Genetics

New research on gene changes linked to prostate cancer is helping scientists better understand how prostate cancer develops. This could make it possible to design medicines to target those changes. Tests to find abnormal prostate cancer genes could also help identify men at high risk who might benefit from screening or from chemo-prevention trials, which use drugs to try to keep them from getting cancer.

Most of the gene mutations that have been studied as factors that might increase prostate cancer risk are from chromosomes that are inherited from both parents. Some research has found that a certain variant of mitochondrial DNA, which is inherited only from a person’s mother, might also raise a man’s risk of developing prostate cancer.

Testing for non-coding RNA molecules in urine may offer a way to detect prostate cancer that is more accurate and reliable than current methods using biomarkers such as PSA and PCA3.

The researchers believe using non-coding RNAs as biomarkers will lead to more reliable and accurate tests for prostate cancer than the current PSA test.

This was the conclusion of a German study presented at the European Association of Urology Congress (EAU16) in Munich, Germany, March 11-15, 2016.

Friedemann Horn, a professor in the University of Leipzig and the Fraunhofer Institute for Cell Therapy and Immunology IZI, and Manfred Wirth, a professor in the University of Dresden – both in Germany – led the work. Prof. Wirth says:”Our work on RNAs [ribonucleic acid] is allowing us to design a completely new kind of prostate cancer test.”

Current biomarker tests for prostate cancer measure levels of PSA (prostate-specific antigen) and PCA3 (prostate cancer gene 3), but they are not particularly accurate and can either miss many cancers or produce false positives.

The researchers behind the new study have identified a series of non-coding RNA molecules that could potentially be combined into a single urine test to detect prostate cancer.They say their test could offer greater sensitivity and specificity than the current biomarker tests and thus make population screening much more viable.

A test with high sensitivity is good at ruling out disease when the result is negative, and a test with high specificity is good at ruling in disease when the result is positive.Non-coding RNAs showed better specificity and sensitivity.

Progress in genomic science is revealing that genetic programming in human beings and other higher organisms is far more intricate and complicated than we thought. It appears our bodies express a huge repertoire of previously overlooked molecules that orchestrate a hidden layer of genetic signals involved in health and disease.

Fast facts about prostate cancer

• Other than skin cancer, prostate cancer is the most common cancer in American men
• About 1 man in 7 will be diagnosed with prostate cancer during his lifetime
• The average age at the time of diagnosis is about 66.

Learn more about prostate cancer

One group of these genetic molecules is non-coding RNA. RNAs are molecules that help to read and translate DNA (deoxyribonucleic acid) to make proteins – the workhorses of cells.Until recently, it was thought that many RNAs that do not help make proteins – called non-coding RNAs – were simply “junk” and had no particular function.

Now, greater understanding of non-coding RNAs reveals they help control many biological processes, including the development and progression of cancer, and measuring them could offer a way to detect disease.

For their study, the researchers took 64 prostate cancer tissue samples obtained from biopsies and read 200 million sequences in genetic molecules from each sample. They found over 2,000 sequences that were significantly different in tumor samples than in healthy controls.

Some of these sequences were for non-coding RNAs that showed better specificity and sensitivity than established prostate markers.The biomarkers were also found to be present in urine samples from cancer patients, and initial tests suggest they offer a precise way to detect the disease.

Combination of biomarkers will give better specificity

One of the non-coding RNAs – called tumor-associated proliferation-inducing RNA (TAPIR) – also showed significant promise in stopping cancer cell growth. However, the team says it is too soon to say whether this result will prove to be clinically useful.The team is now developing a highly specific and sensitive urine test for the early diagnosis of prostate cancer. The test will use a combination of biomarkers rather than just a single one.

