News Article | March 1, 2017
It's what's missing in the tumor genome, not what's mutated, that thwarts treatment of metastatic melanoma with immune checkpoint blockade drugs, researchers at The University of Texas MD Anderson Cancer Center report in Science Translational Medicine. Whole exome sequencing of tumor biopsies taken before, during and after treatment of 56 patients showed that outright loss of a variety of tumor-suppressing genes with influence on immune response leads to resistance of treatment with both CTLA4 and PD1 inhibitors. The team's research focuses on why these treatments help 20-30 percent of patients -- with some complete responses that last for years - but don't work for others. Their findings indicate that analyzing loss of blocks of the genome could provide a new predictive indicator. "Is there a trivial or simple (genomic) explanation? There doesn't seem to be one," said co-senior author Andrew Futreal, Ph.D., professor and chair of Genomic Medicine and co-leader of MD Anderson's Moon Shots Program™. "There's no obvious correlation between mutations in cancer genes or other genes and immune response in these patients." "There are, however, pretty strong genomic copy loss correlates of resistance to sequential checkpoint blockade that also pan out for single-agent treatment," Futreal said. Doctoral candidate Whijae Roh, co-lead author, Futreal, and co-senior author Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine, and colleagues analyzed the genomic data for non-mutational effects. "We found a higher burden of copy number loss correlated to response to immune checkpoint blockade and to lower immune scores, a measure of immune activation in the tumor's microenvironment," said Roh, a graduate student in the University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences. "We also found copy loss has an effect that is independent of mutational load in the tumors." Melanoma tumors with larger volumes of genetic alterations, called mutational load, provide more targets for the immune system to detect and are more susceptible to checkpoint blockade, although that measure is not conclusive alone. "Combining mutational load and copy number loss could improve prediction of patient response," Wargo said. When the team stratified patients in another data set of patients by whether they had high or low copy loss or high or low mutational load, they found that 11 of 26 patients with high mutational load and low copy loss had a clinical benefit, while only 4 or 26 with low mutational load and high copy loss benefited from treatment. In the trial, patients were treated first with the immune checkpoint inhibitor ipilimumab, which blocks a brake called CTLA4 on T cells, the immune system's specialized warriors, freeing them to attack. Patients whose melanoma did not react then went on to anti-PD1 treatment (nivolumab), which blocks a second checkpoint on T cells. Biopsies were taken, when feasible, before, during and after treatment for molecular analysis to understand response and resistance. To better understand the mechanisms at work, the team analyzed tumor genomes for recurrent copy loss among 9 tumor biopsies from patients who did not respond to either drug and had high burden of copy number loss. They found repeated loss of blocks of chromosomes 6, 10 and 11, which harbor 13 known tumor-suppressing genes. Analysis of a second cohort of patients confirmed the findings, with no recurrent tumor-suppressor loss found among any of the patients who had a clinical benefit or long-term survival after treatment. Ipilimumab sometimes wins when it fails The researchers also found a hint that treatment with ipilimumab, even if it fails, might prime the patient's immune system for successful anti-PD1 treatment. The team analyzed the genetic variability of a region of the T cell receptors, a feature of T cells that allows them to identify, attack and remember an antigen target found on an abnormal cell or an invading microbe. They looked for evidence of T cell "clonality," an indicator of active T cell response. Among eight patients with longitudinal