3 and 4 prostate cancer," write the review's authors.
"Meanwhile," they add, "PSA screening is associated with considerable biopsy-related and cancer treatment-related complications."
    "We estimated that, for every 1,000 men screened, approximately one, three, and 25 more men will be hospitalised for sepsis, require pads for urinary incontinence, and report erectile dysfunction, respectively."
At the same time, however, the experts involved in the review note that men who qualify as being at high risk of prostate cancer may still want to consider regular testing after discussing all the possible risks and benefits with their doctors.
Men who are at high risk of prostate cancer, according to guidelines from the Centers for Disease Control and Prevention (CDC), are usually those who have a family history of prostate cancer, as well as those of African descent.
The BMJ panel also says that practicing doctors should not feel like they have to suggest prostate cancer screening to all their male patients, but they should aim to inform those who do wish to undertake PSA testing, assisting them in their decision-making process.
In an editorial written by Prof. Martin Roland and team, from the University of Cambridge in the United Kingdom, other specialists support the conclusions reached by the panel.
The editorial's authors suggest that, when speaking with patients considering a PSA test, clinicians "should explore their reasons for requesting a test, and include evidence-based discussions about possible harms and benefits of PSA testing, informed by the patient's ethnicity and family history."

--------------------------------------------------------------------------------------------------------------------------------------

NCI Expert Stresses Importance of Multimodal Imaging in Prostate Cancer

Brandon Scalea
Peter L. Choyke, MD, FACP
Multimodality imaging holds the keys to providing personalized therapy to patients with prostate cancer, said Peter L. Choyke, MD, FACP.
Each screening platform has pros and cons, but their limitations can be erased with a combined effort, added Choyke, who is director of the Molecular Imaging Program and head of the Imaging Section at the National Cancer Institute (NCI).
For example, an MRI gives a standard anatomical overview of a tumor but is not specific enough, he said. A PET scan offers more specificity but lacks in terms of anatomy. In combination, however, these 2 options have a greater benefit.
“It is really about getting a more complete picture about where a patient stands in their disease’s natural history,” Choyke said.
Additional imaging methods have helped evolve this area in prostate cancer, including MRI ultrasound fusion-targeted biopsy and PSMA-PET.
In an interview with OncLive®, Choyke discussed the clinical implications of emerging technologies for prostate cancer imaging.
OncLive: What newer technologies are you excited about?
Choyke: Our team at the NCI developed a method of fusing MR images with ultrasound images so that we could do fusion biopsies of prostate cancer. It has really taken off. There are now a lot of people doing it, and we are really gratified by that. That is a fusion of MRI and ultrasound. We then moved on to looking at PET scans, particularly one that targets prostate-specific membrane antigen (PSMA), which is found in more aggressive cases of prostate cancer. It is very specific.
We are finding out a lot of new things about prostate cancer because this is a changing picture of the disease. We are combining some of the traditional PET imaging like 18F-sodium fluoride bone scans with PSMA. We are finding some interesting things there. It is combining different methods together to figure out what's going on and guide management of patients.
What is the rationale for combining these technologies?
There was this widespread idea that doctors were either just MRI specialists or they were PET specialists. Now, we view it as whatever the best tool is to handle that particular problem is the way to go. For example, I started out as an MRI specialist, but I quickly realized there were limitations to what an MRI can do. Particularly, an MRI lacks specificity. We could see lesions, but we could not see whether they were cancerous or not. PET offers specificity, but the anatomy is not that good. You get the anatomy from the MRI and the sensitivity from the PET, and those 2 things go together very nicely.
We want to more accurately say, "This is where you are now, and this is the best therapy." We want to match the right diagnosis with the right therapy.
What is the importance of a multimodality approach, specifically in prostate cancer?
It is very important. One of the things we are finding is that the disease goes over multiple disciplines. You have to bring all kinds of different management strategies to the table at different points in the disease. Depending on what the imaging shows, you can bring in different specialists. It is very important to have everybody at the table because the old way is for a patient to see 1 specialist. If the imaging or clinical parameters point in a different direction, you would want an additional specialist. The way to address that is a multidisciplinary approach so everybody sees everything, and you can decide on the best direction. We have done this at the NCI.
What other research would you like to highlight?
We are comparing 2 different kinds of PET scans. We are looking at PSMA scans and 18F-sodium fluoride PET scans, which is a type of bone scan. We are finding that they do not completely match up with each other. Early on in the disease, they match up better. However, as the disease progresses, you get progressively less matching up. This is important because some therapies are very dependent on the bone turnovers. This is reflected by sodium fluoride.
We are finding that PSMA-PET scans, which indicates where the active disease is, sometimes does not overlap with the sodium fluoride. You can administer an agent like radium-223 dichloride (Xofigo), but it will not treat the cancer. We are learning about how to get smarter with selecting patients for radium-223 to make sure the right patient gets the right therapy.
PSMA-PET scan can be linked to a therapeutic radioisotope. It is very exciting to be able to put a therapy on the PSMA, so it will go to the lesion and treat it using targeted radionuclides. It is already in Europe and has had some dramatic responses. Some were even complete responses. We are very eager to go in that direction at NCI, and we have some planned studies coming up.


