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Promising Screening Tool for Early Detection of Ovarian Cancer

Evaluating its change over time, CA-125, the protein long-recognized for predicting ovarian cancer recurrence, now shows promise as a screening tool for early-stage disease, according to researchers at The University of Texas MD Anderson Cancer Center.

The updated findings are published in Cancer; preliminary data were first presented at the 2010 American Society of Clinical Oncology (ASCO) annual meeting. If a larger study shows survival benefit, the simple blood test could offer a much-needed screening tool to detect ovarian cancer in its early stages – even in the most aggressive forms – in post-menopausal women at average risk for the disease.

MD Anderson has a long history in the research of the important biomarker. In the 1980s, Robert Bast, M.D., vice president for translational research at MD Anderson and co-investigator on the ASCO study, discovered CA-125 and its predictive value of ovarian cancer recurrence. Since then, researchers at MD Anderson and beyond have been trying to determine its role in early disease detection. The marker, however, can become elevated for reasons other than ovarian cancer, leading to false positives in early screening.

“Over the last ten years, there’s been a lot of excitement over new markers and technologies in ovarian cancer,” said Karen Lu, M.D., professor and chair, Department of Gynecologic Oncology and the study’s corresponding author. “I and other scientists in the gynecologic oncology community thought we would ultimately find a better marker than CA-125 for the early detection of the disease. After looking at new markers and testing them head-to-head in strong, scientific studies, we found no marker better than CA-125.”

According to the American Cancer Society, 22,240 women will be diagnosed with ovarian cancer in 2013 and another 14,030 are expected to die from the disease. The challenge, explained Lu, is that more than 70 percent of women with ovarian cancer are diagnosed with advanced disease.

“Finding a screening mechanism would be the Holy Grail in the fight against ovarian cancer, because when caught early it is not just treatable, but curable,” said Lu, also the trial’s principal investigator.

For the prospective, single-arm, 11-year study, 4,051 women were enrolled from seven sites across the country, with MD Anderson serving as the lead site. All were healthy, post-menopausal women, ages 50-74, with no strong family history of breast or ovarian cancer. The study’s primary endpoint was specificity, or few false positives. In addition, the study looked at the positive predictive value, or the number of operations required to detect a case of ovarian cancer.

Each woman received a baseline CA-125 blood-test. Using the Risk of Ovarian Cancer Algorithm (ROCA), a mathematical model based on the patient’s age and CA-125 score, women were stratified to one of three risks groups, with the respective follow-up: “low,” came back in a year for a follow-up blood test; “intermediate,” further monitoring with repeat CA-125 blood test in three months; and “high,” referred to receive transvaginal sonography (TVS) and to see a gynecologic oncologist.

Based on the women’s CA-125 change over time, the average annual rate of referral to the intermediate and high groups were 5.8 percent and .9 percent, respectively. Cumulatively, 117 women (2.9 percent) were determined to be high risk, and thereby received the TVS and were referred to a gynecologic oncologist. Of those women, 10 underwent surgery: four had invasive ovarian cancer; two had borderline disease; one had endometrial cancer and three had benign ovarian tumors – a positive predictive value of 40 percent, which greatly surpasses the clinical benchmark of 10 percent, say the researchers. The specificity of the test was 99.9 percent, explained Lu. The screening failed to detect two borderline ovarian cancers.

Of great importance, said Lu, is that the four invasive ovarian cancers detected were high-grade epithelial tumors, the most aggressive form of the disease, and were caught early (stage IC or IIB), when the disease is not only treatable, but most often curable. Lu also noted that all four women found to have invasive disease were monitored at low risk for three years or more prior to a rising CA-125.

“CA-125 is shed by only 80 percent of ovarian cancers,” explained Bast, the study’s senior author. “At present, we are planning a second trial that will evaluate a panel with four blood tests including CA-125 to detect the cancers we may otherwise miss with CA-125 alone. The current strategy is not perfect, but it appears to be a promising first step.”

While encouraging, the findings are neither definitive, nor immediately practice-changing, stressed Lu; who also said a large, randomized prospective screening trial still needs to be conducted. Such research is ongoing in the United Kingdom; results from more than 200,000 women should be known by 2015.

“As a clinician treating women with this disease for more than ten years, I’ve become an admitted skeptic of ovarian cancer screening. Now, with these findings, I’m cautiously optimistic that in the not too distant future, we may be able to offer a screening method that can detect the disease in its earliest, curable stages and make a difference in the lives of women with this now-devastating disease.”

