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Test Could Identify Which Prostate Cancers Require Treatment

The level of expression of three genes associated with aging can be used to predict whether seemingly low-risk prostate cancer will remain slow-growing, according to researchers at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center. Use of this three-gene biomarker, in conjunction with existing cancer-staging tests, could help physicians better determine which men with early prostate cancer can be safely followed with “active surveillance” and spared the risks of prostate removal or other invasive treatment. The findings were published recently in the online edition of Science Translational Medicine.

Biomarker May Predict Prostate Cancers Requiring Treatment

Not all early-stage prostate cancer diagnoses are alike. While some patients have aggressive tumors, others have slow-growing, low Gleason score tumors that may not require treatment, but instead can be monitored with regular clinical evaluations. But distinguishing between prostate cancers that require treatment and those that do not is still a major challenge.

Researchers at Columbia University in New York City have now identified a 3-gene signature that could indicate whether a particular early-stage prostate cancer is indolent. The test relies on a tissue sample, and along with a prostate-specific antigen (PSA) test and a histology assessment, could help clinicians make an accurate diagnosis. The early results, including a blinded retrospective analysis of 43 patients, show that the signature can accurately predict which patients with low-risk disease would develop metastatic prostate cancer and which patients would not progress. The study is published in Science Translational Medicine.

“These types of markers will, for the first time, give us the opportunity to measure biological features of cancer in the same patient, with multiple biopsies spread out over many years,” said Eric Klein, MD, chairman, Glickman Urological and Kidney Institute at the Cleveland Clinic in Ohio.
Cory Abate-Shen, PhD, professor of urological oncology at Columbia University; Andrea Califano, PhD, professor of systems biology at Columbia University; and colleagues used a computational approach that identified three genes—FGFR1, PMP22, and CDKN1A—all associated with aging, that could accurately predict outcomes of low-risk, low Gleason score prostate tumors. Protein and mRNA levels of all three genes were high in those patients who had non-aggressive, indolent disease and low in those who had aggressive tumors.

Clinicians still rely on the Gleason score, a histology and pathology evaluation that does not incorporate any molecular assessment. Those patients with a Gleason score of 8 or higher are candidates for immediate treatment, but whether men with a score of 6 or 7 require treatment is difficult to assess—no test exists to identify the small percentage of patients who have early-stage prostate cancer that is more likely to metastasize.

The 3-gene signature was validated using an independent prostate cancer cohort. According to the study authors, the signature was prognostic and improved prognosis compared with the use of PSA and clinical assessment.

“We would predict that the test would be beneficial for patients with low Gleason score prostate tumors,” said Abate-Shen. “These patients are now typically monitored on active surveillance protocols, and the patients get a biopsy periodically. The test would be conducted on the biopsy.”

Rather than focusing on the entire genome, the researchers focused on 377 genes involved in aging, predicting that genes involved in aging and senescence are critical for tumor suppression. Cellular senescence is known to play a role in tumor suppression and is associated with benign prostate tumors both in the clinic and in mouse models, according to the researchers. Using a computational analysis called gene set enrichment analysis (GSEA), they narrowed the long gene list to 19 genes, and then to a set of 3 genes that could identify indolent tumors.

“To focus on senescence genes is intellectually interesting,” said Klein. “There is already a body of work supporting the role of these genes in prostate cancer, but to my knowledge no one has looked at them in early-stage disease before.”

Forty-three patients, who had been under active surveillance for 10 years at Columbia University Medical School, were used for the blinded retrospective analysis to assess the predictive value of the gene signature. Each patient had been diagnosed with low-risk prostate cancer, with a Gleason score of 6 or less. The test was correctly able to identify all 14 patients who eventually developed advanced prostate cancer.

CDKN1A has been shown to be linked to senescence and to regulate the cell cycle. Previous studies have shown that downregulation of the gene is linked to cancer progression. The correlation of FGFR1 (fibroblast growth factor receptor 1) with indolent tumors was surprising, as fibroblast growth factors have been shown to play a role in prostate cancer development. But, as the authors highlight in their discussion, FGFR1 signaling in prostate cancer is likely complex. The third gene in the signature, PMP22, encodes a glycoprotein expressed in neurons and has not been previously associated with prostate cancer.

This 3-gene signature is different from previously identified biomarkers, which have largely focused on advanced tumors. The potential biomarker test could complement other approaches in development, such as urine or blood tests, according to the authors.

A trial to validate the genetic signature is underway at Columbia University, and a national trial is being planned.

“It is really important to find novel ways to help to define early-stage tumors that may or may not progress to aggressive disease,” said Abate-Shen. “This will ultimately really help to minimize overtreatment, while capitalizing on the benefits of cancer screening.”

Other genomic approaches to distinguish indolent and aggressive disease are also underway. The first-generation expression-based tests, including Oncotype DX prostate and Prolaris, can facilitate clinical decisions based on the molecular characteristics of a prostate tumor. Both the available tests and the new ones “promise to reduce overtreatment and help men make the right decisions based on biology rather than uncertainty,” said Klein. 

Study: A Molecular Signature Predictive of Indolent Prostate Cancer [Science Translational Medicine]

Source: CancerNetwork

OGT Granted Prostate Cancer Biomarker Licence by the ICR

Oxford Gene Technology (OGT), provider of innovative genetics research and biomarker solutions to advance molecular medicine, recently announced that it has been granted a licence by The Institute of Cancer Research (ICR), London, to further develop and commercialise a new panel of diagnostic and prognostic microRNA biomarkers for prostate cancer. The agreement follows a three-year collaboration between OGT and the ICR resulting in the joint discovery of the microRNA biomarkers. These markers have wide-ranging potential applications in diagnosis, prognosis, treatment planning and patient monitoring.