Prof. Wirth says the work is still in the early stages, but results look promising. It offers a new approach to diagnosing prostate cancer and arises from applying basic science to a clinical problem. He concludes: “Given that our initial results show a high specificity for prostate cancer in urine tests, the prospects are good that we will be able to translate this into a better test for prostate cancer. We have several good candidate biomarkers, however we are aiming to design a test which utilizes a combination of biomarkers. This will give significantly better specificity than existing tests.”

The study is part of a project called RIBOLUTION (RIBOnucleic acid-based diagnostic soLUTIONs) – funded by the Fraunhofer Future Foundation – that aims to identify new RNA biomarkers and to develop novel diagnostic tests. The American Cancer Society estimate that in 2016, about 180,890 American men will be diagnosed with prostate cancer, and about 26,120 will die of the disease. Meanwhile, Medical News Today recently learned that the survival time for men with metastatic prostate cancer may depend on which part of the body the disease spreads to.

Specific mutations in the DNA of men with metastatic prostate cancer have been shown to play a larger role in the disease than previously thought. Researchers hope that this finding will help change standard therapy guidelines and open the door to drugs currently being used for other cancers.

Gene mutation research gives a new perspective on prostate cancer.

The new study, published in the New England Journal of Medicine, examined inherited mutations in DNA repair genes. These gene mutations were already known to occur more frequently in prostate cancer patients than the general population.

However, the present study demonstrated that mutations in DNA repair genes were even more prevalent in people with metastatic prostate cancer, specifically.

The research was headed up by Dr. Peter Nelson, a member of the Human Biology, Clinical Research, and Public Health Sciences divisions at Fred Hutchinson Cancer Research Center, WA. The team found that more than 10 percent of men with aggressive prostate cancer displayed inherited mutations in DNA repair genes.

These particular mutations occur in DNA repair genes such as BRCA1 and BRCA2, both of which produce tumor suppressor proteins. These DNA repair genes, as the name suggests, help maintain the integrity of the genetic code. If they are mutated, the DNA is less likely to be repaired correctly, increasing the risk of cancer.

BRCA1 and BRCA2 genes are already known to increase the risk of female breast and ovarian cancer. These two genes alone account for 20-25 percent of all hereditary breast cancers. So, although the role of these genes in cancer is known to be important, their influence in metastatic prostate cancer was not fully recognized.

DNA repair genes and metastatic prostate cancer

The researchers found that 11.8 percent of men with metastatic prostate cancer (regardless of age or family history) had mutations in one of the 20 DNA repair genes they screened for. That’s around four times the rate found in the general population and twice as much as the rate found in men with localized prostate cancer.

BRAC2 showed the clearest change in gene prevalence; men with advanced prostate cancer were 18 times more likely to have a mutation in their BRCA2 gene when compared with men without prostate cancer.

The researchers state their results are important for men who have been diagnosed, as well as for family members who might be at risk:”The result is surprising and important for men with prostate cancer as this information may prioritize certain therapies. It is also important for family members as they may have inherited a gene that predisposes them to developing one of several types of cancer, and heightened awareness could enhance early detection and treatment,” says Dr. Peter Nelson.

In total, the research team used data from 692 men with metastatic prostate cancer across a number of sites, including the Fred Hutchinson Cancer Research Center and the University of Washington. All of the institutions involved in the study carried out independent screening of 20 distinct DNA repair genes.

Importantly, the men used in the current study were not chosen because of family history or age, giving the results extra reliability. Additionally, the independent screening across multiple laboratories produced the same results across the board, adding further strength to the findings.

The future treatment of prostate cancer

This research project could open the door to other forms of treatment for metastatic prostate cancer. PARP inhibitors and platinum drugs are already used in some cancer cases, such as treating ovarian cancer in people with DNA repair gene mutations. PARP inhibitors – poly (ADP-ribose) polymerase – prevent PARP from repairing the damaged DNA of cancer cells, steadily killing them off. Platinum drugs, including cisplatin, carboplatin, and oxaliplatin, also inhibit DNA repair, slowly destroying cancer cells which are unable to fix their faulty genes. The results of this study could lead to the approval of PARP inhibitors and platinum drugs for metastatic prostate cancer, improving overall chances of survival.

