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A DRAMATIC increase in prostate cancer cases has prompted calls for men to think carefully before being tested.
A new study shows the number of diagnoses in Australia jumped 276 per cent over the 20 years from 1987 to 2007.
This is a result of increased testing, says lead author Associate Professor Freddy Sitas of Cancer Council NSW.
He says the PSA test and physical examination are unreliable, giving both false positives and false negatives.
Even if a positive result is correct, unless they operate, doctors have no fool-proof way of knowing if the cancer is aggressive or relatively harmless.
"Saving lives is our priority, but we urgently need a better test," says Prof Sitas.
"The tests have saved men with aggressive forms of the disease, but at a high cost."
A 27 per cent drop in the death rate was observed over the study period, he says. However, the increase in new cases is much greater than this.
"This indicates that many men were diagnosed with cancers that would not have harmed them."
The University of NSW's Professor Mark Harris says: "Until we have a better method of screening, men need to be fully informed about the pros and cons of testing.
"GPs have to be very well informed so they can give the best advice."
It's a difficult area, says Professor Sandro Porceddu, President of Clinical Oncology Society of Australia.
About 30 per cent of PSA tests will give false positives.
"In other words there will be a group of people who have an elevated PSA but do not have prostate cancer.
"This can lead to further investigations, which have their own side effects."
He says there is no right or wrong answer for men trying to decide whether to be screened or not.
"Men who do have a concern should have a good and thorough talk to their doctor about the implications.
"The patient needs to decide if it is the most appropriate thing for them."
Register TodayEarn Free CME Credits by reading the latest medical news in your specialty.Sign Up By Charles Bankhead, Staff Writer, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San FranciscoNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.Almost a third of men on active surveillance for prostate cancer had an upgrade in Gleason pathology grade during follow-up, biopsy results for almost 600 patients showed.Point out that clinical stage at diagnosis, PSA velocity, number of involved biopsy cores, and the interval to follow-up biopsy predicted an increased likelihood of Gleason upgrading.
ORLANDO -- Almost a third of men on active surveillance for prostate cancer had an upgrade in Gleason pathology grade during follow-up, biopsy results for almost 600 patients showed.
During median follow-up of 6.4 years, 31.3% of the localized cancers were upgraded. The proportion of men with upgraded tumors increased over time, D. Andrew Loblaw, MD, reported here at the Genitourinary Cancers Symposium. "This increase over time was not statistically significant, but it allows for some hypothesis generation."
Clinical stage at diagnosis, PSA velocity, number of involved biopsy cores, and the interval to follow-up biopsy predicted an increased likelihood of Gleason upgrading, according to Loblaw, who practices at Sunnybrook Health Sciences Center in Toronto.
Intermediate-risk tumors had an upgrade probability more than double that of low-risk tumors -- 1.9% per year compared with 0.75%, although the difference did not achieve statistical significance.
"Gleason upgrading increases with time from diagnostic biopsies and might be higher in patients with initial Gleason 7 disease as opposed to Gleason 6," Loblaw said.
Men with localized prostate cancer have a 10-year disease-specific survival exceeding 97%, making active surveillance a reasonable option for many patients. Considerable research has focused on factors that can identify men who have an increased risk of progression, but pathologic upgrading has received little attention, said Loblaw.
In the largest published study to date, investigators at the University of California San Francisco found that a third of 377 patients in surveillance had pathologic upgrading of their tumors during 4 years of follow-up (J Clin Oncol 2011; 9: 2185-2190).
However, studies have produced little information about factors associated with upgrading, said Loblaw. In an effort to gain some insight into those factors, he and his colleagues analyzed a prospective database of patients entered into active surveillance at Sunnybrook Health Sciences Center
Eligibility for active surveillance required a biopsy Gleason score =6 and a PSA level =10 ng/mL. For patients older than 70, the criteria consisted of a Gleason score =3+4 and a PSA level =15 ng/mL.
Patients had repeat PSA testing every 3 months for 2 years and then every 6 months thereafter. Scheduled follow-up biopsies occurred after 1 year and then every 3 years until age 80.
Patients and physicians considered active treatment in the event of a PSA doubling time <3 years, histologic upgrading, and clinical progression, as well as patient preference.
As of August 2012, the database included 862 patients, including 592 who had at least one repeat biopsy. The subgroup of re-biopsied patients had a median age of 68 and a median baseline PSA of 5.5 ng/mL.
Loblaw reported that 83% of the patients had T1 disease and 17% had T2. Additionally, 20.2% of patients had intermediate-risk disease, 0.3% had high-risk prostate cancer, and 79.4% had low-risk cancer.
Multivariate analysis of baseline and dynamic factors associated with upgrading identified clinical stage at diagnosis (OR 2.301, P=0.0028), percentage of involved prostate biopsy cores at diagnosis (OR 1.768, P=0.0007), PSA velocity >2 (3.274, P<0.0001), and interval to re biopsy (OR 1.437, P=0.0102).
Subsequently, 114 (62%) of men whose tumors were upgraded chose to undergo treatment. The investigators found that a higher proportion of treated patients had a Gleason score of 8 (22% versus 2.9% of untreated patients), and treated patients had a significantly higher PSA velocity (1.2 versus 0.42 ng/mL/y, P=0.01).
The likelihood of upgrading increased over time, including 18.4% of patients followed for up to a year to 36% of patients followed for 7 to 8 years, 36% of patients followed for 8 to 9 years, and 26% of patients followed for more than 9 years.
In the discussion that followed the presentation, a panel of prostate cancer specialists and the audience engaged in a prolonged discussion about the future of surveillance for localized prostate cancer. Eric Klein, MD, of the Cleveland Clinic, suggested the time has come to reconsider the focus of surveillance.
"We have all patted ourselves on the back that we can identify patients who aren't going to die of their prostate cancer, with appropriate surveillance criteria," said Klein. "Shouldn't we raise the bar now?
"Given the cost and morbidity of metastatic disease [should we be asking] how much longer patients with metastatic disease are living? Should we say the goal of therapy or surveillance ought to be to avoid metastatic disease, rather than simply avoid death?"
The Genitourinary Cancers Symposium is co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
Loblaw and co-investigators had no relevant disclosures.
Primary source: Genitourinary Cancers Symposium Source reference: Jain S, et al "Gleason upgrading with time in a large, active surveillance cohort with long-term follow-up" GuCS 2013; Abstract 1.
Charles Bankhead
Staff Writer
Working from Houston, home to one of the world's largest medical complexes, Charles Bankhead has more than 20 years of experience as a medical writer and editor. His career began as a science and medical writer at an academic medical center. He later spent almost a decade as a writer and editor for Medical World News, one of the leading medical trade magazines of its era. His byline has appeared in medical publications that have included Cardio, Cosmetic Surgery Times, Dermatology Times, Diagnostic Imaging, Family Practice, Journal of the National Cancer Institute, Medscape, Oncology News International, Oncology Times, Ophthalmology Times, Patient Care, Renal and Urology News, The Medical Post, Urology Times, and the International Medical News Group newspapers. He has a BA in journalism and MA in mass communications, both from Texas Tech University.
Register TodayEarn Free CME Credits by reading the latest medical news in your specialty.Sign Up By Charles Bankhead, Staff Writer, MedPage Today Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerEndometrial cancers have been broadly classified into two groups: Type I endometrioid tumors with favorable prognosis and type II, primarily serous, tumors that have a worse outcome and different treatment approaches.This study proposes a reclassification of endometrial carcinoma which may affect therapy.
A comprehensive molecular analysis separated endometrial cancers into four distinct subtypes that have the potential to influence decision making about adjuvant therapy, investigators reported.
The analysis allowed scientists to categorize the cancers as microsatellite instability hypermutated, copy-number low, copy-number high, and a previously unrecognized subset of high-grade endometrioid tumors -- POLE ultramutated -- that have a molecular phenotype similar to that of uterine serous carcinomas.
Given that early serous-type uterine cancers are usually treated by chemotherapy and early endometrioid cancers by radiotherapy, the reclassification resulting from the analysis suggests a need to rethink treatment and clinical trial strategies, the researchers wrote online in Nature.
"The compelling similarities between this subset of endometrioid tumors and uterine serous carcinomas suggest that genomic-based classification may lead to improved management of these patients," Douglas A. Levine, MD, of Memorial Sloan-Kettering Cancer Center in New York City, and co-authors concluded.
"Clinicians should carefully consider treating copy-number-altered endometrioid patients with chemotherapy rather than adjuvant radiotherapy and formally test such hypotheses in prospective clinical trials. Furthermore, the marked molecular differences between endometrioid and serous-like tumors suggest that the tumors warrant separate clinical trials to develop the independent treatment paradigms that have improved outcomes in other tumor types, such as breast cancer."
Historically, endometrial cancer has been divided into two classifications: type I endometrioid and type II serous. The former is associated with estrogen excess, obesity, hormone-receptor positivity, and more favorable prognosis. Type II cancers occur more often in older, non-obese women and are associated with worse prognosis.