--------------------------------------------------------------------------------------------------------------------------------------

IL23 promotes the development of castrationresistant prostate cancer

Juming Yan
Daniel J Cua
Michele WL Teng
First published: 08 September 2018
https://doi.org/10.1111/imcb.12195

Androgendeprivation therapy is standardofcare for prostate cancer (PCa). Although nearly all patients respond to treatment, most will eventually progress to a fatal stage of the disease, termed castrationresistant prostate cancer (CRPC).1 While deregulation of androgen receptor (AR) signalling in PCa is a known mechanism of resistance to androgendeprivation therapy,1 whether immune cells also contribute to the emergence of CRPC is unclear. Now Calcinotto et al. has reported that androgen deprivation promotes invasion of IL23producing myeloidderivedsuppressor cells (MDSCs) into the tumor microenvironment (TME) (Figure 1). Remarkably, IL23 can directly activate the AR signalling pathway in prostate tumor cells to promote their survival and proliferation.2
MDSCs have been shown to infiltrate the TME of many human cancer types, including PCa, and can be categorized into two subgroups, monocytic MDSCs or polymorphonuclear (PMN)MDSCs.2 Using multiplex immunofluorescence, the authors reported that PMNMDSCs were selectively enriched in human biopsies of CRPC compared to CSPC, and the PMNMDSCs were localized in close proximity to tumor cells.2 Preclinically, the Ptennull prostate conditional knockout mouse model (PtenPC/) develops castratesensitive prostate cancer (CSPC), which progresses to CRPC following surgical castration, and this mimics the disease progression observed in humans.3 Using this model, the authors demonstrated that surgical castration of these mice led to initial tumor regression followed by progression and emergence of CRPC. Similar to their observation in human CRPC biopsies, castration led to a selective increase of PMNMDSCs in the prostate of the PtenPC/ mice and this coincided with the emergence of CRPC. This increase in PMNMDSCs was also observed in castrated mice harbouring subcutaneous androgendependent mouse PCa cell lines, TRAMPC1 and MyCCaP.