A decade-long increase in the number of men who have incurable prostate cancer at their initial diagnosis has been documented by an new study; an ominous finding that prostate cancer-screening proponents have been predicting.

Both screening and diagnosis of early-stage prostate cancer have declined, coinciding with recommendations from an influential government advisory panel. In 2008, the U.S. Preventive Services Task Force said not to do routine PSA blood testing of men over age 74. And in 2012, it said to not screen any men – not even those at high risk – because the harms of unnecessary treatment outweigh the benefits of catching cancer early.

Despite less testing, death rates have been falling since 2007.

The new analysis, published in the journal Prostate Cancer and Prostatic Diseases, is the first to find an increase in metastatic cancers.

The Northwestern University analysis does not necessarily reflect a national trend. The study used a national cancer database from more than 1,000 hospitals rather than a representative sample of the population, so researchers could not calculate rates of disease.

Nevertheless, the statistics are stark: The annual number of metastatic prostate cancers at first diagnosis rose from 1,685 in 2004 to 2,890 in 2013 – a 72 percent increase the researchers call a “skyrocket” in a news release. The upturn was even greater among men 55 to 69, the age group believed to benefit most from early detection because of their risk level and life expectancy.

Over the same period, early-stage cancer diagnoses dropped from 25,708 to 16,223, or 37 percent.

Given that the surge in metastatic cases began before the U.S. Preventive Services Task Force’s recommendations against routine PSA testing, other factors must also be at work, the Northwestern researchers concluded. They speculated that some tumors are more aggressive, and that better imaging technology has improved detection of the spread to lymph nodes or beyond.

But the implications, they wrote, “highlight the need for nationwide refinements in prostate-cancer screening.”
“If you don’t screen, you don’t detect it early”, said senior author Edward M. Schaeffer, chair of urology at Northwestern’s Feinberg School of Medicine. “This is going to affect mortality rates. Metastatic disease is incurable. They will die.”

Eric Horwitz, a Fox Chase Cancer Center radiation oncologist, said the new study gives credence to anecdotal reports of spikes in metastatic cases – and to fears that the shift away from screening has gone too far.”We really do need to adjust the guidelines,” Horwitz said.

Thomas Jefferson University prostate cancer researcher Karen E. Knudsen said, “The challenge will be to refine guidelines so as to not miss men who would have benefited from earlier therapy, while at the same time not overtreating patients with a low likelihood of developing lethal prostate cancer.”

In its controversial 2012 disavowal of PSA screening, the advisory panel concluded that early detection saves few, if any, lives, while treatment leaves many men with sexual or urinary problems or both. The panel said “most” cancers found by screening are innocuous and would not cause harm if left undiagnosed.

The task force, which influences insurance coverage, relied heavily on two major clinical trials that compared screening to no screening. A European trial showed screening reduced deaths by 21 percent. A U.S. trial found no difference in death rates, but it has been widely dismissed as flawed because so many men in the no-screening group got PSA tests anyway.

Asked about the new study, panel chair Kirsten Bibbins-Domingo, an epidemiologist at the University of California, San Francisco, said in an email: “The Task Force welcomes new research. . . . As part of our normal process, we are currently reviewing the latest evidence to update our 2012 recommendation.”

She said that any man who is concerned about his risk of prostate cancer should talk to his doctor, “as this recommendation does not preclude a man choosing to be screened.”
Debate about the value of screening has raged for decades for both prostate and breast cancers.

Even Dartmouth Medical School researcher H. Gilbert Welch, an outspoken critic of overdiagnosis and overtreatment, believes the advent of routine PSA testing a quarter-century ago explains a “steep” decline in metastatic prostate disease.

