May, 2013

Genomic Analysis Lends Insight to Prostate Cancer

May 28th 2013 Mayo Clinic researchers have used next generation genomic analysis to determine that some of the more aggressive prostate cancer tumors have similar genetic origins, which may help in predicting cancer progression. The findings appear online today in the journal Cancer Research. “This is the first study to examine DNA alterations using next generation sequencing in adjacent Gleason patterns in the same tumor allowing us to correlate genomics with changes in pathology,” says John Cheville, M.D., Mayo Clinic pathologist and one of the authors on the paper. The standard method of evaluating prostate cancer biopsy samples is a numerical scoring system called Gleason grading. A pathologist examines the tumor sample under the microscope, giving it a Gleason score based on the pattern of its cells. Since many prostate cancers contain more than one pattern, the two most common patterns are added together to provide the Gleason score. The Gleason score is the strongest predictor of outcome, with high scores indicating more aggressive prostate cancer. This study focused on Gleason patterns of three and four (Gleason score 7), a combination that indicates a cancer with increased risk of progression. “While each pattern had its own breakpoints, they shared identical ones, which implies a common origin,” Dr. Cheville says. DNA changes associated with aggressive prostate cancer were identified in the lower Gleason pattern, indicating that genomic changes occurred before they could be recognized by a pathologist. By understanding these lineage relationships within a tumor, he says, physicians will be better able to predict progression of the cancer and, in turn, better manage patients including those who chose no treatment but enter a follow-up program called active surveillance. To determine relationships among the Gleason patterns of each tumor sample the team used laser capture micro dissection, whole genome amplification and next generation sequencing. They examined 14 tumors and found over 3,000 unique chromosomal alterations among all tumors and 300 that appeared in at least two of the tumors. They also found that Gleason pattern 3 in each tumor had more alterations in common with its corresponding Gleason pattern 4 than it did with Gleason pattern 3 from other patients. Others involved in the study are co-first author Irina Kovtun, Ph.D.; Stephen Murphy, Ph.D.; Sarah Johnson; Shabnam Zarei, M.D.; Farhad Kosari, Ph.D.; William Sukov, M.D.; R. Jeff Karnes, M.D. and George Vasmatzis, Ph.D. The research was supported by a Waterman Biomarker...

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Individualised decisions needed in PSA screening

Medical Journal of Australia, National 6th May 2013, by No author available Decisions to undergo prostate-specific antigen (PSA) screening in older men should include individualised discussion about when to pursue biopsy and treatment, according to a US study. The longitudinal cohort study assessed 295 645 men aged 65 years or older who underwent PSA screening in the Veterans Affairs (VA) health care system in 2003 and were followed up for 5 years using VA and Medicare data. In total, 8.5% of the men had an index PSA level exceeding 4.0 ng/mL. During the 5-year follow-up, 33.0% of these men had at least one prostate biopsy and 62.8% of those who did were diagnosed with prostate cancer. Of those diagnosed, 82.1% underwent treatment. “Performance of prostate biopsy decreased with advancing age and worsening comorbidity, whereas the percentage treated for biopsydetected cancer exceeded 75% even among men 85 years or older”, the authors wrote.   Source: JAMA Intern Med 2013;15 April (online)...

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Agent Orange Exposure Linked to Life-Threatening Prostate Cancer

A new analysis has found a link between exposure to Agent Orange and lethal forms of prostate cancer among US Veterans. Published early online in Cancer, a peer-reviewed journal of the American Cancer Society, the findings suggest that Agent Orange exposure history should be incorporated into prostate screening decisions for Veterans. The herbicide Agent Orange was heavily used during the Vietnam War era and was often contaminated with dioxin, a dangerous toxin and potential carcinogen. Prior research suggests that exposure to Agent Orange may increase men’s risk of developing prostate cancer, but it is unclear whether it specifically increases their risk of developing lethal forms of the disease. “This is an important distinction as the majority of prostate cancer cases are non-lethal and thus do not necessarily require detection or therapy. Having a means of specifically detecting life-threatening cancer would improve the effectiveness of screening and treatment of prostate cancer,” said Mark Garzotto, MD, of the Portland Veterans Administration Medical Center and Oregon Health & Science University. To look for a link between Agent Orange exposure and life-threatening, or high-grade, prostate cancer, Nathan Ansbaugh, MPH, designed and conducted analyses on a group of 2,720 US Veterans who were referred by multiple providers for initial prostate biopsy. Biopsy results and clinical information were compiled for analysis by principal investigator Dr. Garzotto. Prostate cancer was diagnosed in 896 (32.9 percent) of the Veterans; 459 (16.9 percent) had high-grade disease. Agent Orange exposure was linked with a 52 percent increase in overall risk of prostate cancer detection by biopsy. Exposure to the herbicide did not confer an increase in risk of low-grade prostate cancer, but it was linked with a 75 percent increase in risk of high-grade prostate cancer. In addition, Agent Orange exposure was associated with more than a two-fold increase in the highest-grade, most lethal cancers. This study indicates that determining men’s Agent Orange exposure status is a readily identifiable means of improving prostate cancer screening for US Veterans, allowing for earlier detection and treatment of lethal cases and potentially prolonging survival and improving quality of life. “It also should raise awareness about potential harms of chemical contaminants in biologic agents used in warfare and the risks associated with waste handling and other chemical processes that generate dioxin or dioxin-related compounds,” said Dr. Garzotto. Journal reference: Nathan Ansbaugh, Jackilen Shannon, Motomi Mori, Paige E. Farris, Mark Garzotto. Agent Orange as...