samples taken before treatment with both checkpoint types, all three who responded to anti-PD1 therapy had shown signs of T cell activation after anti-CTLA treatment. Only one of the five non-responders had similar indicators of T cell clonality. "That's evidence that anti-CTLA4 in some cases primes T cells for the next step, anti-PD1 immunotherapy. It's well known that if you don't have T cells in the tumor, anti-PD1 won't do anything, it doesn't bring T cells into the tumor," Futreal says. Overall, they found that T cell clonality predicts response to PD1 blockade but not to CTLA-4 blockade. "Developing an assay to predict response will take an integrated analysis, thinking about genomic signatures and pathways, to understand the patient when you start therapy and what happens as they begin to receive therapy," Wargo said. "Changes from pretreatment to on-therapy activity will be important as well." The Science Translational Medicine paper is the third set of findings either published or presented at scientific meetings by the team, which is led by Futreal and Wargo, who also is co-leader of the Melanoma Moon Shot™. Immune-monitoring analysis showed that presence of immune infiltrates in a tumor after anti-PD1 treatment begins is a strong predictor of success. They also presented evidence that the diversity and composition of a patient's gut bacteria also affects response to anti-PD1 therapy. The serial biopsy approach is a hallmark of the Adaptive Patient-Oriented Longitudinal Learning and Optimization™ (APOLLO) platform of the Moon Shots Program™, co-led by Futreal that systematically gathers samples and data to understand tumor response and resistance to treatment over time. The Moon Shots Program™ is designed to reduce cancer deaths by accelerating development of therapies, prevention and early detection from scientific discoveries. Futreal holds the The Robert A. Welch Distinguished University Chair in Chemistry at MD Anderson. Co-authors with Roh, Futreal and Wargo are co-first authors Pei-Ling Chen, M.D., of Genomic Medicine and Pathology, and Alexandre Reuben, Ph.D., of Surgical Oncology; also Christine Spencer, Feng Wang, Ph.D., Zachary Cooper, Ph.D., Curtis Gumbs, Latasha Little, Qing Chang, Wei-Shen Chen, M.D., and Jason Roszik, Ph.D., of Genomic Medicine; Michael Tetzlaff, Ph.D., M.D., and Victor Prieto, M.D., Ph.D., of Pathology; Peter Prieto, M.D., Vancheswaran Gopalakrishnan, Jacob L. Austin-Breneman, Hong Jiang, Ph.D., and Jeffrey Gershenwald, M.D., of Surgical Oncology; John Miller, Ph.D., Oncology Research for Biologics and Immunotherapy Translation (ORBIT); Sangeetha Reddy, M.D., Division of Cancer Medicine; Khalida Wani, Ph.D., Mariana Petaccia De Macedo, M.D., Ph.D., Eveline Chen, and Alexander Lazar, M.D., Ph.D., of Translational Molecular Pathology; Michael Davies, M.D., Ph.D., Hussein Tawbi, M.D., Ph.D., Patrick Hwu, M.D., Wen-Jen Hwu, M.D., Ph.D., Adi Diab, M.D., Isabella Glitza, M.D., Ph.D., Sapna Patel, M.D., Scott Woodman, M.D., Ph.D., and Rodabe Amaria, M.D., of Melanoma Medical Oncology; Jianhua Hu, Ph.D., of Biostatistics; Padmanee Sharma, M.D., Ph.D., and James Allison, Ph.D., of Immunology; Lynda Chin, M.D., University of Texas System; and Jianhua Zhang Ph.D., of the Institute for Applied Cancer Science. Wargo, Sharma and Allison are all members of the Parker Institute for Cancer Immunotherapy. The research was funded by MD Anderson's Melanoma Moon Shot™, the Melanoma Research Alliance Team Science Award, the John G. and Marie Stella Kenedy Memorial Foundation, the University of Texas System STARS program; the Cancer Prevention and Research Institute of Texas; the American Society of Clinical Oncology; Conquer Cancer Foundation; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; and grants from the National Cancer Institute of the National Institutes of Health (U54CA163125, 1K08CA160692-01A1, T32CA009599, NIH T32 CA009666, R01 CA187076-02) and MD Anderson's Institutional Tissue Bank (2P30CA016672) Spencer and Gopalakrishnan are graduate students in The University of Texas Health Science Center at Houston School of Public Health.
