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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.

COPD Biomarker Qualification Consortium Making Strides with Plasma Fibrinogen as New Biomarker

The COPD Biomarkers Qualification Consortium (CBQC) recently announced at the European Respiratory Society Annual Congress that it has submitted a Qualification Package to the Food and Drug Administration (FDA) for plasma fibrinogen as a new drug development tool. The Qualification Package is the result of progressive discussions between the FDA’s Qualification Review Team and the CBQC. The CBQC looks forward to the results of FDA review while planning for a fall 2013 submission to the European Medicines Agency.

Dr. Ruth Tal-Singer, CBQC co-chair, vice president, Clinical Discovery, Respiratory Area Therapy Unit at GlaxoSmithKline, notes, “To the best of CBQC’s knowledge, fibrinogen is the first clinical biomarker achieving this milestone in the U.S. This is a major milestone for the CBQC, and it highlights the power of working together across multiple companies, academic centers and government organizations to achieve our common objective of improving the way we study novel medicines for patients who need them.”

To support the submission, the CBQC compiled a unique database of subjects from five individual studies, allowing integrated analyses to support two proposed uses as a prognostic biomarker to enrich clinical trial populations with Chronic Obstructive Pulmonary Disease (COPD) subjects at increased risk for all-cause mortality or COPD exacerbations.

A biomarker is a tool that can be used for early detection of a disease, selection of subjects for clinical trials or as an outcome for clinical trials. Fibrinogen, a protein that can be measured in the blood, is a promising biomarker which identifies a group representing 25 to 30 percent of all COPD patients (a COPD subtype).

Dr. Stephen Rennard, CBQC co-chair and Larson Professor of Medicine, University of Nebraska, adds, “COPD is extremely heterogeneous. This complicates development of new treatments, as individual COPD patients may respond differently. Fibrinogen has been submitted to the FDA as a tool that will help address this problem. Specifically, fibrinogen measurement can help identify COPD patients at risk for death or hospitalization, which can allow individuals to participate in studies of novel treatments designed to improve those outcomes.”

The CBQC, organized under the auspices of the COPD Foundation, is a public-private partnership among academic researchers, pharmaceutical companies and government parties and agencies.

John W. Walsh, president and co-founder, COPD Foundation, states, “The Consortium is providing a unique and productive opportunity to bring new drug development tools to the research community, with the ultimate goal of providing new treatments to patients who urgently need them.”

The CBQC Fibrinogen Working Group is composed of the following members:

  • Bruce Miller, industry co-chair, GlaxoSmithKline
  • Ruth Tal-Singer, GlaxoSmithKline
  • Mike Lowings, GlaxoSmithKline
  • Ubaldo Martin, AstraZeneca
  • Jeff Snyder, Boehringer-Ingelheim
  • Kay Tetzlaff, Boehringer-Ingelheim
  • Armin Furtwaengler, Boehringer-Ingelheim
  • Nicholas Locantore, GlaxoSmithKline
  • Nancy Leidy, Evidera
  • Amber Martin, Evidera
  • Jason Simeone, Evidera
  • David Mannino, academic co-chair, University of Kentucky
  • Stephen Rennard, University of Nebraska
  • David Lomas, University College London, U.K.
  • Jorgen Vestbo, University of Southern Denmark, University Hospital Manchester, U.K.
  • Graham Barr, Columbia University
  • Debora Merrill, COPD Foundation

Source: COPD Foundation

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

Aetna Collaborates With CVS Caremark And Dovetail Health To Help Members Manage Their Prescriptions

Aetna (NYSE: AET) recently announced a new pilot program called the Aetna Rx Home Success Program. Supported by CVS Caremark (NYSE: CVS), the Aetna Rx Home Success Program works with CVS Caremark pharmacists and Dovetail Health to support Aetna members who are taking multiple medications. The program helps members manage their health through personal support from a pharmacist including offering in-home consultations — and focuses on those who have recently been discharged from a hospital, nursing home or rehabilitation facility.

How The Aetna Rx Home Success Program Works 

Members who decide to enroll in the Aetna Rx Home Success Program are contacted by a pharmacist who will work with them to schedule an in-home visit or a detailed phone consultation. The pharmacist will review any new and/or pre-existing medications and help create a detailed care plan with the member and their doctor. The pharmacist will address potential medication-related issues, identify gaps in care, and educate members about their medicine(s). The pharmacist will also consider other risk factors, including chronic conditions, home safety, and will aid in arranging physician follow-up visits.