Recent studies have identified new characteristics that might further distinguish type I and type II tumors, the authors noted in their introduction. Most of the observations have come from studies of type I cancers and include early occurrence of PTEN mutations, co-occurrence with other mutations in the PI3K/AKT pathway, and microsatellite instability in about one third of the tumors.
Studies of type II tumors have show that microsatellite instability is an infrequent occurrence and that mutations in TP53, PIK3CA, and PPP2R1A occur frequently.
Previous studies have been limited to DNA sequencing of heterogeneous samples. Levine and colleagues in the Cancer Genome Atlas Research Network performed a more comprehensive, multiplatform analysis of low- and high-grade endometrioid tumors and serous uterine carcinoma designed to provide more insight into molecular basis of uterine cancer.
The analysis involved specimens and germline DNA from 373 patients: 307 with endometrioid tumors, 53 with serous tumors, and 13 with mixed histology.
The investigators performed multiples tests on varying fractions of the specimens/DNA, including somatic copy number alterations; exome sequence analysis; subtype classification via expression of messenger RNA, protein, and microRNA, and DNA methylation; somatic chromosomal (structural) aberrations; and pathway alterations. They also compared clinical/pathologic features of uterine serous carcinoma to those of serous ovarian and basal-like breast cancers.
Broadly speaking, the analysis showed that serous tumors and about one fourth of high-grade endometrioid tumors had extensive copy number alterations, few DNA methylation changes, low estrogen/progesterone receptor levels, and frequent TP53 mutations.
Most of the remaining endometrioid tumors had few copy number alterations or TP53 mutations, but frequently harbored mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS. Investigators also found novel mutations in the SWI/SNF chromatin remodeling-gene ARID5B.
A subset of endometrioid tumors frequently harbored transversion mutations and newly identified hotspot mutations in POLE, which were associated with worse prognosis.
Levine and colleagues found that uterine serous carcinoma shared many molecular features with high-grade serous ovarian carcinoma and basal-like breast carcinoma, despite having more mutations. The observation suggests opportunities for overlapping treatment strategies, they said.
The results make a compelling argument in favor of broadening the classification system for uterine cancer to improve diagnostic precision and to guide selection of treatment for uterine cancer, according to Thanh Dellinger, MD, of City of Hope in Duarte, Calif.
“We have been treating uterine cancers based essentially on histopathologic criteria. This model is really outdated. This kind of two-tier classification really has not helped us out,” she said. “We need to predict who should receive radiation and who should receive chemotherapy. We really need a new, more personalized approach of molecular assays to identify genetic aberrations to predict who will do well, who will live longer, what type of therapy they should receive.”
The findings derived from the Cancer Genome Atlas Research Network are an important first step “in the right direction,” Dellinger added.
UPDATE: This article, originally published May 2, 2013 at 8:07 a.m. was updated with new material at 1:01 p.m.
The Cancer Genome Atlas Research Network is supported by the National Institutes of Health.
The authors reported no competing interests.
Charles Bankhead
Staff Writer
Working from Houston, home to one of the world's largest medical complexes, Charles Bankhead has more than 20 years of experience as a medical writer and editor. His career began as a science and medical writer at an academic medical center. He later spent almost a decade as a writer and editor for Medical World News, one of the leading medical trade magazines of its era. His byline has appeared in medical publications that have included Cardio, Cosmetic Surgery Times, Dermatology Times, Diagnostic Imaging, Family Practice, Journal of the National Cancer Institute, Medscape, Oncology News International, Oncology Times, Ophthalmology Times, Patient Care, Renal and Urology News, The Medical Post, Urology Times, and the International Medical News Group newspapers. He has a BA in journalism and MA in mass communications, both from Texas Tech University.
Register TodayEarn Free CME Credits by reading the latest medical news in your specialty.Sign Up By Michael Smith, North American Correspondent, MedPage Today Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerThis study suggests that plasma fibulin-3 levels can distinguish healthy persons with exposure to asbestos from patients with mesothelioma.The study also suggests that in conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels can differentiate mesothelioma effusions from other malignant and benign effusions.
Glycoprotein fibulin-3 can be used to identify patients with pleural mesothelioma and may be a useful biomarker for the asbestos-related illness, researchers reported.
Plasma levels of the protein were higher in people with the disease than they were in people exposed to asbestos but who did not have mesothelioma, according to Harvey Pass, MD, of New York University Langone Medical Center in New York City, and colleagues.
And levels in effusions from mesothelioma patients were higher than they were in patients with effusions from other causes, Pass and colleagues reported in the Oct. 11 issue of the New England Journal of Medicine.