News Article | February 15, 2017
The session will focus on various aspects of designing and conducting clinical trials for submission to the FDA, as well as, communicating with FDA during the pre-submission and submission process TORONTO, ON--(Marketwired - February 13, 2017) - On Tuesday, March 7, 2017, Xtalks will host a complimentary webinar featuring Richard Kotz, Senior Medical Research Scientist, Biostatistics from NAMSA as the keynote speaker. The advice provided during the session will be based on Richard Kotz's 25 years of experience gained as a statistical reviewer and biostatistics team leader at FDA's Center for Devices and Radiological Health. He, along with his team of biostatisticians, has reviewed 100's of medical devices for a wide variety of medical conditions. He has also participated in numerous FDA/sponsor meetings. Utilizing this experience and expertise, Mr. Kotz will share insights into key topics related to successful study design, with an emphasis on those trial elements which were most likely to lead to poorly designed and executed clinical trials. The discussion will provide best practices and tips on getting the most out of communications with the FDA and include a Q&A period with the audience. For more information or to register for this free webinar visit: Designing an Effective Clinical Trial Xtalks, powered by Honeycomb Worldwide Inc., is a leading provider of educational webinars to the global Life Sciences community. Every year thousands of industry practitioners (from pharmaceutical & biotech companies to private & academic research institutions, healthcare centers, etc.) turn to Xtalks for access to quality content. Xtalks helps Life Science professionals stay current with industry developments, trends and regulations. Xtalks webinars also provide perspectives on key issues from top industry thought leaders and service providers. To learn more about Xtalks visit http://xtalks.com For information about hosting a webinar visit http://xtalks.com/sponsorship.ashx
News Article | February 28, 2017
Adding two blood-borne proteins associated with cancer cell migration increases the predictive ability of the current biomarker for pancreatic cancer to detect early stage disease, a research team from The University of Texas MD Anderson Cancer Center reports in the Journal of the National Cancer Institute. The trio of biomarkers, tested in three separate cohorts, including two blinded validation studies, improved the detection of patients with early stage disease compared to healthy or benign disease controls. "Adding these two biomarkers provided statistically significant improvement for all early stage cancer versus healthy controls as well as other subcohorts when used with the current gold standard biomarker, CA 19-9," said Ann Killary, Ph.D., professor of Translational Molecular Pathology. While CA 19-9 is the only biomarker approved for use by the U.S. Food and Drug Administration, and only for monitoring treatment for the disease, according to first author Seetharaman Balasenthil, Ph.D., instructor in Translational Molecular Pathology. The marker of antigens produced by pancreatic cancer has a low positive predictive value for identifying early stage disease. At early stages, pancreatic cancer can be successfully removed with surgery, but 80 percent of patients are diagnosed with either locally advanced disease (stage III) or cancer that has spread to other organs (stage IV), when surgery is no longer a curative option. Pancreatic cancer is the fourth-leading cause of deaths from cancer in the United States, with an estimated 53,070 new cases diagnosed in 2016 and 41,780 deaths, according to the National Cancer Institute. "Our goal is to identify more patients at those earlier, resectable stages, when treatment could lead to a five year survival rate of 30 percent or more, depending on stage," Killary said. Only about 7 percent of patients survive for five years following diagnosis of the disease. Additional studies in larger cohorts will be needed to validate these findings, and more biomarkers will be needed to get the completely accurate set needed to screen the general population with the long term goal of identifying precursor lesions before they become malignant. Killary and colleagues earlier identified a cluster of genes involved in cancer migration and then analyzed the proteins produced by those genes. Two, known as TFPI and tenascin C, emerged as the strongest biomarker candidates. The team first compared their predictive ability by comparing their presence in healthy volunteers and those with primarily stage IV pancreatic cancer. In the current study, deploying TFPI and an isoform of tenascin C, TNC-FN IIIC, with CA 19-9 improved performance discriminating stage I and II disease from healthy or benign disease controls. The principal measure of efficacy is called Area Under the Curve (AUC), a measure of how well biomarkers identify true cases of disease (sensitivity) while avoiding false positives (specificity). A perfect AUC would have a score of 1.0. Any biomarker test for the general public will need to be close to a perfect 1.0, Killary noted, given the infrequency of pancreatic cancer in the population at large. In the group's analysis of three cohorts of samples, AUC scores for the combination consistently outscored CA-19-9 alone. For the first cohort of samples, comparing stage I/IIA and healthy controls yielded an AUC of 0.72 for CA-19-9 alone compared to 0.84 for the combination. For stage IIB vs. controls, the combination raised CA-19-9's performance from an AUC of 0.87 to 0.98. The second blinded cohort also showed improvements in AUC over CA19-9. A third, larger blinded validation study of 252 samples of cases and controls from the Early Detection Research Network of the National Cancer Institute further confirmed those findings and also permitted the team to measure the trio's ability to detect disease in patients without a history of pancreatitis or diabetes. The AUC for those patients was 0.87 for Stage I/IIA, 0.93 for Stage IIB and 0.89 for all early stages of the disease using the combination, pointing to a potential ability to detect disease in those who lack either of those known risk-raising conditions. Killary said the team is working to use the biomarkers in MD Anderson's high-risk clinic, established through MD Anderson's Pancreatic Cancer Moon Shot™, part of the institution's Moon Shots Program™ to accelerate the development of life-saving advances based on scientific discovery. The clinic monitors people who are already at high risk of pancreatic cancer due to family history or having known risk-raising genetic mutations. "In this population, our biomarker panel might prove very useful in early detection," Killary said. Co-author Subrata Sen, Ph.D., also a professor of Molecular Translational Pathology, notes, "These findings are a significant advance considering that there's nothing else available now to detect early stage pancreatic cancer that has gone through blinded validations in multiple patient cohorts." Co-authors with Killary, Balasenthil and Sen are Nanyue Chen, M.D., Ph.D., of Translational Molecular Pathology; Suyu Liu, Ph.D., and J. Jack Lee, Ph.D., of Biostatistics; Jinyun Chen, M.D., Pharm.D., and Marsha Frazier, Ph.D. of Epidemiology; Ying Huang, Ph.D., and Tracey Marsh, of Fred Hutchinson Cancer Research Center, Seattle; Sanford Stass, M.D., and Debra KuKuruga , Ph.D., of the University of Maryland Medical Center, Baltimore; Randall Brand, M.D., University of Pittsburgh Medical Center; and Sudhir Srivastava, M.D., of the National Cancer Institute. This research was funded by Early Detection Research Network grants (U01 CA111302 and U24 CA115091-10) and by MD Anderson's Moon Shots Program.