“We are very excited to partner with CVS Caremark and Dovetail Health on this program. By providing a personalized approach to health care we can help our members stay on track with their medications, educate them about their treatment, and prevent a repeated trip to the hospital,” said Dr. William Fried, senior medical director of Aetna’s Southeast Region.

More Than 1 In 4 Members Are At Risk

Hospital readmissions due to not properly taking their medication affect nearly 3.5 million patients and result in about $15.2 billion dollars in health care costs each year. Aetna’s innovative approach to health care, blending the expertise of CVS Caremark and a Dovetail Health pharmacist, provides a complete circle of care, ensuring positive health outcomes for its members.

“We look forward to piloting this program with Aetna as high rates of hospital readmissions result in increased costs for the patient and the payor, which can negatively impact a patient’s health outcomes,” said Troyen A. Brennan, M.D., M.P.H., executive vice president and chief medical officer for CVS Caremark. “Many patients who are newly discharged from a hospital or rehab facility are taking multiple medications. Trying to navigate multiple treatment guidelines provided by the patient’s primary care physician and the treatment facility discharge team can be overwhelming. Our research shows that the intervention of a clinical pharmacist helps patients better understand their medications and avoid potential setbacks to recovery after returning home.”

Identifying At-Risk Members

Members are identified by an Aetna case manager as either “high risk” or “moderate risk” for hospital readmission. Within two days of discharge, high-risk members are contacted to schedule an in-home medication review performed by a Dovetail pharmacist. CVS Caremark pharmacists contact the moderate risk members to schedule a medication review over the phone. All members receive ongoing support in the form of follow-up phone calls for a 30-day period. Aetna case management nurses for continuing care coordination also mentor members. After the 30 days, the member will be discharged from the program and moved back to Aetna Case Management for continued follow-up and care.

“The average patient in the program takes over ten prescription medications per day; our pharmacists are uniquely trained to optimize these difficult medication regimens and lessen associated risks,” said Diane Gilworth, NP, chief clinical officer for Dovetail Health. “Working with Aetna and CVS Caremark allows us to deliver a complete and coordinated approach to reduce readmission rates for some of the highest risk patients.” The six month pilot program will be offered in the District of Columbia, Maryland, and Northern Virginia. Readmission rates and member satisfaction of enrollees will be measured at the conclusion of the pilot.

Source: CVS Caremark

Urine Biomarker Test Can Diagnose as well as Predict Rejection of Transplanted Kidneys

A breakthrough non-invasive test can detect whether transplanted kidneys are in the process of being rejected, as well as identify patients at risk for rejection weeks to months before they show symptoms, according to a study published in The New England Journal of Medicine (NEJM).

By measuring just three genetic molecules in a urine sample, the test accurately diagnoses acute rejection of kidney transplants, the most frequent and serious complication of kidney transplants, says the study’s lead author, Dr. Manikkam Suthanthiran, the Stanton Griffis Distinguished Professor of Medicine at Weill Cornell Medical College and chief of transplantation medicine, nephrology and hypertension at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

“It looks to us that we can actually anticipate rejection of a kidney several weeks before rejection begins to damage the transplant,” Dr. Suthanthiran says.

The test may also help physicians fine-tune the amount of powerful immunosuppressive drugs that organ transplant patients must take for the rest of their lives, says Dr. Suthanthiran, whose laboratory developed what he calls the “three-gene signature” of the health of transplanted kidney organs.

“We have, for the first time, the opportunity to manage transplant patients in a more precise, individualized fashion. This is good news since it moves us from the current one-size-fits-all treatment model to a much more personalized plan,” he says, noting that too little immunosuppression leads to organ rejection and too much can lead to infection or even cancer.

Given the promise of the test first developed in the Suthanthiran laboratory at Weill Cornell and previously reported in NEJM, the National Institutes of Health (NIH) sponsored a multicenter clinical trial of nearly 500 kidney transplant patients at five medical centers, including NewYork-Presbyterian/Weill Cornell Medical Center and NewYork-Presbyterian/Columbia University Medical Center. The successful results of that trial are detailed in the July 4 issue of NEJM.

Such a test is sorely needed to help improve the longevity of kidney transplants and the lives of patients who receive these organs, says study co-author Dr. Darshana Dadhania, associate professor of medicine and medicine in surgery at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital.

Dr. Dadhania says that the primary blood test now used to help identify rejection — creatinine, which measures kidney function — is much less specific than the three-gene signature.

