Category: Diagnostics, Genetics, Imaging
Potential Diagnosis of Prostate Cancer Using Urine Biomarker Protein Signatures.
A recent study revealed protein biomarker combinations in urine that are unique to prostate cancer and 2 of its stages. A team from the University Health Network in Toronto Canada analyzed urine samples from 50 patients with prostate cancer — 37 with prostate-confined tumors and 13 with tumors that spread — and 24 healthy controls. A targeted protein screen revealed 34 potentially useful biomarkers. Twenty-four of these showed differences between patients with cancer and healthy controls, suggesting these markers could be useful for diagnosis. Fourteen were different between those with prostate-confined tumors and those with tumors that spread, suggesting these markers may be useful for predicting prognosis, or the cancer’s aggressiveness. The team next analyzed urine samples collected from a second, independent group of 117 healthy controls and 90 patients with prostate cancer (61 with stage T2, prostate-confined cancer and 29 with stage T3, cancer that’s spread to nearby tissues called seminal vesicles). The team found a combination of protein biomarkers that predicted the diagnosis correctly in 70% of cases and the stage with 69% accuracy. These “biomarker signatures” outperformed the predictive accuracy of the prostate-specific antigen (PSA) protein, which is currently used for making early diagnoses of prostate cancer. The next step will be further studies with urine samples from 1,000 international patients to validate if the biomarkers identified have broader clinical utilities in prostate cancer. For more details, see the article recently published in National Institutes of Health (NIH) Research Matters.
High Prostate Cancer Risk Linked to Inherited Mutations in DNA-repair Genes.
Mutations in DNA-repair genes, including the breast cancer genes BRCA1 and BRCA2, are involved in an inherited high risk of prostate cancer and, potentially, the risk of an aggressive cancer, according to researchers at Fred Hutchinson Cancer Research Center and the University of Washington.
The study, “Inherited DNA -Repair Gene Mutations in Men with Metastatic Prostate Cancer” published in The New England Journal of Medicine, (see the following link) found the mutations in about 12 percent of men with the cancer — and found that men with metastatic prostate cancer were five times more likely than most people to have these DNA-repair gene mutations. Results suggest that screening for such mutations could help tailor their treatment and encourage family members to consider their own cancer risk.
Because BRCA1 and BRCA2 mutations have long been associated only with breast and ovarian cancers, it was thought that the mutations only affected women.
The team analyzed 20 DNA-repair genes in metastatic prostate tumors and healthy tissues of 692 men. They found that 16 of the genes were mutated in both malignant and healthy cells in 12 percent of the metastatic cancer patients — much higher than researchers ever suspected, said first author Dr. Colin Pritchard.
The findings are also important because men with advanced prostate cancer who have the mutations in DNA-repair genes could be treated with PARP inhibitors or platinum chemotherapy (cis-platin) which is commonly used in breast cancer patients. Although not yet approved for prostate cancer treatment, the treatments are on fast-track review by the U.S. Food and Drug Administration.
“For men with metastatic disease who are found to have these mutations, there are very clear treatment implications that would not otherwise be considered for prostate cancer. It would essentially expand [the patients’] toolbox of treatments,” Cheng said. The researchers hope the findings will lead to future coverage by insurance companies.
The study authors state that it may be of interest to routinely examine all men with metastatic prostate cancer for the presence of germline mutations in DNA-repair genes. Future work by investigators will focus on determining which mutations predispose patients to the most aggressive type of prostate cancer.
The National Cancer Institute (NCI ) of the National Institutes of Health (NIH) also recently published a Cancer Currents Blog on the same subject. See the following link.
The FDA Approves a New Diagnostic Imaging Agent (Axumin) to Detect Recurrent Prostate Cancer.
Several positron emission tomography (PET) scans (including C-11 choline and acetate PET scans) exist whose purpose is to detect the location of recurrent prostate cancer when the PSA is at low levels. Within the last few days, the U.S. Food and Drug Administration approved another scan using an injected radioactive agent called Axumin. The following link from the FDA provides additional information concerning the reliability of the new scan and its comparison with existing PET scan reagents. Axumin is marketed by Blue Earth Diagnostics, Ltd., Oxford, United Kingdom.