News Article | February 27, 2017
The combined results of two ovarian cancer screening trials suggest that a personalized strategy involving frequent screening of high-risk women could improve the chance that tumors are detected at early stages when they are easier to treat. As reported in a paper published in Clinical Cancer Research, these trials imply that a protocol involving quarterly blood test to identify significant increases above each patient's personal baseline in levels of the protein CA125, followed by ultrasound examination when such elevations are detected, could reduce the risk of diagnosis with advanced cancer in high-risk women who choose to delay recommended preventive surgery. "The standard advice for women at high risk of ovarian cancer, due to either family history or inherited gene mutations, is to have their ovaries and fallopian tubes removed once their families are complete. Some women choose to postpone this surgery," says Steven Skates, PhD, of the Massachusetts General Hospital (MGH) Cancer Center and the Biostatistics Unit, co-lead and corresponding author of the report. "Our screening protocol increased the proportion of tumors detected at early stages from 10 percent - which is typically seen in high-risk women who are not screened - to 50 percent." CA125 levels are known to be raised over the level of 35 in the blood of most women with ovarian cancer. While screening for raised CA125 and/or transvaginal ultrasound may be considered for high-risk women who postpone surgery, that approach has not been shown to improve patient outcomes. The two trials reported in the current paper utilize the Risk of Ovarian Cancer Algorithm (ROCA) - co-developed by Skates and Ian Jacobs, MD, FRCOG, of the University of New South Wales in Australia and University College London - which tracks CA125 levels over time to identify significant elevations above each patient's baseline levels, even those that do not exceed the traditional threshold of 35. One trial conducted through the National Cancer Institute's Cancer Genetics Network (CGN) - with additional patients from two ovarian Specialized Programs of Research Excellence (SPORE) and two Early Detection Research Network sites (EDRN) - was led by Skates. The other, conducted through the Gynecologic Oncology Group (GOG), was led by Mark H. Greene, MD, of the Clinical Genetics Branch at the National Cancer Institute (NCI). Both trials followed similar protocols, enrolling women at elevated risk for ovarian cancer - based on either a strong family history of ovarian and/or breast cancer or the presence in the patient or in close blood relatives of risk-associated mutations in the BRCA1 or BRCA2 genes - who had not yet had risk-reducing surgery. Participants had CA125 blood tests utilizing ROCA every three months, compared with screening for raised CA125 values every 6 or 12 months as in previous screening studies. The investigators calculated a patient's ROCA risk by analyzing the results of each new CA125 test, combined with previous results, and factors such as participant's age and menopausal status. Women at intermediate ROCA risk were referred for an ultrasound examination, while those at an elevated ROCA risk received both ultrasound and clinical evaluation by either a gynecologic oncologist or the site principal investigator. While the results of those examinations were used to guide decisions about surgical treatment, study participants were free to choose to have their ovaries and fallopian tubes removed at any time during the clinical trials, as is standard practice for women with a BRCA1/2 mutation. Between 2001 and 2011, the CGN trial enrolled 2,359 women at 25 U.S. sites. The GOG trial enrolled 1,459 women at 112 sites in the U.S. and Australia between 2003 and 2006 and screened them for five years. Among the more than 3,800 participants in both studies, 19 malignant tumors of the ovaries or fallopian tubes were identified during the study periods. Ten cases were diagnosed during screening, and nine were diagnosed by preventive surgery. Of the ten cases, there was evidence that four were present at the outset of the trial, while six tumors were likely to have developed during the trial period after a CA125 baseline had been measured. While the algorithm can calculate risk without a baseline, ROCA works best when a baseline has been established. The results in these six cases reflect the benefits of a long-term ROCA screening program; all but one were diagnosed by ROCA, giving a sensitivity of over 80 percent ,and 50 percent were detected at early stages. Another study - the UK Familial Ovarian Cancer Screening Study, led by ROCA co-developer Jacobs and published today in the Journal of Clinical Oncology - found that a similar protocol using ROCA-based testing every four months was also better than current practice at diagnosing early-stage tumors in high-risk women. Skates notes that a formal analysis of the data from all three