Figure 1

IL23 promotes the development of castrationresistant prostate cancer. Androgendeprivation therapy promotes the infiltration IL23producing myeloidderivedsuppressor cells (MDSCs) to the tumor microenvironment (TME) where it directly activates the androgen receptor (AR) signalling pathway in prostate tumor cells (PC) to promote their survival and proliferation.
The authors hypothesized that factors produced by tumor infiltrating PMNMDSCs may directly contribute to the development of CRPC. They first generated conditioned media using either human or mouse bonemarrow derived MDSCs and showed that the media contained a growth factor that promoted AR gene activation even when the cells were grown in fully androgendeprived media. This suggests that a myeloid cellderived factor is able to replace androgen to fuel PCa tumor survival and growth. By comparing tumors from castrated PtenPC/mice to controls, the authors observed significant upregulation of the genes encoding proinflammatory IL23 and IL23R as well as the chemokine receptor/ligand pair CXCR2 and CXCL5, which are required for the recruitment of MDSCs. Using flow cytometry, the authors also showed that PMNMDSCs from tumors of castrated PtenPC/mice expressed higher levels of IL23p19, a subunit of IL23. However, it appears that PMNMDSCs from WT control mice do express surprisingly large amounts of IL23p19. IL23 is a heterodimeric cytokine comprising the IL23p19 and IL12p40 subunits and can only be secreted when both subunits are produced by the same cell. Although the authors showed that in vitro stimulated BMMDSCs secreted IL23, it remained unclear whether the circulating IL23 was actually produced by PMNMDSCs in the castrated versus control PtenPC/mice. In humans, plasma levels of IL23 were significantly higher in CRPC compared to CSPC although in general their levels were low and its basal level in healthy volunteers was not examined. Importantly, IL23R was upregulated in the prostate tumors of castrated PtenPC/mice, although tumors from shamcastrated PtenPC/ mice already expressed high levels of IL23R. This was interesting as mouse tumor cell lines are generally thought to not express IL23R. In contrast, IL23R expression on human tumor cell lines such as lung adenocarcinoma, oral squamous cell carcinoma and colon carcinoma has been reported, where its engagement generally increased proliferation and invasive capability depending on the concentration of IL23.4 Although androgendeprivation therapy can directly suppress PCa growth, it is also known to increase the infiltration of lymphoid and myeloid immune cells into the TME early postcastration, which diminishes as castration resistance emerges.5 Potentially this inflammatory infiltration may suppress PCa growth initially, but over time with the increase in IL23, this inflammatory reaction may sculpt the tumor and its TME to promote its growth and escape in the process of cancer immunoediting.6 The balance of IL12IL23 axis has previously been shown to have an important role in controlling the equilibrium phase of cancer immunoediting, which has been best characterized in an MCA carcinogeninduced mouse fibrosarcoma model.7 IL23 has also been shown to promote tumor initiation, growth and metastases in experimental and de novo mouse models of cancer by indirectly suppressing T and NK cell effector function.7
Overall, androgen deprivation results in mobilization and recruitment of IL23producing PMNMDSCs to the PCa TME and enhances PCa expression of IL23R and subsequent activation of STAT3 and RORγ transcription factors.8, 9 RORγ then recruits transcription coactivators, SRC1 and SRC3 to the ROR response elements (RORE) within the ARRORγ target gene clusters.9 Therefore, IL23 activation of RORγ is an alternate survival pathway that can replace ARdependent signalling. Next, the authors showed that androgendeprived PCa cells from PtenPC/x Il23a/ mice that could not produce IL23, had reduced levels of STAT3 and RORγ, consistent with the premise that IL23R activation on PCa cells maintained their proliferation and survival. The importance of MDSCs in promoting CRPC was also shown, where a CXCR2 antagonist reduced infiltration of PMNMDSCs into the tumors of castrated PtenPC/ mice or TRAMPC1, MyCCaP tumorbearing mice. By inhibiting PMNMDSCs, AR proliferative genes were suppressed and tumor growth was reduced in all three models. To support the therapeutic relevance of their findings, castrated PtenPC/ mice were treated with antiIL23p19 and AR antagonist enzalutamide either alone or in combination in mice that started to develop CRPC. Strikingly, the combination therapy was highly effective in reversing PCa resistance to castration as a greater proportion of mice had normalappearing prostate glands and decreased prostate volume after 5 weeks of treatment.
The demonstration that androgen deprivation may upregulate IL23R on PCa, suggests an unappreciated link between sex hormones and IL23R expression on nonimmune somatic cells. Going forward, it will be interesting to determine whether this is limited to androgens, or whether estrogen deprivation similarly upregulates IL23R in estrogen receptor positive breast and ovarian cancer. Somatic cells of epithelial origin from various organs such as liver, kidney and gastrointestinal tract can express IL23R (https://www.proteinatlas.org/ENSG00000162594-IL23R/tissue) and may have the potential to further upregulate IL23R under pathological conditions; this should now be investigated. Indeed, there are multiple colorectal cancerderived cell lines that express high levels of IL23R (Dan Cua, personal observation). Given that neutralizing antibodies to IL23 are clinically available and safe, it will be interesting to evaluate their use in combination with enzalutamide to treat men with CRPC. We recently reported that blocking IL23R may be more effective than neutralizing IL23 ligand in the suppression of tumor metastases.10 Given the direct effects of IL23R on driving the emergence of CRPC, and the availability of experimental antihuman IL23R neutralizing antibodies,11 it will be of interest to determine whether antiIL23R in combination with enzalutamide may be an even more effective combination than antiIL23p19 plus enzalutamide for the treatment of CRPC.

No comments: