Diagnostics, Genetics, Imaging – Page 8

New Prostate Cancer Diagnostic Tests

In the area of prostate cancer diagnoses, the ultimate goal is to find methods which would reveal whether a man has prostate cancer or is cancer-free, and if cancer is detected, is it aggressive requiring treatment or slow-growing requiring only monitoring. Many of these tests utilize biomarkers, substances like prostate-specific antigen (PSA) measured in a body fluid. While much data is available on the use of PSA, published studies on newer tests is very limited. Such tests can also be marketed without proof of benefit and may contain unsubstantiated claims. Given these limitations, here are some tests that are commercially available. Your personal physician should be consulted first and foremost. Costs and insurance coverages vary greatly. Insurance carriers and test manufacturers should be contacted for further information and possible assistance.

In addition to PSA, two tests that could help to decide whether a biopsy is necessary include the Prostate Health Index (phi test) and the 4Kscore. The phi test measures blood levels of PSA, free PSA and a precursor of PSA called pro-PSA or p2PSA. The phi test combines all three measurements mathematically to better determine whether prostate cancer is present. The phi test results (scaled from zero to 55 and above) reflect the probability that a biopsy will detect cancer. Research suggests that pro-PSA levels are a better indicator of prostate cancer than total or free PSA levels. Men with elevated pro-PSA levels are at risk for a more aggressive form of cancer. The test is indicated for men 50 years and older who have negative digital rectal exams and PSA levels of 4-10 ng/mL. For additional information on the phi test and its availability, see the following link to Beckman Coulter Diagnostics. The 4Kscore is a blood test which measures levels of three variants of PSA (total, free and intact PSA) plus an enzyme called human kallikrein 2 (hK2) which is elevated in men with prostate cancer and may promote its growth and spread. The 4Kscore is slated to be released in the United States in 2014.

Other tests are available to help determine whether a repeat biopsy is necessary as some initial prostate biopsies are inconclusive or negative in high-risk men. Progensa is a urine test that detects the presence of a gene called prostate cancer antigen 3 (PCA3). This gene is over-expressed (more active) in 95% of men with prostate cancer but not in men with healthy or enlarged prostates. Progensa can be used in men over 50 who have had one or more negative biopsies but who may be deemed candidates for prostate cancer nonetheless. This test has been discussed on this website in blogs dated 3/26/2012, 7/16/2013, 10/8/2013 and 12/31/2013. ConfirmMDx is a test that analyzes the DNA methylation status of a man’s biopsied prostate tissue. DNA methylation is a biochemical process that “tags” specific parts of DNA (the building blocks of genes). The result of this process is that the activity of tumor suppressor genes is decreased or turned “off'”, thus facilitating cancer development. The Prostate Core Mitomic Test analyzes a man’s biopsied tissue looking for damage to mitochondrial DNA caused by cellular changes associated with prostate cancer. A negative test indicates a low risk for undiagnosed prostate cancer and repeat biopsies can be deferred.

If prostate cancer is detected, the big question is whether treatment is immediately required or could active surveillance be invoked. Is the tumor low-risk or aggressive? Gleason score and other information are currently used to provide these answers however several tests may also help. Prolaris is a test that uses a sample of biopsied tumor tissue to measure how rapidly cells are dividing. Prolaris scores range from -1.3 to + 4.7, with higher scores indicating a greater risk of dying from prostate cancer. Prolaris may also help to determine the risk of recurrence after a prostatectomy and to determine whether a man would benefit from additional therapies such radiation or hormone therapy. The Prolaris test has been described on this website in the April 12th, 2014 blog. The test called ProstaVysion analyzes biopsied tissue for the presence of two biomarkers. One is TMPRSS2:ERG, a fusion of two genes associated with the presence of prostate cancer. The other is PTEN, a gene that normally help suppress certain forms of cancer and is missing in 60% of men with metastatic prostate cancer. These two markers help provide a molecular analysis of prostate cancer aggressiveness and the patient’s long term prognosis. These genetic markers were also discussed in previous website blogs dated July 16, 2013, October 8th, 2013, December 31st, 2013 and January 4th, 2014. Thirdly, Oncotype DX examines the interactions between 17 genes in a biopsy sample to predict whether a tumor is likely to be aggressive. The resulting Genomic Prostate Score ranges from 0 to 100; a lower score suggests that the tumor is less likely to grow and spread while a higher score suggests a poorer prognosis and the need for immediate treatment. This test was also described previously in posts dated June 21, 2013 and January 10th, 2014. Finally, the NADiA ProsVue blood test measures the rate of tiny changes in PSA levels over time which can suggest the level of risk for recurrence for several years following a prostatectomy.