trials could increase the statistical power of these studies and could lend stronger support to recommending frequent ROCA-based screening for high-risk women who choose to postpone surgery or while waiting for surgery. While the pattern of cancers detected in these studies supported the potential value of ROCA screening, these studies were not designed to assess whether screening reduced deaths due to ovarian cancer, the authors note. "It is important to note that removal of ovaries and fallopian tubes remains the standard of care when women at increased familial or genetic risk complete their families and reach an age when their risk exceeds that of the general population," stresses Skates, who is an associate professor of Medicine at Harvard Medical School. Adds Greene, who is a senior principal investigator at the NCI, "Surgery is the primary and best option for reducing the risk of ovarian cancer, and ROCA should only be considered as a promising but unproven option for patients who decide, against medical advice, to postpone their surgery." Both investigators note that further research to identify a greater range of ovarian cancer biomarkers and improved imaging technologies is needed to help detect even more tumors at even earlier stages. Skates is leading a program to discover new biomarkers for early detection of ovarian cancer as part of NCI's Early Detection Research Network. Skates and Greene are co-lead authors of the Clinical Cancer Research report; and Dianne Finkelstein, PhD, MGH Biostatistics, and Karen Lu, MD, M.D. Anderson Cancer Center, are co-senior authors. Support for the study includes multiple grants from the National Cancer Institute to the Cancer Genetics Network, the Specialized Programs of Research Excellence, and the Early Detection Research Network, and support from the NCI Intramural Research Program. Massachusetts General Hospital has co-licensed software implementing ROCA. Skates is on the scientific advisory board of SISCAPA Assay Technologies, a consultant for Abcodia, and has received a speaker honorarium from Astra-Zeneca. The NCI Division of Cancer Epidemiology and Genetics (DCEG), home to the Clinical Genetics Branch, is a global leader in cancer epidemiology and genetics research. With its cadre of renowned epidemiologists, geneticists and biostatisticians, DCEG conducts population and multidisciplinary research to discover the genetic and environmental determinants of cancer and new approaches to cancer prevention. The DCG research portfolio informs biological concepts, clinical practice and public health policy. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
News Article | February 20, 2017
PORTLAND, OR - Nine years ago, SWOG researchers confirmed a new standard of care for patients with incurable gastrointestinal stromal tumors (GIST), who could survive by being treated with imatinib mesylate, the breakthrough drug marketed as Gleevec. SWOG researchers are back with long-term findings from that study, which estimate that nearly one in four patients treated with Gleevec will survive 10 years. Results are published in JAMA Oncology. "This is a really exciting finding," said Dr. Michael Heinrich, a SWOG investigator and a professor of medicine and cell and developmental biology at Oregon Health & Science University, where SWOG is based. "Until Gleevec arrived on the scene 15 years ago, patients with advanced GISTs faced a life expectancy of 18 months. Now we've learned that some might live a decade or longer. And we've come to understand which class of patients benefit the most from Gleevec." In new study results published in JAMA Oncology, researchers from SWOG, the international cancer research community supported by the National Cancer Institute, report a follow-up of patients originally enrolled in S0033, a SWOG-led trial supported by other groups in the NCI's National Clinical Trials Network (NCTN). This was a Phase III study that began in 2000. Initial results published in 2008 confirmed Gleevec as an effective treatment for advanced GIST patients, and recommended that therapy start with a 400 mg daily dose. The SWOG team decided to collect post-study data on S0033 patients, and from 2011 to 2015 gathered information. As part of their research, the team used next-generation DNA sequencing on some tumor tissue samples taken for S0033, which had been deposited in a biospecimen bank. The team reanalyzed tissue from 20 patients originally classified as having a wild-type tumor - one without any mutations of KIT, a gene implicated in 85 to 88 percent of all GISTs. Analysis showed that of the 695 eligible patients originally enrolled in S0033, 189 survived eight years or longer, with a 10-year estimate of overall survival of 23 percent, or nearly one in four patients. DNA sequencing also showed that survival rates were significantly higher for patients with a KIT exon-11 mutant GIST, when compared with patients whose tumor had a KIT exon-9 mutation