Welch analyzed a federal cancer database and found the incidence of metastatic cases fell by half in the seven years after the start of widespread PSA use in 1990. “It’s hard to imagine another factor . . . exerting an effect so quickly,” Welch wrote last year in the New England Journal of Medicine.

The Northwestern study’s inability to calculate rates leaves unanswered questions. Perhaps the hospitals’ increase in advanced disease simply reflected a proportionate increase in the vulnerable age group – namely, older men.

“It is very possible” that less early detection will result in more advanced disease, said Otis Brawley, chief medical officer for the American Medical Association and a critic of overdiagnosis. “They simply did not prove it.”

Prostate cancer remains the second-leading cause of cancer death among men, behind lung cancer, so finding the right balance between early detection and overdiagnosis is essential. Schaeffer said his team plans to publish a profile of the metastatic patients in their study, analyzing their age, race, education, income, insurance coverage, and PSA level. The insights, he hopes, will help target screening to the men who need it most.

The task force four years ago “basically shot a volley across the bow, saying that screening the average person is not warranted,” he said. “If you can understand who is diagnosed with metastatic disease, that would be one way to be smarter about screening.”

According to a recently published pilot study from the Northwestern University Feinberg School of Medicine, men with prostate cancer who are under close medical surveillance reported significantly greater resilience and less anxiety over time after receiving an intervention of mindfulness meditation.

Even when there is no sign of tumor progression, the anxiety and uncertainty that men who choose active surveillance experience when diagnosed with prostate cancer causes one in four to receive definitive therapies within one to three years.

One researcher focusing on the emotional stress of active surveillance and how mindfulness training helps alleviate the anxiety is Health psychologist David Victorson, the principal investigator of the study and an associate professor of medical social sciences at Northwestern University Feinberg School of Medicine.

Dating back some 2,500 years, mindfulness meditation is a well-known contemplative awareness practice. This form of meditation is designed to develop the skill of paying attention to patients’ inner and outer experiences with acceptance, patience and compassion.

Victorson said, “It’s very understandable that some men will feel concerned with the knowledge that they indeed have prostate cancer but are asked to NOT do anything to remove it. For many men this can create a great deal of inner turmoil. This turmoil can build up over time and eventually lead to men to seek surgical intervention when it may not ultimately be necessary.”

Now partnering with other academic medical institutions, Victorson and his Northwestern team are conducting a five-year multi-site controlled trial where men and their spouses will be randomized to eight weeks of intensive mindfulness meditation training or an eight-week control group.

According to Mr. Victorson, “I believe we have an opportunity to investigate and equip men with additional tools above and beyond surgical intervention that can help them manage cancer-related uncertainty intolerance.”

The radioactive imaging agent, fluciclovine F18 (Axumin), was approved by the FDA for use in positron emission tomography (PET) scans in men with suspected recurrence of prostate cancer whose prostate-specific antigen (PSA) levels rise following prior treatment.

Clinicians now hope to be able to better determine the location of the recurrence in the prostate, as this defines optimal choice of therapy. There is a low diagnostic accuracy with standard imaging tests used to determine identification of sites of recurrence, which is the reason why more accurate techniques are needed.

“When the PSA is at very low levels, imaging tests are not able to determine the location of the recurrent prostate cancer,” said Libero Marzella, MD, PhD, of the FDA’s Center for Drug Evaluation and Research and director of the Division of Medical Imaging Products, in a statement. “Axumin is shown to provide another accurate imaging approach for these patients.”

Experts estimate that up to one-third of patients who receive curative treatment after a diagnosis of primary prostate cancer will experience recurrence within 10 to 15 years following primary treatment.

PET scans are a well-established non-invasive imaging technique that uses the radiotracer [18F]flouro 2-deoxyglucose (FDG) for many tumor types. However, this agent is not widely used in imaging prostate cancer because of poor uptake and high urinary excretion limiting imaging quality.