The study is continuing; and, as follow-up, Lu and her team plan to look at combining other markers with CA-125 to determine the screening impact of their combined change over time.

The study was supported by the National Cancer Institute, and was a research project of MD Anderson’s ovarian cancer Specialized Program of Research Excellence (SPORE), NCI P50 CA83639, the Bioinformatics Shared Resources of MD Anderson CCSG NCI P30 CA16672, the National Foundation for Cancer Research. It has also received philanthropic funds from Golfers Against Cancer, the Tracy Jo Wilson Ovarian Cancer Foundation, the Mossy Foundation, the Norton family and Stuart and Gaye Lynn Zarrow.

In addition to Lu, and Bast, other authors on the study include: Therese Bevers, M.D. Department of Clinical Cancer Prevention, Herbert Fritsche, Ph.D., Department of Laboratory Medicine, Deepak Bedi, M.D., Department of Diagnostic Radiology, Michael T. Deavers, M.D., Department of Pathology and Clinical Pathology; Charlotte Sun, Dr.PH, Department of Gynecologic Oncology, Mary A. Hernandez, Office of Translational Research, all with MD Anderson; Steven Skates, Ph.D., Massachusetts General Hospital and Harvard Medical School; Olasunkanmi Adeyinka, M.D., UT Physicians Family Physicians; William Newland, M.D., The Iowa Clinic; Richard Moore, M.D. and Cornelius Granai, M.D., both with Women & Infants Hospital, Brown University; Leroy Leeds, M.D., OGA Medical Center; Steven Harris, M.D., OB/GYN Associates of Dallas; Jeremy Geffen, M.D., Geffen Cancer Research Institute; and Nora Horick, Harvard Medical School and Massachusetts General Hospital.

As a co-inventor of the CA-125, Bast receives royalties from, and has served as an advisor to, Fujirebio Diagnostics, Inc.

Study: A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value [Cancer]

Source: MD Anderson Cancer Center

MicroRNAs have diagnostic and prognostic potential in urinary bladder cancer

German researchers have identified four biomarkers that correctly determine malignancy of urinary bladder cancers and contribute to the accurate prediction of patient outcomes. Their results are published in the September issue of The Journal of Molecular Diagnostics.

Current prognosticators of bladder cancer, such as tumor grade, stage, size, and number of foci, have limited usefulness for clinicians since they do not accurately reflect clinical outcomes. Therefore, investigators have been searching for new biomarkers with better diagnostic and prognostic capabilities. Focusing on the role of microRNAs (miRNAs), small non-coding RNAs, researchers have identified four miRNAs that together perfectly discriminated between nonmalignant and malignant tissue, including one alone that classified 81% of the samples correctly. Levels of two miRNAs correlated with overall survival time.

Urinary bladder cancer is the fourth most common cancer in the West. According to the National Cancer Institute, it is estimated that in the United States 72,570 individuals will be diagnosed with and 15,210 will die of cancer of the urinary bladder in 2013. At presentation, in 75% of patients the cancers are confined to the mucosa or submucosa (known as non-muscle invasive bladder cancer, NMIBC), whereas in 25% of cases the cancers have already invaded nearby muscle (muscle-invasive bladder cancer, MIBC).

In a series of experiments, investigators analyzed bladder tissue from patients with NMIBC, MIBC, and nonmalignant bladders. After screening 723 miRNAs by microarray, they selected a subset of 15 distinctively deregulated miRNAs for further validation by real-time quantitative PCR. Seven miRNAs were found to be up-regulated, and eight were down-regulated in malignant bladder tissue samples compared to healthy tissue. Four miRNAs were expressed differently in bladder cancers that invaded muscle compared to those that did not. With one exception, no correlation was found between tumor stage and miRNA levels.

When all 15 of the selected miRNAs were considered together, they correctly classified 100% of tissues as either normal or malignant. Further analysis identified four miRNAs that led to 100% correct classification, and one miRNA (miR-130b) that by itself had an 81% accuracy rate. “These results underline the great potential of miRNAs to serve as diagnostic markers, as previously noted for other urological tumors,” says lead investigator Klaus Jung, MD, the Department of Urology at the University Hospital Charité, Berlin and the Berlin Institute for Urologic Research.