or with no KIT mutations or mutations in the platelet-derived growth factor receptor gene, or PDGFRA. "Our findings show two things," Heinrich said. "One is that Gleevec has revolutionized treatment for patients with advanced GISTs. Our findings also highlight the importance of banked biospecimens to drive new scientific findings, and how tumor mutation testing can optimize treatment for cancer patients." GISTs are different from more common types of gastrointestinal tumors because of the type of tissue in which they start. GISTs belong to a group of cancers called soft-tissue sarcomas. Soft-tissue sarcomas develop in the tissues that support and connect the body, including muscles, nerves, tendons, and joints. GIST is a rare cancer, with about 6,000 new cases diagnosed in the United States each year. Researchers at Oregon Health & Science University have pioneered the treatment of GISTs. Dr. Brian Druker, director of the OHSU Knight Cancer Institute, conducted the most influential work in the development of Gleevec, and OHSU researchers have been part of major discoveries in the use of the drug to treat GISTs, as well as chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). Along with Heinrich, lead author of the JAMA Oncology article, the SWOG study team includes: Cathryn Rankin, MS, of Fred Hutchinson Cancer Research Center; Dr. Charles D. Blanke of Knight Cancer Institute; Dr. George Demetri of Dana-Farber Cancer Institute; Dr. Ernest Borden of Cleveland Clinic; Dr. Christopher Ryan of Knight Cancer Institute; Dr. Margaret von Mehren of Fox Chase Cancer Center; Dr. Martin Blackstein of Mount Sinai Hospital; Dr. Dennis Priebat of MedStar Hospital Research Center; Dr. William Tap of Memorial Sloan Kettering Cancer Center; Dr. Robert Maki of Norwell Health and Cold Spring Harbor Laboratory; Dr. Christopher Corless of Knight Cancer Institute; Dr. Jonathan Fletcher of Dana-Farber Cancer Institute; Kouros Owzar, PhD, of Duke University School of Medicine; John Crowley, PhD, of Cancer Research And Biostatistics; Dr. Robert Benjamin of University of Texas MD Anderson Cancer Center; and Laurence Baker, DO, of University of Michigan. Research reported in this article was supported by the NCI of the National Institutes of Health (NIH) in part under award numbers U10CA180888 and U10CA180819. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Novartis Pharmaceuticals also supported the research. SWOG is a global cancer research community of over 12,000 members in 47 states and six foreign countries who design and conduct publicly funded clinical trials. Since 1956, SWOG trials have led to the approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 2 million years of human life. The group is a proud member of the NCI's National Clinical Trials Network and the NCI Community Oncology Research Program, and is a major part of the cancer research infrastructure in the U.S. and the world. Headquartered at the Knight Cancer Institute at Oregon Health & Science University in Portland, Ore., SWOG's Statistics and Data Management Center is based at Fred Hutchinson Cancer Research Center in Seattle, Wash. and its Operations Office is located in San Antonio, Texas. Learn more at swog.org.
News Article | February 22, 2017
The human heart beats more than 2.5 billion times in an average lifetime. Now scientists at Vanderbilt University have created a three-dimensional organ-on-a-chip that can mimic the heart's amazing biomechanical properties. "We created the I-Wire Heart-on-a-Chip so that we can understand why cardiac cells behave the way they do by asking the cells questions, instead of just watching them," said Gordon A. Cain University Professor John Wikswo, who heads up the project. "We believe it could prove invaluable in studying cardiac diseases, drug screening and drug development, and, in the future, in personalized medicine by identifying the cells taken from patients that can be used to patch damaged hearts effectively." The device and the results of initial experiments demonstrating that it faithfully reproduces the response of cardiac cells to two different drugs that affect heart function in humans are described in an article published last month in the journal Acta Biomaterialia. A companion article in the same issue presents a biomechanical analysis of the I-Wire platform that can be used for characterizing biomaterials for cardiac regenerative medicine. The unique aspect of the new device, which represents about two millionths of a human heart, is that it controls the mechanical force applied to cardiac cells. This allows the researchers to reproduce the mechanical conditions of the living heart, which is continually stretching and contracting, in addition to its electrical and biochemical environment. "Heart tissue, along with muscle, skeletal and vascular tissue, represents a special class of mechanically active biomaterials," said Wikswo. "Mechanical activity is an intrinsic property of these