Low Vitamin D Levels May Signal More Aggressive Prostate Cancer But Don’t Expect Supplements to Ward Off Fast-Growing Tumors.
A Northwestern University study of 190 men of median age 64 having their prostate removed found those with low vitamin D levels were more likely to have rapidly growing tumors than those with normal levels of the “sunshine” vitamin. The study was published on-line in the Journal of Clinical Oncology. The researchers found that nearly 46 percent of the men had aggressive cancer, and these men had vitamin D levels about 16 percent lower than men with slower-growing tumors. Racial distinctions were also noted in this study with black men having more aggressive tumors and lower vitamin D levels than white men. After accounting for age, PSA levels and abnormal rectal exams, researchers found that blood vitamin D levels below 30 nanograms per milliliter (ng/mL) were linked to higher odds of aggressive prostate cancer. The study however does not necessarily prove that vitamin D deficiency causes aggressive prostate cancer, only that the two are associated. Experts quoted herein state that while these results are important enough to spur further study into the vitamin D – prostate cancer potential biomarker connection, there is not sufficient evidence at this time to recommend vitamin D supplements to prevent prostate cancer or to make it less aggressive. It should be noted however that most Americans in general have lower than normal vitamin D levels which seem to be implicated in several medical conditions. It is recommended that men and women be blood-tested routinely for vitamin D levels using the 25-hydroxy vitamin D assay. Optimum levels should be at least 30 ng/mL. (One can get too much vitamin D so consult your physician to discuss test results and supplement recommendations if needed.) It was also suggested that perhaps men should be tested for Vitamin D when they are diagnosed with prostate cancer and subsequently supplemented with vitamin D if they are deficient. For further information, see the link to this study published in the National Institutes of Health Medline. For an additional summary of this study see the following link from Cancer Therapy Advisor.
Everything You Need to Know About Pathology Reports and Gleason Grade.
An excellent review by Dr. Jonathan Epstein of Johns Hopkins was just published in the Prostate Cancer Research Institute Insights. Please see the entire link for the questions and answers from Dr. Epstein.
PSA Testing Do-Overs Recommended
According to a recent Canadian study, if your doctor suspects you may have prostate cancer because of an elevated prostate-specific antigen (PSA) level, you might want to ask for a repeat PSA test to confirm the results. It could save you from undergoing an unnecessary prostate biopsy that could entail serious complications. Of 1,268 men who underwent a second PSA test within three months of their first test showing elevated PSA levels, 315 (24.8 percent) had normal results the second time around. As a result of their finding, the researchers recommend that men with elevated PSA levels should repeat the test before undergoing a biopsy. The American Urological Association echoes this recommendation. Elevated PSA levels may result from infection, physical activity or sexual activity. Other studies revealed that only 16 to 56 percent of primary care physicians ordered a repeat test for patients with abnormal PSA results. Most experts agree that PSA screening should be used in conjunction with a digital rectal examination, and additional information such as family history, race, and age to assess the likelihood of prostate cancer being present. The information presented here came from the Mayo Clinic Proceedings, published online in December, 2015 and re-printed in HealthAfter50, Scientific American Consumer Health.
Prostate Cancer Lesions Accurately Detected by New Imaging Agent
Current tests to initially detect prostate cancer rely on biopsies. Scans such as bone and CT scans, and choline-11 and acetate-11 PET scans are used to identify sites of cancer metastases. Researchers at Thomas Jefferson University have now developed a new imaging technique to detect prostate cancer cells and malignant lesions. Their technique is both highly accurate and more effective than current detection methods. Details of their imaging technique (see link) entitled “VPAC1 Targeted 64Cu-TP3805 Positron Emission Tomography (PET), were recently published in the journal Urology. The novel copper-peptide (small protein) imaging agent 64Cu-TP3805 attaches itself to VPAC1 receptors on the surface of cancer cells. The TP3805 peptide portion of the agent hooks on to the cell receptors and the copper-64 radiation-emitting peptide allows their detection by PET-CT scanning. The technique was tested on 25 prostate cancer patients undergoing radical prostatectomies. Compared to conventional biopsies, this technique found 105 out of 107 cancerous lesions in the removed prostates as well as nine lesions not found by conventional pathology. Positive and negative lymph nodes, cases of benign prostatic hyperplasia (BPH), and cysts were also identified. Larger studies are planned.