Currently, the biomarker prostate-specific antigen (PSA) and a digital rectal examination are used to test for prostate cancer and to determine whether a biopsy is required. However, increasing evidence1 indicates that PSA may not be an effective screening tool for prostate cancer due to a high false positive rate and an inability to distinguish between more aggressive and indolent cancers.

Unlike the present screening techniques, the biomarkers discovered by OGT and the ICR have a specificity of over 90% plus the potential to not only identify prostate cancer but also to assess its aggressiveness. This is important as it will allow treatment to be tailored to specific features of the cancer. At present, a diagnosis of prostate cancer can mean removal of the prostate and chemotherapy; patients with indolent cancer often receive, but do not require, such excessive treatment.

Dr Mike Evans, CEO at OGT, said: “We look forward to continuing our work with the ICR and developing this biomarker panel further. We are hopeful that these biomarkers will change the way that patients with prostate cancer are treated. OGT has a rapidly expanding portfolio of biomarkers for early disease detection which includes highly prevalent cancers of major clinical significance, including colorectal cancer.”

Colin Cooper, Professor of cancer genetics at the University of East Anglia, who led the study at the ICR, said: “OGT and the ICR have made significant progress. Prostate cancer is the most common type of cancer in men with over 240,000 new cases diagnosed each year in the US alone; we need to focus our efforts not only on ensuring accurate diagnosis but also individualised treatment tailored by prognosis.”

In addition to further validation of the biomarker panel in tissue samples, OGT is evaluating the panel in both blood and urine samples, with initial translation of the assay to blood-based PCR testing showing very encouraging results. OGT is currently reviewing potential options for future commercialisation, including making the resulting test available through OGT’s service laboratories.

Source: Oxford Gene Technology

FDA Approves New Blood Test to Improve Prostate Cancer Detection

Beckman Coulter, Inc., the leader in prostate cancer diagnostics, announces Premarket Approval (PMA) from the U.S. Food and Drug Administration (FDA) for the Prostate Health Index (phi), a simple, non-invasive blood test that is 2.5 times more specific in detecting prostate cancer than PSA (prostate-specific antigen) in patients with PSA values in the 4-10 ng/mL range and is proven to reduce the number of prostate biopsies.

Mayo Clinic Researchers Discover Biomarkers for Prostate Cancer Detection, Recurrence

Alterations to the “on-off” switches of genes occur early in the development of prostate cancer and could be used as biomarkers to detect the disease months or even years earlier than current approaches, a Mayo Clinic study has found. These biomarkers — known as DNA methylation profiles — also can predict if the cancer is going to recur and if that recurrence will remain localized to the prostate or, instead, spread to other organs. The study, published in the journal Clinical Cancer Research, is the first to capture the methylation changes that occur across the entire human genome in prostate cancer.

The discovery could someday help physicians diagnose prostate cancer earlier and make more effective treatment decisions to improve cure rates and reduce deaths. It also points to the development of new drugs that reverse the DNA methylation changes, turning the “off” switch back “on” and returning the genetic code to its normal, noncancerous state.

“Our approach is more accurate and reliable than the widely used PSA (prostate-specific antigen) test,” says senior author Krishna Donkena, Ph.D., a Mayo Clinic molecular biologist.

The PSA test detects any prostate abnormality, whether inflammation, cancer, infection or enlargement, while the DNA methylation changes are specific to prostate cancer, she says.

Though the instructions for all the cell’s activities lie within the genes, whether a particular gene is turned “off” or “on” is determined by the presence or absence of specific chemical tags or methyl groups — methylation — along the underlying DNA of cells. When this process of DNA methylation turns off the activity of tumor suppressor genes, cancer develops.

Dr. Donkena and her colleagues analyzed the methylation status of 14,495 genes from 238 prostate cancer patients. The patients included people who remained cancer-free after treatment, those who had a localized tumor recurrence and those whose cancer spread.. The researchers found that the DNA methylation changes that occurred during the earliest stages of prostate cancer development were nearly identical in all patients.

Having discovered DNA methylation patterns that could distinguish between healthy and cancerous tissue, the researchers then searched for similar biomarkers that could distinguish between patients with varying levels of recurrence risk. They found distinct methylation alterations that corresponded to whether a patient had a slow-growing tumor known as an indolent tumor, or had a more aggressive one.

If physicians can determine what type of tumor patients have, they can avoid exposing patients with indolent tumors to unnecessary treatment, and can treat those with aggressive tumors earlier and more effectively, Dr. Donkena says.

Dr. Donkena and her colleagues are working to develop a DNA methylation test that is more cost-effective and practical for use in clinical settings. Currently, the test relies on microarray or gene “chip” technology that assesses methylation status of genes across an entire genome. The researchers are trying to generate more economical custom microarray to specifically look at only the genes that predict the development of prostate cancer or recurrence.

They also hope to develop drugs that can reverse DNA methylation in prostate cancer cells. Similar drugs are already being used to treat certain forms of leukemia.

Study: Global Methylation Profiling for Risk Prediction of Prostate Cancer

Source: Mayo Clinic