tissues so you can't fully understand how they function and how they fail without taking this factor into account." "Currently, we don't have many models for studying how the heart responds to stress. Without them, it is very difficult to develop new drugs that specifically address what goes wrong in these conditions," commented Charles Hong, associate professor of cardiovascular medicine at Vanderbilt's School of Medicine, who didn't participate in the research but is familiar with it. "This provides us with a really amazing model for studying how hearts fail." The I-Wire device consists of a thin thread of human cardiac cells 0.014 inches thick (about the size of 20-pound monofilament fishing line) stretched between two perpendicular wire anchors. The amount of tension on the fiber can be varied by moving the anchors in and out, and the tension is measured with a flexible probe that pushes against the side of the fiber. The fiber is supported by wires and a frame in an optically clear well that is filled with liquid medium like that which surrounds cardiac cells in the body. The apparatus is mounted on the stage of a powerful optical microscope that records the fiber's physical changes. The microscope also acts as a spectroscope that can provide information about the chemical changes taking place in the fiber. A floating microelectrode also measures the cells' electrical activity. According to the researchers, the I-Wire system can be used to characterize how cardiac cells respond to electrical stimulation and mechanical loads and can be implemented at low cost, small size and low fluid volumes, which make it suitable for screening drugs and toxins. Because of its potential applications, Vanderbilt University has patented the device. Unlike other heart-on-a-chip designs, I-Wire allows the researchers to grow cardiac cells under controlled, time-varying tension similar to what they experience in living hearts. As a consequence, the heart cells in the fiber align themselves in alternating dark and light bands, called sarcomeres, which are characteristic of human muscle tissue. The cardiac cells in most other heart-on-a-chip designs do not exhibit this natural organization. In addition, the researchers have determined that their heart-on-a-chip obeys the Frank-Starling law of the heart. The law, which was discovered by two physiologists in 1918, describes the relationship between the volume of blood filling the heart and the force with which cardiac cells contract. The I-Wire is one of the first heart-on-a-chip devices to do so. To demonstrate the I-Wire's value in determining the effects that different drugs have on the heart, the scientists tested its response with two drugs known to affect heart function in humans: isoproterenol and blebbistatin. Isoproterenol is a medication used to treat bradycardia (slow heart rate) and heart block (obstruction of the heart's natural pacemaker). Blebbistatin inhibits contractions in all types of muscle tissue, including the heart. According to Veniamin Sidorov, the research assistant professor at the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE) who led its development, the device faithfully reproduces the response of cardiac cells in a living heart. "Cardiac tissue has two basic elements: an active, contractile element and a passive, elastic element," said Sidorov. "By separating these two elements with blebbistatin, we successfully characterized the elasticity of the artificial tissue. By exposing it to isoproterenol, we tested its response to adrenergic stimulation, which is one of the main systems responsible for regulation of heart contractions. We found that the relationship between these two elements in the cardiac fiber is consistent with that seen in natural tissue. This confirms that our heart-on-a-chip model provides us with a new way to study the elastic response of cardiac muscle, which is extremely complicated and is implicated in heart failure, hypertension, cardiac hypertrophy and cardiomyopathy." Other members of the VIIBRE research team are Professor of Pathology, Microbiology and Immunology Jeffrey Davidson, former Assistant Professor of Medicine Chee Lim (now at NIH), Assistant Professor of Biostatistics Matthew Shotwell and Associate Professor of Biomedical Engineering David Merryman, Senior R&D Engineer Philip Samson, postdoctoral fellow Tatiana Sidorova and doctoral student Alison Schroer. The I-Wire technology has been patented and is available for licensing. Interested parties should contact Ashok Choudhury or Masood Machingal at the Vanderbilt Center for Technology Transfer and Commercialization. The research was supported by National Institutes of Health grants 1R01118392-01, R01 HL118392, R01 HL095813 and 5R01-AR056138; National Science Foundation grants 1055384 and DGE-0909667; Defense Threat Reduction Agency grant CBMXCEL-XL1-2-001; American Heart Association grant 15PRE25710333; and by the Department of Veterans Affairs.