Gleason Score in Diagnosing Prostate Cancer
The following is an excerpt from a January 12th, 2016 blog called Prostate Snatchers by Mark Scholz, M.D.
The latest craze in medical technology is genetic analysis of tumor cells (GAT). “The scientific progress that has been made with GAT in my opinion is the second most exciting area of advancement in medical technology today (see below for more about the first most exciting area).” GAT technology is already being commercialized for use in the medical marketplace in products like Prolaris and Oncotype. (For a review of both, see Godanprostate.net November 27,2015 post). These technologies are able to predict the aggressiveness of prostate cancers, enabling us to differentiate between the men who need immediate treatment and those who can postpone treatment safely.
“The predictive power of GAT is certainly exciting, but there is already an effective form of genetic testing available that has been around for more than 40 years, the Gleason scoring system. The Gleason system relies on the visual appearance of cells under the microscope to draw conclusions about their inner genetic makeup. In the medical world, using the visual appearance of the cancer cells is called phenotypicanalysis. GAT is genotypicanalysis.”
“So how can Gleason score draw conclusions about the underlying genetic potential for tumor aggressiveness simply by looking at the appearance of cells under a microscope? The answer is to do a comparison of the visual appearance of cancer cells with the appearance of normal prostate cells. Normal cells in the prostate perform varied functions but still work together as a team. Specifically, healthy cells form into definable structures called glands. In these glands some cells manufacture prostatic fluid, a complex liquid comprising the ejaculate for the sperm to swim in. Other cells organize to form ducts, a piping system to drain the fluid from the outer periphery of the gland and channel it into the middle of the prostate so that a large quantity of fluid can be expelled through the urethra at just the right moment. All of these different cells work as a team and coexist in the prostate functioning together in a structured glandular arrangement.”
“When a trained pathologist looks at tumor cells under the microscope he grades them by the degree of cellular disorder. He is asking himself the question, ‘How much do these cells retain the normal glandular characteristics of the prostate gland?’ If a cross section of the tumor looks like an unbroken sheet of uniform cells, the cancer is high-grade; the cells have lost their ability to cooperate with each other and form glands. The cancer cells have been honed down into little race cars with only one mission, to aggressively pursue its own replicative destiny. When tumors have this appearance they are graded as a Gleason 9 or 10. On the other hand, if the appearance of the tumor shows residual glandular components, it is less aggressive, perhaps a Gleason 7.” Gleason 6 cancer looks almost like normal prostate gland tissue.
“Predicting future tumor behavior is obviously very important. How fast will it grow? Is it likely to spread? How well can it be expected to respond to treatment? As a result of decades of experience, doctors have learned to use the Gleason scoring system to accurately predict the long-term outcome in individual patients. The new GAT tests represent an important additional refinement, further enhancing our ability to predict the future behavior of an individual cancer. GAT holds one even bigger promise. In the future we believe GAT testing will be a powerful aid in the selection of targeted therapy, i.e., picking cancer treatments with anticancer activity tailored to individual tumor types. This hope, however, will have to be postponed until our limited armamentarium of effective treatments is further expanded.”
“Now, what is it that I” (Dr. Scholz) “consider to be the most exciting area of medical progress? Since I am an impatient type of guy, someone who is looking for quick results, I find immunotherapy more exciting than GAT. To fully exploit the potential of GAT we will need to invent new pills for each of the myriad of genetically different tumor types. Immunotherapy on the other hand comes with its own ‘built-in’ GAT system that enables it to target the unique genetic signature of individual cancer cells. The immune system is so smart, all we have to do is ‘flip the switch on’ and starts cranking out genetically targeted anticancer therapy. Recent developments in the field of immunology are truly mind-boggling and hold promise for a big revolution in cancer therapy within the next 5-10 years.”