More specific information can be found in an article written by Dr. H. Ballentine Carter, Director of Adult Urology at Johns Hopkins in the May, 2014 issue of the Johns Hopkins Medicine Health After 50. One can subscribe to receive this periodical from Johns Hopkins for a fee.

Screening and Treatment News Items from the Prostate Cancer Research Institute (PCRI) Highlights

The Prostate Cancer Research Institute publishes a monthly periodical called “Insights”. At the end of 2013, they also updated their user-friendly and searchable website, http://www.pcri.org. The February 2014 issue of Insights contained considerable information which I will briefly summarize. I encourage you to see the articles in their entirety.

First, Dr. John Davis from MD Anderson Cancer Center describes the “Prolaris Test for Prostate Cancer” which serves as an introduction to this novel genomic test and its role in improving clinical decisions about treating prostate cancer. Prolaris is a test performed on biopsy tissue that looks at the average expression of 31 Cell Cycle Progression (CCP) Genes, which are involved in telling a cell to divide in two. Such a test result can be grouped with other factors to help determine the potential prostate cancer aggressiveness or lack thereof. The test can be helpful in men who are interested in active surveillance but may not have low-grade, low-volume disease. It can help define the risk of cancer-related mortality if left untreated. The test is expensive (around $3400) and insurance coverage can vary.

Secondly, an article by Dr. Mark Scholz summarizes presentation highlights from a recent Prostate Cancer Foundation retreat. One presentation described the discovery of a new gene product called SCHLAP-1 that can help predict the likelihood of future metastases. SCHLAP-1 may have the same predictive power as a Gleason score in distinguishing low-grade from high-grade disease. Another presentation discussed the role of PSA decline as a measure of treatment effectiveness. PSA can be notably inaccurate as demonstrated with Provenge and Xofigo as neither causes a consistent decline in PSA though both have been shown to improve survival. Dr. Howard Scher of Sloan-Kettering described studies that rely on measuring a decline in circulating tumor cells (CTC) in response to therapy as an accurate method for early prediction of long-term survival. Dr. Scher combines CTC levels with measurement of an enzyme called lactate dehydrogenase (LDH) to differentiate patients into low, intermediate or high risk categories. The system has been tested and validated to predict survival and could be used by the FDA for evaluating new drugs according to Dr. Scher. Dr. Victor Velculescu from Johns Hopkins presented his work which suggests that the presence or absence of microscopic residual disease (micro-metastases) could be detected with new genetic tests called genomic analysis. If a test could confirm that a patient was free of metastases, then long-term hormonal treatment might be unnecessary.

An effect called the Abscopal Effect states that radiation may actually stimulate one’s immune system according to Dr. Mark Scholz. Presently, little is known about how anti-cancer therapies such as radiation interact with immunotherapy in a clinical setting. Phoenix, AZ – based 21st Century Oncology is beginning a clinical trial designed to determine if radiation-induced tumor death augments the anti-tumor responses from Provenge. Patients treated with a combination of spot radiation and Provenge will have their tumor responses tracked with C11-acetate PET scans. See the article for details.

In an article named “A New Approach to Prostate Cancer Screening”, the authors suggest that “rather than doing an immediate biopsy, doctors should consider prostate imaging with multi-parametric MRI or Color Doppler Ultrasound. In experienced hands with state-of-the-art equipment, high grade cancer can be ruled out with 95 to 98% accuracy. And when imaging detects a high-grade lesion, a targeted biopsy directed specifically at the area of abnormality can be performed. If the scans show that no high-grade disease is present, the patient can forgo biopsy and simply monitor the situation with further PSA testing and, if necessary, consider additional imaging in six to twelve months.” The same issue contains an article called “What’s New in Prostate Cancer” by Dr. Stanley Brosman. He discusses the use of multi-parametric-MRI (mp-MRI) to see abnormalities suspicious for prostate cancer. mp-MRI does tend to miss cancers that are low-grade which may be a good thing. In experienced hands, the ability to detect Gleason score 7 or 8 tumors was 98% accurate and the ability to predict the absence of aggressive tumors was 91%. This technique also allows for a more targeted approach to doing a needle biopsy. The mp-MRI is also very useful for following prostate cancer patients who are on Active Surveillance. A drawback is that a specific type of MRI, namely a 3-Tesla MRI, is needed in the hands of a highly trained radiologist. The test is also currently expensive and may not be covered by all types of insurance.

Finally, medications to treat osteoporosis in men receiving hormone therapy have been widely used for years. It has now been learned that men who have bone metastases can have stabilization and regression of the tumor with the use of these agents. Denosumab (Prolia) and XGEVA are being used with good results. It was reported that the use of Denosumab (Prolia) may be a preventive agent and delay the onset of bone metastases in high-risk patients.

Prostate Biopsies

I recently heard an interesting talk given by my local urologist in which he traced the history of prostate biopsies to detect cancers. I’d like to share a couple of insights that I learned. When my own cancer was first detected in 1995, the surgeons collected six samples via the trans-rectal route. I assume that at that time, this was the standard protocol. Currently, I understand twelve samples is the norm. However, my urologist stated that the trans-rectal route can easily miss cancers located in the anterior tissues of the prostate gland. Therefore, he recommended that the best route for biopsies is trans-perineal, i.e., the genital area between the scrotum and anus. This route provides better access to the anterior prostate. He also mentioned that a value called PSA-density, i.e. the amount of PSA produced per volume of gland, continues to be a useful indicator of possible malignancy. PSA density values have been used since the 1990’s. In fact, without realizing it personally, I had used it in my own case in 1995. An ultrasound had revealed that my prostate was not especially enlarged yet my PSA was consistently somewhat high in the 4.o ng/ml range. Naively, I reasoned that if a smaller gland was producing a higher than normal amount of PSA, something might be wrong. I was correct. Numerical guidelines for PSA densities are available though I don’t have that information at hand. My urologist also discussed the increasing use of magnetic resonance imaging (MRI) in guiding biopsies and delineating the prostate and surrounding tissues. An excellent overview of prostate MRI was written by UCLA Radiologist Dr. Daniel Margolis and published in the November, 2010 issue of the Prostate Cancer Research Institute (PCRI) Insights. An on-going clinical trial at the National Cancer Institute using MRI-guided focal therapy to treat low-risk, localized prostate cancer was also posted on this website on July 11th, 2012.

1) Financial Assistance for Prostate Cancer (PC) Patients; 2) Three New Commercially-Available Genetic PC Tests; 3) Phase 2 Clinical Trials for Metastatic PC Patients.

Fishing for information? Cornfield in Middletown Valley, Maryland; BJarne Gabrielsen photo

1) Payment Assistance for Under Insured Patients. The Patient Access Network (PAN) Foundation offers financial assistance to prostate cancer patients who lack full insurance coverage, allowing access to treatments previously out of reach. In 2012, PAN started an initiative to raise funds to provide castrate-resistant patients access to new and necessary treatments. To date, 2,200 men have enrolled and $22 million in financial assistance has been allocated. Current co-pay programs include treatments involving androgen receptor inhibitors, immunotherapy, radioisotope and metastatic castrate-resistant prostate cancer. Travel assistance for treatments are also available. Application information and details can be found in the November 2013 PCRI Insights.

2) Three new, commercially-available genetic tests for prostate cancer. Prolaris from Myriad Genetics and Oncotype Dx from Genomic Health can help obtain a more accurate measure of tumor aggressiveness. Both tests examine multiple genes in prostate cells that are removed at the time of biopsy. Polaris predicts the risk of ten-year mortality from prostate cancer while Oncotype Dx seeks to more precisely define the risk category of the individual prostate cancer. A third, Confirm MDx from MDxHealth can provide additional assurance that a negative biopsy is truly negative and that the needle did not simply miss the cancer. It is as accurate as a second biopsy without the unwanted complications.