On the other hand, the researchers cautioned, it's too early to say that the protein can be used for early detection because of a lack of prospective longitudinal studies.
Despite advances in therapy, median survival for pleural mesothelioma remains about a year from diagnosis, the researchers noted.
Earlier detection might help, but "is limited by the long latency period, an inability of imaging to detect the disease at an early stage even when it is used as a screening strategy, and the lack of sensitive and specific blood-based markers."
The latter gap, they hypothesized, might be filled by fibulin-3 if it could be shown to be a "robust biomarker."
To test the idea, they measured fibulin-3 levels in stored plasma samples from 92 patients with mesothelioma, 136 people exposed to asbestos but who did not have the disease, 93 patients with effusions not caused by mesothelioma, and 43 healthy controls.
They also measured levels in stored effusions from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not caused by mesothelioma. Some participants had both types of samples.
The stored samples were collected in Detroit from 1998 through 2005 and in New York from 2005 through 2011, Pass and colleagues reported.
The researchers also conducted two validation analyses – one each using serum and plasma from mesothelioma patients and cancer-free people with asbestos exposure.
Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes.
On the other hand, they were significantly higher in patients with pleural mesothelioma than in asbestos-exposed people without the disease. In the Detroit cohort, mesothelioma patients averaged 105 nanograms per ml of plasma, compared with 13.9 among the asbestos-exposed controls (P<0.001) and in the New York cohort, the respective averages were 112.9 and 24.3 nanograms per ml (P<0.001).
The same was true for fibulin-3 levels in effusions.
In the Detroit cohort, effusion levels averaged 694.4 nanograms per ml higher in patients with pleural mesothelioma and 211.5 in patients with effusion from other causes. In the New York cohort, the respective averages were 636.4 and 150.6 nanograms per milliliter. Both differences were, again, significant at P<0.001.
In the validation study using serum, fibulin-3 levels were unable to discriminate between patients with mesothelioma and those exposed to asbestos but cancer-free, Pass and colleagues reported.
One possible explanation is that the samples, which were collected from 1985 through 1996 during the Carotene and Retinol Efficacy Trial, might have degraded over time, they suggested.
In the other validation study, a set of plasma samples from the University of Toronto showed lower levels in both patients and asbestos-exposed controls than either of the American cohorts – 66.4 and 13.9 nanograms per milliliter, respectively.
But, Pass and colleagues reported, the difference remained significant at P<0.001.
In an overall comparison of patients with and without mesothelioma, the researchers reported, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 nanograms per milliliter.
While more research is needed, they concluded, plasma fibulin-3 levels can help tell people with mesothelioma from those who remain healthy after exposure to asbestos.
Together with levels in effusions, plasma fibulin-3 can also differentiate mesothelioma effusions from other malignant and benign effusions, they argued.
The study had support from the Princess Margaret Hospital Foundation, the Princess Margaret Hospital Mesothelioma Research Program (funded by the Masters Insulators Association of Ontario, International Association of Heat and Frost Insulators and Asbestos Workers, Local 793, and other unions, and the Imperial Oil Charitable Foundation), the M. Qasim Choksi Chair in Lung Cancer Translational Research, the Alan B. Brown Chair in Molecular Genetics, the Ontario Ministry of Health and Long-Term Care, Belluck and Fox, the Simmons Foundation, Levi Phillips and Konigsberg, the Stephen E. Banner Fund for Lung Cancer Research, the Rosenwald Family, the Anderson Family, and the NIH.
Pass reported fnancial links with Champions Oncology, Rosetta Genomics, Pinpoint Genomcs, and SomaLogic.
Michael Smith
North American Correspondent
North American Correspondent for MedPage Today, is a three-time winner of the Science and Society Journalism Award of the Canadian Science Writers' Association. After working for newspapers in several parts of Canada, he was the science writer for the Toronto Star before becoming a freelancer in 1994. His byline has appeared in New Scientist, Science, the Globe and Mail, United Press International, Toronto Life, Canadian Business, the Toronto Star, Marketing Computers, and many others. He is based in Toronto, and when not transforming dense science into compelling prose he can usually be found sailing.
Register TodayEarn Free CME Credits by reading the latest medical news
By Charles Bankhead, Staff Writer, MedPage Today Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerEndometrial cancers have been broadly classified into two groups: Type I endometrioid tumors with favorable prognosis and type II, primarily serous, tumors that have a worse outcome and different treatment approaches.This study proposes a reclassification of endometrial carcinoma which may affect therapy.