The other PET radiotracer that is available, C11 choline, has been shown to improve detection in men with biochemical recurrent prostate cancer, but its 20-minute half-life limits use to medical centers with specialized on-site C11 production capability.

Axumin is a synthetic amino acid that is actively transported into prostate cancer cells by amino acid transporters. It is not metabolized, nor is it incorporated into newly synthesized proteins. Imaging studies have demonstrated that Axumin is preferentially taken up into prostate cancer compared with surrounding normal tissue and visualization is not obscured by bladder uptake.

Across the nation researchers continue to look for foods (or the substances within them) that can help lower prostate cancer risk. To date scientists have found that some of the substances in tomatoes (lycopenes) and soybeans (isoflavones) might help prevent prostate cancer. New studies are now taking a closer look at the possible effects of these compounds.

Some scientists are also trying to develop related compounds that are even more potent and might be used as dietary supplements. Most of the current research suggests that a balanced diet including these foods as well as other fruits and vegetables is probably more beneficial than taking these substances as dietary supplements.

Vitamin D may prove to be an important in preventative. Some studies have found that men with high levels of vitamin D seem to have a lower risk of developing the more lethal forms of prostate cancer. However, studies have not proved conclusively that vitamin D protects against prostate cancer.

People often assume that vitamins and other natural substances are completely safe to take, but recent research has shown that high doses of some may be harmful, including those in supplements marketed specifically for prostate cancer. For example, one study found that men who take more than 7 multivitamin tablets per week may have an increased risk of developing advanced prostate cancer. Another study showed a higher risk of prostate cancer in men who had high blood levels of omega-3 fatty acids. Fish oil capsules, which some people take to help with their heart, contain large amounts of omega-3 fatty acids.

Some research has suggested that men who take a daily aspirin for a long time might have a lower risk of getting and dying from prostate cancer. Still, more research is needed to confirm this, and to confirm that any benefit outweighs potential risks, such as bleeding.

Scientists have also tested certain hormonal medicines called 5-alpha reductase inhibitors as a way of reducing prostate cancer risk. Studies like all of these mentioned here could prove to be very beneficial for men in the future.

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As recognized and respected leaders in the field of da Vinci® Robotic Surgery for prostate cancer, Dr. Christopher Knoedler and Dr. Robert Gaertner stay on top of the latest developments in their field. Recently they flew out to the headquarters of Intuitive Surgical in Sunnyvale, California to be introduced to a new robotic surgery prototype.

The doctors were asked to visit the headquarters of Intuitive Surgical to see the newest robot that is currently in development. They engaged with the engineers on a back and forth with their own ideas and suggestions on the new (were asked to help engineers trouble-shoot and refine this new) high tech piece of surgical equipment.

Currently when performing robotic prostate surgery, Drs. Knoedler and Gaertner create six small incisions. The new robot would reduce the number of sites that the instruments need to pass through from six to either two or three. When surgeries become less invasive it benefits patients with quicker recovery times.

The new version of the robot also allows the surgeons easy visual access to all four quadrants of the abdomen and allows them to operate in all four areas as well.

Dr. Knoedler and Dr. Gaertner are pioneers in the utilization of da Vinci Robotic Surgery and have trained hundreds of physicians in the use of this revolutionary technology. They were among the first doctors in the region to routinely use this robotic surgery system and have led the way in using it to improve the extremely challenging surgical procedure to remove the prostate gland (Prostatectomy). To date this team has performed more than 3,000 robotic surgeries.

In 1999 Intuitive Surgical introduced the da Vinci® Surgical System and today they are the global leaders in robotic-assisted minimally invasive surgery. This technology features a 3D high definition vision system for a clean and magnified view inside the patient’s body. The instruments used bend and rotate far greater than the human wrist. The surgeon controls the system which translates hand movements into smaller, more precise movements of tiny instruments inside the patient’s body. This technology allows surgeons to perform complex procedures through a few small openings.