3) Several specific open Phase 2 clinical trials for men with castrate-resistant, metastatic prostate cancer are listed in the November 18th, 2013 PCRI Insights. These trials involve new therapeutic agents such as Provenge, Xofigo and Cabozantinib (XL184). Enrollment information, criteria and locations are found in the Nov. 18th issue.

As always, your reader comments are valued. You can also sign up for automatic receipt of blogs as they are posted. See the home page.

Highlights of 2013-continued. Inflammation,Diet and Prostate Cancer; FDA Approvalof Xofigo; and, a Guide to Genes and Prostate Cancer.

Chronic inflammation is suspected to play a role in numerous diseases such as heart disease, Alzheimer’s, arthritis and cancer. If this is the case, then could reducing chronic inflammation by dietary means reduce the incidence of prostate cancer for example? This question is being studied extensively and is the focus of an article in the December 20th issue of the Prostate Cancer Foundation NewsPulse. Researchers at Johns Hopkins are studying prostate cells as they transition from normal to pre-cancerous and finally to cancerous. They speculate that inflammation may be an early factor inducing healthy prostate epithelial cells into the cancerous cycle. Since obesity is already linked to an increase risk of death from prostate cancer, could an anti-inflammatory diet have an effect on the incidence and severity of prostate cancer? A diet similar to the Mediterranean diet may be of help and is described in the NewsPulse article. Helpful foods include whole grains, healthy fats (as opposed to animal or trans fats), fruits and vegetables, spices such as ginger, garlic, cinnamon, and curcumin, green or oolong tea, nuts such as walnuts, oil-based salad dressing, omega-3 fatty acids derived from vegetable oils or flaxseed (as opposed to fish such as salmon), and others in the PCF article. While the anti-inflammatory diet includes many foods that may have health benefits for men with prostate cancer, further research is needed into specific components and the dietary patterns as a whole in order to assess how this diet may affect men with prostate cancer. As always, be advised to consult with your medical professional.

A second major story in this year-end issue of the PCF NewsPulse cites the FDA approval in spring, 2013 of Xofigo, radium-223-chloride, also known as alpharadin for the treatment of men with advanced metastatic prostate cancer. Xofigo extends survival, improves quality of life, requires less opioid medication for bone pain and its resulting side effects, and reduces complications such as spinal cord compression and bone fractures which result from bone tumors. Additional information is available in the accompanying article. This website has also posted information on this agent in previous blogs dated November 5th, 2011, January 3rd, 2012, April 28th, 2012 and June 3rd, 2013.

The third article from NewsPulse provides an excellent summary of a number genes and their proposed involvement in prostate cancer. Specific genes include HOXB13 (associated with hereditary prostate cancer), the female breast cancer susceptibility genes BRCA1 and BRCA2, the fused genes TMPRSS2-ERG and others. This review would be useful for physicians as well as laymen.

Highlights of 2013; New Urine Test for Prostate Cancer.