“Creatinine can go up for many reasons, including simple dehydration in a patient, and when this happens we then need to do a highly invasive needle-stick biopsy to look at the kidney and determine the cause. Our goal is to provide the most effective care possible for our transplant patients, and that means individualizing their post transplant care,” she says. “Using an innovative biomarker test like this will eliminate unnecessary biopsies and provide a yardstick to measure adequate immunosuppression to keep organs — and our patients — healthy.”

Although a number of researchers have tried to develop blood or urine-based tests to measure genes or proteins that signify kidney organ rejection, Dr. Suthanthiran and his research team were the first to create a gene expression profile urine test — an advance that was reported in NEJM in 2001 and, with an update also in NEJM, in 2005.

The research team measured the levels of messenger RNA (mRNA) molecules produced as genes are being expressed, or activated, to make proteins. To do this, they developed a number of sophisticated tools to measure this genetic material. “We were told we would never be able to isolate good quality mRNA from urine,” he says. “Never say never.”

He and his colleagues found that increased expression of three mRNAs can determine if an organ will be, or is being, rejected. The mRNAs (18S ribosomal (rRNA)–normalized CD3ε mRNA, 18S rRNA–normalized interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA) indicate that killer T immune cells are being recruited to the kidney in order to destroy what the body has come to recognize as alien tissue.

The signature test consists of adding levels of the three mRNAs in urine into a composite score. Tracked over time, a rising score can indicate heightened immune system activity against a transplanted kidney, Dr. Suthanthiran says. A score that stays the same suggests that the patient is not at risk for rejection.

“We were always looking for the most parsimonious model for an organ rejection biomarker test,” Dr. Suthanthiran says. “Minimizing the number of genes that we test for is just more practical and helps to give us a clearer path towards diagnosis and use in the clinic.”

Physicians can tailor a patient’s use of multiple immunosuppressive drugs by lowering the doses steadily, and monitoring the patient’s composite score over time. Any increase would suggest a somewhat higher dose of therapy is needed to keep the organ safe.

“This is akin to monitoring blood glucose in a patient with diabetes,” Dr. Suthanthiran says. “Because different people have different sensitivity to the two-to-four immunosuppressive drugs they have to take, this test offers us a very personalized approach to managing transplantations.”

Predicting rejection weeks before it happens

The clinical trial began in 2006 with participation from five medical centers — NewYork-Presbyterian/Columbia University Medical Center, the University of Pennsylvania’s Perelman School of Medicine, the Northwestern University Feinberg School of Medicine, the University of Wisconsin School of Medicine and Public Health and NewYork-Presbyterian/Weill Cornell Medical Center, which contributed 122 of the total 485 kidney transplant patients.

The gene-expression studies were led by Dr. Suthanthiran with his laboratory serving as the Gene Expression Monitoring (GEM) core and the clinical trial was led by Dr. Abraham Shaked, director of the PENN Transplant Institute at the Perelman School, on behalf of the Clinical Trials in Organ Transplants 04 (CTOT-04) Study Investigators. The GEM core was blinded to the clinical status of the patients including their biopsy results and the data collection and analysis were performed by an independent statistical center sponsored by NIH.

Researchers collected 4,300 urine specimens during the first year of transplantation, starting at day three post-transplantation. The urine samples were shipped to the GEM core at Weill Cornell Medical College, where analysis of the urine revealed that the three gene-based biomarkers signature could distinguish kidney recipients with biopsy confirmed rejection from those whose biopsies did not show signs of rejection or who did not undergo a biopsy because there was no clinical sign of rejection.

The researchers used the signature to derive a composite score and identify a threshold value indicative of rejection. This score accurately detected transplant rejection with a low occurrence of false-positive and false-negative results. “It is about 85 percent accurate, which is much higher than the creatinine test used today,” Dr. Suthanthiran says. Investigators then validated the diagnostic signature by obtaining similar results when they tested a set of urine samples collected in a separate CTOT clinical trial.

Dr. Suthanthiran anticipates conducting another NIH-funded clinical trial to test whether the signature test can be used to personalize individual immunosuppressive therapy. He says that NIH is also interested in submitting the test to the federal Food and Drug Administration for approval.

These studies have provided enough information that many medical centers can test their own kidney transplant patients for rejection using the publicly-available formula for the biomarker test. Dr. Suthanthiran also is working to develop a way for patients to submit samples via mail for biomarker testing, and avoid an office visit. The study was supported by NIH grants UO1AI63589 and R37AI051652, the Qatar National Research Foundation (NPRP 08-503-3-111) and by a Clinical and Translational Science Center Award (UL1TR000457, to Weill Cornell Medical College).

Study: Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts

Source: Weill Cornell Medical College