The investigators found that tumor grading could not be correlated with overall survival. Yet, they were able to find two miRNAs that significantly correlated with survival: miR-141 and miR-205. miR-141 showed a trend (P=0.08) of being able to stratify patients with muscle-invasive tumors into two groups with different overall survival times. “This finding could be of clinical importance, but these results must be interpreted cautiously,” says Dr. Jung. “However, previously published studies underline the possible prognostic potential of miRNAs to predict progression and disease-specific or overall survival in bladder cancer patients.”

miRNAs are small non-coding RNAs that contain between 19 and 24 nucleotides. miRNAs regulate gene expression by degrading messenger RNAs or impairing their translation. In recent years there has been a growing interest in miRNAs as potential diagnostic and/or prognostic biomarkers in cancers and other diseases.

Study: miRNA Profiling Identifies Candidate miRNAs for Bladder Cancer Diagnosis and Clinical Outcome [The Journal of Molecular Diagnostics]

Source: EurekAlert!

Harmony Prenatal Test Now Being Offered in Mexico for Safe and Timely Risk Assessment of Chromosome Conditions During Pregnancy

Ariosa Diagnostics announced the offering of its Harmony™ Prenatal Test in Mexico through a partnership with Advance Medical on August 22, making the Latin American nation with over 2 million live births one of 46 countries around the world where the Harmony Prenatal Test can be ordered by healthcare providers. The Harmony test enables clinicians throughout Mexico to offer a non-invasive, early, reliable blood test to pregnant women. The Harmony test is both safe and cost effective, providing a personalized risk assessment for chromosome conditions such as Down syndrome.

The Harmony test has an accuracy rate above 99% for evaluation of fetal trisomy 21 risk, and a false positive rate of 0.1%, which is 50 times lower than conventional serum screening, translating into fewer referrals to unnecessary invasive diagnostic procedures such as amniocentesis that carry the inherent risk of miscarriage.

According to Dr. Dora Gilda Mayen Molina, Medical Genetic Specialist at the Hospital Angeles Lomas and Hospital Angeles Mexico, “The Harmony Prenatal Test can be performed for women with pregnancies of at least 10 weeks gestational age, and it is available for any singleton or twin pregnancy, including all those conceived by IVF.”

A recent study published in the American Journal of Obstetrics and Gynecology provided new evidence that non-invasive prenatal testing, specifically the Harmony test, is effective for screening in the general population. In the study of more than 2,000 women undergoing routine screening for fetal trisomies, the Harmony Prenatal Test accurately assessed the risk of all cases of fetal trisomy 21 and 18, with a false positive rate of 0.1 percent.

According to Dr. Thomas Musci, vice president of clinical and medical affairs for Ariosa Diagnostics, this partnership will “allow us to bring the highest quality and most clinically validated prenatal test to patients in Mexico for the betterment of prenatal medicine. We are very pleased to have partnered with Advance Medical.”

Source: PR Newswire

Ariosa Diagnostics, CHU de Quebec and Genome Canada to Launch Large-Scale Cost-Effectiveness Study of Non-Invasive Prenatal Testing in Canada

A team of researchers led by CHU de Quebec and Universite Laval, have received CAN$10.5 million from Genome Canada, the Canadian Institutes of Health Research (CIHR), Genome Quebec and other partners to conduct a large-scale comparative effectiveness study on non-invasive prenatal screening techniques. Dr. Francois Rousseau and his team will examine current prenatal screening practices for chromosomal conditions, such as Down syndrome, among pregnant women in Canada in order to improve screening approaches and avoid unnecessary procedures.

Each year in Canada, about 450,000 women become pregnant and are offered Down syndrome prenatal screening using biochemical and ultrasound markers. The vast majority will be negative or low risk. However, for positive or high-risk results, those pregnant women are referred to amniocentesis, which is an invasive procedure done to confirm the screening result. Approximately 5% of all biochemical screening results are falsely positive, attributing to unnecessary invasive procedures that pose a 1 in 300 risk for miscarriage.

Genome Quebec is a strong supporter of public-private partnerships, such as the one developed between Ariosa Diagnostics and Dr. Francois Rousseau’s team. The PEGASUS: PErsonalized Genomics for prenatal Aneuploidy Screening USing maternal blood project, made possible through such partnerships in personalized medicine, will help meet women’s healthcare needs by giving them access to safer prenatal screening tests, explains Marc LePage, Genome Quebec’s President and CEO.

The research project aims at independently comparing the performances of different such approaches that involve various combinations of the available tools for screening of chromosomal conditions, as well as to evaluate the cost-effectiveness, the ethical and social aspects of this new technology and to identify and adapt the best implementation tools for users in the health care system. The researchers will recruit 5600 pregnant women (3600 at high-risk of trisomy conditions and 2000 at low-risk). Samples from these women will be tested in parallel using different screening approaches that involve genomic-based NIPT, but also existing or new biochemical and ultrasound screening tools. The samples will be analyzed without knowledge of the true status of the pregnancy outcome. This will provide a comprehensive evaluation of the most efficient ways to improve the prenatal screening techniques widely used today.