A new urine test for prostate cancer that measures minute fragments of ribonucleic acid (RNA) is now commercially available nationwide through the University of Michigan MLabs. The new test [Mi-Prostate Score (MiPS)], improves the utility of the PSA blood test, increases physicians’ ability to differentiate high-risk prostate tumors from low-risk tumors in patients, and may help many men avoid unnecessary biopsies. While there are currently no perfect biomarkers that identify only high-risk prostate cancer, the MiPS test incorporates blood PSA levels and two molecular RNA biomarkers specific for prostate cancer in one final score that provides men and their doctors with a more personalized prostate cancer risk assessment. One biomarker is a snippet of RNA made from a gene (PCA3) that is overactive in 95 percent of all prostate cancers. The second biomarker is RNA that is made only when two genes (TMPRSS2 and ERG) abnormally fuse. The presence of this fusion RNA in a man’s urine is very specific for prostate cancer. A commercial urine test (PROGENSA PCA3) for PCA3, developed and marketed by the California-based biotech company Gen-Probe, gained FDA approval in 2012 for use in men who are considering repeat biopsy after an initially negative result. The new urine test offered by MLabs that measures both PCA3 and TMPRSS2:ERG should improve a doctor’s ability to stratify men suspected of having prostate cancer. In a study published in Science Translational Medicine, University of Michigan investigators found a correlation between the highest rates of cancer in men with the highest levels of TMPRSS2:ERG and PCA3 in their urine. The men in the study were divided into three groups based upon the levels of TMPRSS2:ERG and PCA3 in their urine: low, intermediate and high levels. Cancer was diagnosed in each of the groups respectively: 21%, 43%, and 69%. High-grade prostate cancer, defined in the study as a Gleason score greater than 6, also occurred at different frequencies in the three groups with 7%, 20%, and 40% diagnosed in each group respectively. For additional information on this test, see the following link from the December 20^th, 2013 Prostate Cancer Foundation Newsletter. Earlier references to these tests can also be found on this website in 2013 posts dated October 8th, and July 16th as well as those dated March 25th, 2012 and September 21st, 2011.

A New Urine Test for Prostate Cancer Combining Genetic Biomarkers.

Considerable academic and commercial research efforts are underway in order to identify and utilize genetic biomarkers to aid in the diagnosis and characterization of prostate cancers, to determine their aggressiveness, to ascertain the need for biopsies, and to monitor therapeutic regimens. These have been reviewed in this website’s blog posts dated March 26th, 2012 and more recently, July 16th, 2013. Two such genetic markers found in urine are PCA3 (developed by Gen-Probe and approved by the FDA as PROGENSA PCA3) and TMPRSS2:ERG (from the University of Michigan). A three-way collaboration is underway between these two entities and the National Cancer Institute (NCI) of the National Institutes of Health (NIH) to combine and maximize the accuracy and utility of these tests. These efforts have been described in detail in an article published on September 30th by the Prostate Cancer Foundation (PCF). I suggest reading the entire article. If you feel that these tests may be applicable to your specific prostate cancer condition, definitely discuss them with your urologist, oncologist or medical provider.

Measuring PSA Activity May Be a Better Predictor of Prostate Cancer Aggressiveness.

Standing room only; Gasparilla Bay, Placida, Florida; BJ Gabrielsen photo.

Research results recently published online in the August 9th issue of The Prostate (Prostate 2013, DOI:10.1002/pros.22714) suggest that measuring the biological enzymatic activity (or lack thereof) of prostate-specific antigen (PSA) could be used as a predictor of prostate cancer (PCa) aggressiveness. As we know, the level of PSA in serum is often used to determine the necessity of prostate biopsies in the diagnosis of prostate cancer. Much research is on-going to discover tests which can be used to measure the aggressiveness of the cancer while at the same time, minimizing the negative side effects often accompanying prostate biopsies. Such a test could also be useful in determining which cancers could be candidates for active surveillance. In a study of 778 surgically-treated prostate cancer patients, a research team from Ohmx Corporation and Northwestern University have found that higher levels of PSA’s enzymatic activity (aPSA) correspond with less aggressive types of PCa (and vice versa). Stated differently, the activity of PSA (aPSA) is inversely proportional to disease stage. “Patients with the most aggressive PCa have significantly reduced PSA activity compared to those with less aggressive disease.” The researchers note that 22% of the men in their study population, namely the diagnosed patients with non-aggressive prostate cancer, could have averted or delayed radical prostatectomy based on their PSA activity findings. Ohmx Corporation is continuing validation studies and developing a commercial test, which they have trademarked PPA (PSA Peptidase Activity). Biochemically, PSA (a protein) is an androgen (hormone) – regulated serine protease enzyme produced by both prostate epithelial and prostate cancer cells. PSA is the major protein found in semen. It is secreted into the prostatic ducts in an inactive form that is then activated biochemically. PSA that enters the circulation is rapidly “bound” although a fraction is inactivated and circulates as “free PSA”. High PSA levels may be predictive of advanced PCa but a large fraction of organ-confined cancers show much lower PSA values that overlap those levels found in men without PCa. Measurement of free versus total PSA can increase specificity for PCa. PSA is also used widely to monitor responses to therapy and is under investigation as a therapeutic target itself. Remember to always discuss these issues with your physician before taking any actions.

