Each year more than a million men who are suspected of having prostate cancer undergo prostate biopsy evaluation, which is an outpatient procedure during which a fine needle is used to take a few tissue samples from prostate glands. Pathologists then examine the biopsy and in approximately 20% of the cases (about 200,000 men) they find cancer. Decisions on how to treat are largely dependent on how aggressive the cancer appears on the biopsy, and for that, a tumor grading system, called Gleason Score is used. Tumors with higher Gleason Score are often more aggressive. Tumors with Gleason Score 6 (GS6) are generally not lethal and recently, a growing number of men diagnosed with GS6 tumors on needle biopsy are selecting active surveillance rather than surgery or radiation therapy. On the other hand, tumors with Gleason Score 7 and higher (GS7+) are often treated with surgery. Decision on how to treat patients with a tumor that appears to be GS6 on biopsy, which happens in a majority of time, is complicated by the fact that in about 30% of cases these tumors have areas of higher grade that was missed during biopsy. Most patients with biopsy GS6 tumors have surgery to take out their prostate even though in many instances these tumors are found to be "clinically insignificant" after surgery. The surgery, called radical prostatectomy (RP), has serious side effects. The common of the side effects are impotence and incontinence, which significantly compromise patients' quality of life. The situation for the other 80% of the biopsies (from about 800,000 men), which do not show cancer, is also complicated by the fact that about one-third of the time these patients do in fact have cancer that was missed by the biopsy needle. A recent bulletin from Johns Hopkins University described biopsy evaluations as an "often hit-or-miss affair" and prostate tumors as "a few small seeds on a large strawberry." Often, patients with no cancer on the first biopsy undergo repeat biopsies with all the frustration and anxiety that go along with them. Though not as severe as RPs, biopsies also have side effects like blood in the urine or stool for a few days and in the semen for more than a month.
In biopsies evaluations, doctors have been mainly focusing on tumor cells and almost completely ignoring examinations of areas that appear benign and that comprise the bulk of biopsy tissue. This is despite a considerable body of evidence that there are important molecular changes in those "benign" looking areas that provide important clues about the status of the tumor. Our proposal is to do a comprehensive analysis to catalogue molecular changes in the benign areas when cancer is present, and to develop tests based on these changes (gene markers) to determine if there is a "clinically significant" tumor with GS7+ in the prostate. The first test will use GS6 biopsy samples and predict if higher grade tumors were missed. The second test will use biopsy samples from patients who did not show cancer and determine if GS7+ cancer was indeed present. The performance of these tests will be compared with existing models and the results reported.
The developed tests will have a high statistical power because of the sizable volume of clinical samples that are available for research from consented patients at the Mayo Clinic. The most important limitation of this study is that it will not detect "clinically significant" tumors by every definition of the term, though it detects the great majority. After the completion of this project in 3 years, our findings can be tested in a larger prospective study across multiple institutions.
This research will also improve our understanding of prostate cancer. It will provide the first comprehensive molecular profiles of benign prostate tissue from both men who did and men who did not have cancer. When these profiles are made public, they can be used to identify early events leading up to prostate cancer and used as a baseline of comparison in the study of cancer and other diseases of the prostate. Tests developed here will be helpful for a majority of the one million men who are biopsied each year. Doctors will be given a more exact tool to identify tumors that need treatment. And, for patients with negative or Gleason score 6 biopsies that are found not to be at risk of having significant tumors, these tests will provide additional assurance and lift some of the anxieties that comes with the suspicion of significant cancer.
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