Ariosa Diagnostics is one of the major commercial partners for this project and will provide testing for part of this large sample that will include mainly low-risk women. The investigators have chosen the Harmony™ Prenatal Test as the commercially available NIPT assay to be included as one the various screening tests that will be compared.

Dr. Rousseau, Leader of the Project, mentions: “We are happy that Ariosa Diagnostics has joined this effort and provided a significant contribution to this Project. Ariosa’s Harmony test is the most affordable commercial NIPT available, and it was chosen by the research team for this study because it is the most likely to be used in the Canadian context.”

Dr. Thomas Musci, VP of Clinical and Medical Affairs at Ariosa remarked that: “Ariosa, as a core corporate value, is committed to furthering rigorous clinical and scientific study of cell-free DNA technology and the Harmony Prenatal Test in a variety of clinical settings and in a number of different countries. We are extremely pleased to support this collaboration with Genome Canada and fully support the goals of their research efforts.”

Dr. Serge Rivest, Director of the research Centre at the CHU de Qudbec, stated that: “The leadership of the researchers from CHU de Quebec Research Center was key in putting this exceptional academic team together to tackle one of the hottest clinical application of next-generation sequencing in the context of a population-based screening program.”

Source: Ariosa Diagnostics

Breakthrough Case Study Highlights New Biomarker for Cancer and Inflammation

A groundbreaking peer reviewed case report by Dr. Isaac Eliaz, M.D. of Amitabha Medical Clinic, demonstrates for the first time the clinical use of novel biomarker galectin-3 to assess cancer progression and inflammation. The case study titled, “The Role of Galectin-3 as a Marker of Cancer and Inflammation in a Stage IV Ovarian Cancer Patient with Underlying Pro-Inflammatory Comorbidities,” was published in the July 2013 issue of Case Reports in Oncology. This report is the first of its kind to expand the diagnostic and prognostic applications of the galectin-3 blood serum test, introducing an important clinical tool to assess risk and progression of metastatic cancer and inflammatory diseases.

In 2011, the galectin-3 blood test was approved by the U.S. Food and Drug Administration for the screening and prognosis of congestive heart failure and cardiovascular disease. Approval was granted after an extensive body of published data, including long-term population studies, demonstrated the active role of elevated galectin-3 in cardiovascular conditions, fibrosis and early mortality. However, a rapidly expanding field of published galectin-3 research also highlights the significance of this rogue molecule as a novel biomarker that is both an active culprit as well as a byproduct of numerous inflammatory and malignant cellular processes beyond cardiovascular disease.

An expert on galectin-3, Dr. Eliaz applies the data obtained in this case study to shed further light on excess galectin-3’s mechanisms of action, specifically inflammatory response to injury and cancer progression. In this report, Dr. Eliaz presents the first published case documenting the clinical use of galectin-3 to monitor cancer progression and treatment response, as well as inflammatory conditions. These findings point to an expanded clinical model using galectin-3 testing in the diagnostic and prognostic assessment of numerous chronic, inflammatory diseases.

Unlike biomarkers such as C-reactive protein (CRP), which only indicate the presence of inflammation, galactin-3 is shown to play a direct role in initiating disease progression. It is a protein normally present in the body at low concentrations, where it is involved in numerous functions including cell growth and communication. At elevated levels, however, galectin-3 fuels numerous pathologic processes including chronic inflammation and the progression of inflammation to fibrosis; cancer cell adhesion, migration, angiogenesis, and metastasis. Elevated galectin-3 also allows cancer cells to evade immune response. Research demonstrates elevated galectin-3 levels in patients with melanoma, lung, breast, prostate, colorectal, ovarian, and head and neck cancers as well as non-Hodgkin’s lymphoma and others. Galectin-3 levels are also found to be higher in patients with metastatic disease than in patients with localized tumors.

Dr. Eliaz states, “This new case report and significant clinical observation supports the need for further research on the role of galectin-3. The galectin-3 test could well become one of our most important clinical tools in assessing and monitoring a wide range of conditions beyond cardiovascular disease, including metastatic cancer and inflammatory conditions.”

Study: The Role of Galectin-3 as a Marker of Cancer and Inflammation in a Stage IV Ovarian Cancer Patient with Underlying Pro-Inflammatory Comorbidities. [Case Reports in Oncology]

Source: PR Newswire