Predicting Prostate Cancer’s Future Behavior
Developing an accurate prognosis, i.e., predicting how a man’s cancer is likely to behave in the future, is the first and most important step toward optimal care. Future predictions are often looked at with some suspicion. With prostate cancer, however, our power to anticipate future cancer behavior is quite accurate unless there is a lack of thoroughness in gathering information. One system designed to evaluate the risk of prostate cancer recurrence following localized treatment was formulated in 1998 by Dr. Anthony D’Amico. For a summary of the D’Amico system, see this link.
The Size of the Tumor
Tumor size is a universally important prognostic sign for almost all types of cancer including prostate cancer. The method for incorporating tumor size into the Anthony D’Amico’s staging system relies on the degree of PSA elevation, the tumor grade and on how the prostate “feels” with the finger of a trained practitioner. These indicators are useful but don’t incorporate information from modern imaging. Imaging provides accurate information about tumor size and the presence or absence of extracapsular extension. These are very powerful prognostic predictors and it would be foolish to disregard their importance. As things stand presently these indicators are often used to divide the low, intermediate and high risk D’Amico categories into “favorable” and “unfavorable” subcategories, each with a different spectrum of recommended treatment options.
Knowing Past Treatments Tells Something about Future Prognosis
Historically, since the total number of available treatments is relatively limited, practitioners have used a sequential “trial and error” treatment methodology that administers the standard treatment options in a fairly predictable sequence. For example, it is not uncommon for men to start with surgery or radiation. When a relapse occurs, standard hormone therapy (Lupron) is often started and given intermittently or continuously. Hormone therapy usually controls the disease for an average of 10 years. When Lupron stops working, immunotherapy with Provenge may follow. After Provenge, more potent hormone therapy with Xtandi or Zytiga is started. If these two agents prove ineffective, chemotherapy with Taxotere (docetaxel®) or radiation with Xofigo would be considered next. The whole point of presenting the treatment sequence described in this paragraph is to convey the idea that the number of previous treatments communicates important information about that patients’ future prognosis. Having “failed” Lupron, for example, bespeaks of a much more worrisome prognosis compared to the situation where Lupron continues to be effective.
Response to Lupron, The Mother of All Metrics
The quality of the “response” to Lupron is actually one of the most powerful prognostic metrics available. The degree of PSA decline after Lupron is incredibly important. How low the PSA drops after starting Lupron is called the “PSA nadir.” The specific PSA threshold used to determine a “good response” is less than 0.1. Believe it or not, there is a huge difference in prognosis between a man on Lupron for six months who has a PSA of 0.1 versus a man whose PSA levels off at 1.0.
An Established History is also a Prognostic Indicator
Another somewhat obvious prognostic indicator that is often overlooked and almost never discussed in textbooks has to do with the prognosis of men who have been diagnosed years ago — over time it is apparent that things are turning out much better than what might have been expected based on their initial indicators. For example, take the case of a man who started off with a panoply of bad indicators—tumor is in the lymph nodes and Gleason 10—but after aggressive treatment remains in remission for 5 years. The fact that things have gone well for five years counts big-time in his favor going forward. Remember, the original prognostic predictors of a Gleason 10 were just that, predictors. No predictor is 100% accurate. Five years of established history is a stronger predictor than the original Gleason score. The fact that things have gone well for five years, strongly indicates that the future is for that individual is bright. Such individuals may have “beaten the odds.”
The Location of the Tumor in the Body
Another extremely important indicator of prognosis, something that even laypeople anticipate by simple common sense, is the location of the cancer in the body. Location says volumes about how things are likely to progress in the future. For example, consider the following sequence of progressively more serious cancer sites:
•Contained within the prostate
•Extended into the seminal vesicle
•Spread to the lymph nodes
•Bone metastases
•Liver metastasis
Each of these locations is very important for determining prognosis.
This short blog is just an introduction to some of the “profiling” methods utilized in generating an accurate prognosis. Space limitations preclude discussion here about other known prognostic factors such as the size of the prostate gland, genetic tests and PSA doubling time. The D’Amico risk categories constitute the backbone of useful prognostic information. However, the additional prognostic information beyond the D’Amico risk categories that are discussed in this blog, provide additional useful information necessary for determining an accurate prognosis. An accurate prognosis is the starting point for accurate selection of treatment.