But more importantly, whatever your current situation, if you are concerned about prostate cancer either personally or for someone else, remember that God Himself has a message for you. David writes in Psalm 55:22, “Cast your burden upon the Lord and He will sustain you; He will never allow the righteous to be shaken.” In addition, Psalm 34:19 states “many are the afflictions of the righteous; but the Lord delivers him out of them all.”

Using Genetic Biomarkers in Prostate Cancer Diagnoses- A Review.

Looking for something? Sandhill cranes in my yard. Photo: BJ Gabrielsen

New research has identified several ‘biomarkers’ or genetic fingerprints that report the underlying biology of a tumor. Combinations of these biomarkers can aid clinical management of prostate cancer by: 1) allowing accurate diagnoses; 2) establishing whether a patient’s cancer is aggressive or indolent; 3) deciding if repeat biopsies are needed; 4) aiding clinical decisions on therapeutic options (drug combinations for maximal patient benefit); and, 5) evaluating whether a patient’s cancer is responding to therapy or not. For an excellent review article describing many of the diagnostic (including genetic) tests currently available or in the developmental pipeline, see the March 29th, 2013 Prostate Cancer Foundation (PCF) NewsPulse and the articles contained therein. Many of these biomarker-driven diagnostic / prognostic tests nearing clinical use are in the final stages of clinical validation and are listed in table form in the Newspulse article. The New York Times recently published a feature article discussing many of these new tests. These latest prostate cancer tests evaluate blood, urine or prostate biopsy specimens for the presence of either an abnormal gene activity pattern, or specific chemicals that are released by cancer cells. For example, the GenProbe test currently evaluates urine samples for the expression of PCA3 (prostate cancer antigen) DNA. It is anticipated that the GenProbe test evaluating both PCA3 DNA and expression of the TMPRSS2-ERG gene fusion will soon be approved for use. The abnormal TMPRSS2-ERG gene fusion is present in 50 percent of all prostate tumors, and PCA3 is expressed at high levels in 95 percent of prostate cancer patients, therefore the combination of these two tests has a high probability of accurate diagnoses. Testing these biomarkers in urine samples holds potential due to the non-invasiveness of urinalysis, ease of collection, and the fact that prostate cells are directly released into the urethra through prostatic ducts after a digital rectal exam (DRE) or prostate massage.

A Genetic Mutation Found in Some Younger Prostate Cancer Patients.

In an attempt to identify younger men who are at risk for prostate cancer, researchers at Johns Hopkins in Baltimore, MD studied 94 men who had been diagnosed with prostate cancer when they were 55 years old or younger or who had close blood relatives with prostate cancer. Past research led the investigators to suspect that one particular region of the human chromosome, known as 17q21-22, might be the location of one or more prostate cancer susceptibility genes. The team analyzed 200 genes located in this region. They found that four of the 94 men had a mutation on a gene known as HOXB13, which plays an important role in the development of the prostate. These four men were also found to have a total of 18 close male relatives with prostate cancer. Blood tests revealed that every one of these men had the HOXB13 gene mutation — powerful evidence that it might be linked to hereditary prostate cancer. In a larger study of 5,100 men who had been treated for prostate cancer, it was found that 72 of them had the same mutation on the HOXB13 gene. In addition, these men were highly likely to have been diagnosed with prostate cancer at a young age or to have one or more relatives with the disease. For comparison, the team studied 1,400 men who didn’t have prostate cancer. Just one man had the HOXB13 mutation. “This study, which was published in the New England Journal of Medicine, found that men who carry the HOXB13 mutation are up to 20 times more likely than non-carriers to develop prostate cancer. It is important to keep in mind that the mutation discovered on the HOBX13 gene is rare and explains only a small number (between 2%-5%) of prostate cancer patients but it is an excellent example of the use of an individual’s personalized genomic information as a predictor of future health issues.

A brief description of terms as used in discussions about genes and prostate cancer was recently published in the July 13th edition of the Johns Hopkins Health Alerts. (See link).