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Nearly Half of All Deaths from Prostate Cancer Can Be Predicted Before Age 50

April 16th, 2013 Focusing prostate cancer testing on men at highest risk of developing the disease is likely to improve the ratio between benefits and the harms of screening, suggests a new paper. Prostate specific antigen (PSA) screening is widely used for the early detection of prostate cancer, but remains highly controversial, as it became widespread long before evidence to prove its value. There is now evidence that PSA screening can reduce prostate cancer mortality in men who would not otherwise be screened. However, this can come at considerable harm. As there is little evidence to support many aspects of screening guidelines, researchers from Sweden and the USA carried out a case-control study taking data from the Malmo Preventative Project (MPP) cohort, in an attempt to develop an evidence-based scheme for prostate cancer testing. A previous study from the MPP, published in the BMJ in 2010, demonstrated that PSA level at age 60 is strongly predictive of the risk of death from prostate cancer by age 85. The Malmo cohort included 21,277 men aged 27 to 52 who participated in the MPP between 1974 and 1984. All these men gave a blood sample. A smaller group of these men were then invited to provide a second blood sample about six years later: 4922 (72%) of those re-invited complied. The researchers focused their studies on men close to age 40, mid-to-late forties (45-49) and early-to-mid fifties (51-55). Within 25 to 30 years, 44% of deaths from prostate cancer occurred in those with the top 10% of PSA levels at age 45-49, a PSA of about 1.5 ng / ml or more. The risk of prostate cancer death was more than 10 times greater in this group compared to men with the lowest 25% of PSA levels. The researchers questioned whether PSA screening should start at age 40, mid-to-late 40s or early 50s: they found that even for men with PSA in the top decile at age 40, the risk of metastatic prostate cancer was very low at 0.6%, after 15 years of follow-up. The researchers say that due to this, it would be difficult to justify initiating PSA testing at age 40 for men with no other significant risk factor. In contrast, the risk of developing metastatic prostate cancer within 15 years is close to three-fold higher for men in the top level PSA at age 45-49 (1.7%) and close...

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On-And-Off Approach to Prostate Cancer Treatment May Compromise Survival

April 3rd 2013 Taking a break from hormone-blocking prostate cancer treatments once the cancer seems to be stabilized is not equivalent to continuing therapy, a new large-scale international study finds. Based on previous smaller studies, it looked like an approach called intermittent androgen deprivation therapy might be just as good as continuous androgen deprivation in terms of survival while meanwhile giving patients a breather from the side effects of therapy. In fact, researchers believed intermittent therapy might help overcome treatment resistance that occurs in most patients with metastatic hormone-sensitive prostate cancer. But this new study, which treated 1,535 patients with metastatic prostate cancer and followed them for a median of 10 years, finds that’s not the case. Results appear in the New England Journal of Medicine. “We tried to see whether intermittent androgen deprivation is as good as continuous androgen deprivation, but we did not prove that. We found that intermittent therapy is certainly not better and moreover we cannot even call it comparable,” says lead study author Maha Hussain, M.D., FACP, a prostate cancer expert oncologist at the University of Michigan Comprehensive Cancer Center. The study was sponsored by SWOG, a National Cancer Institute-supported cancer clinical trials cooperative group. In the study, men with metastatic hormone-sensitive prostate cancer were given an initial course of androgen deprivation therapy (hormone therapy), which is standard therapy for this disease. Patients with a stable or declining PSA level equal to or below a cut-off of 4 ng/ml were then randomly assigned either to continue or to discontinue the hormone therapy. Patients were carefully monitored with monthly PSAs and a doctor’s evaluation every three months and therapy was resumed in the intermittent arm when PSA climbed to 20 ng/ml. The intermittent cycle continued on-and-off based on the PSA levels. Survival among the two groups showed a 10 percent relative increase in the risk of death with intermittent therapy, with average survival of 5.8 years for the continuous group and 5.1 years for the intermittent group from the time of randomization. Further, the researchers looked at quality of life between the two groups of patients. Initially the intermittent therapy group showed significant improvement in impotence and emotional function in the first three months and had improved trends in other aspects of quality of life compared to the continuous group. But these differences leveled off over time. “The improvements in some aspects of quality of...

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