News Article | February 15, 2017
For women with intermediate risk recurrence score from 21-gene expression assay, less may be more Women with early-stage breast cancer who had an intermediate risk recurrence score (RS) from a 21-gene expression assay had similar outcomes, regardless of whether they received chemotherapy, a new study from The University of Texas MD Anderson Cancer finds. The encouraging research, published in the journal CANCER, still needs to be validated in an ongoing international trial. If verified, women with intermediate scores may one day be able to avoid chemotherapy as standard of care. Historically, the management of women with early-stage breast cancer has been aggressive, explained Carlos H. Barcenas, M.D., assistant professor, Breast Medical Oncology, with many Stage I and all Stage II patients receiving chemotherapy. Fortunately, over the last decade, research discoveries across the breast cancer landscape have evolved such that less is now more, for women with early-stage disease, said Barcenas. "Through years of research discoveries, it became clear that we were over-treating many women with breast cancer, especially those with early-stage disease. In addition to chemotherapy's obvious side effects, there were also long-term complications for these women as survivors," said Barcenas, the study's corresponding author. One such practice-changing clinical discovery was that a 21-gene-expression assay could predict the risk of recurrence among some with early-stage breast cancer. In 2015, initial results from the international clinical trial, TAILORx, found that women with hormone receptor positive, HER2 and lymph node negative early stage disease with a low RS of 0-10 could have chemotherapy omitted altogether. While the findings dramatically changed care for women with a low RS, many questions remain regarding the management of women with an intermediate RS, defined by this trial as a score of 11-25. The conversation to give or not give chemotherapy is one Barcenas often has in his clinic, he said. "This study evolved out of my patients' frustration that I could not provide a definitive answer to their paramount question: 'Do I need chemotherapy?' As we wait for the TAILORx findings, we decided to look at MD Anderson's own experience to glean insight on how best to care for these women with an intermediate risk recurrence score," said Barcenas. For the retrospective, single-institution analysis, Barcenas and his MD Anderson colleagues identified 1,424 Stage I and II breast cancer patients treated at the institution between 2005 and 2011. All underwent the 21-gene expression assay. In addition, the women were hormone receptor positive, HER2 and lymph node negative. None of the MD Anderson patients identified participated in the TAILORx trial. Barcenas and his colleagues used the same RS cutoff scores as the TAILORx trial. Of the MD Anderson patients, the RS distribution was: 297 (21 percent) scored 0 - 10; 894 (63 percent) scored 11-25; and 233 (16 percent) scored greater than 25. Of those groups, 1.7, 15 and 73.4 percent received chemotherapy, respectively. With a median follow-up of 58 months, those with a RS of 11-25 had an invasive disease-free survival (IDFS) rate at five years of 92.6 percent, regardless of whether patients received chemotherapy or not. Among those patients who did not receive chemotherapy, the estimated rates of IDFS and overall survival was 93 percent and 98 percent, respectively, which was comparable to those who did receive chemotherapy. The study has a number of limitations, said Barcenas. Due to a relatively short follow-up and the few number of outcome events, the researchers feel that the benefit of chemotherapy cannot be ruled out yet in this group of patients. While not practice changing, the findings do give Barcenas more information when discussing the benefits of chemotherapy in early-stage breast cancer patients, should their RS score be 11-25. "Our research is likely the most comprehensive data we will have about this patient population until the international randomized trial is published," said Barcenas. "Hopefully our findings will serve as a discussion point between physicians and patients as they are making critical decisions regarding a woman's breast cancer care." The study was funded by The MD Anderson Cancer Center Support Grant from the National Cancer Institute (grant CA016672), which supports the Biostatistics Shared Resource. In addition to Barcenas, authors on the all-MD Anderson study include: Akshara Singareeka Raghavendra, M.D., Arup K. Sinha, Masood P. Syed, M.D., Limin Hsu, Modesto G. Patangan, Jr., Debu Tripathy, M.D., chair, Naoto T. Ueno, M.D., Ph.D., Gabriel Hortobagyi, M.D., Vicente Valero, M.D., all of Breast Medical Oncology; Mariana Chavez-Mac Gregor, M.D., and Sharon Giordano, M.D., chair, both of Health Services Research: and Yu Shen, Ph.D. of Biostatistics.
News Article | February 22, 2017
HOUSTON--(BUSINESS WIRE)--Pharm-Olam International LLC, a multinational, full-service Clinical Research Organization (CRO) serving the biopharmaceutical and medical device industries, today announced the appointment of Julia Graz as Senior Director, Biostatistics. Ms. Graz adds over 25 years of progressive pharmaceutical industry experience to the Pharm-Olam team. Her interests and specialties are varied and well-tested. She has worked in biostatistics, programming, data management, pharmacokinetics and quality control. Her multidisciplinary experience spans dozens of pre-clinical and Phase I-IV clinical trials. “Biostatistics is a key component of our full-service offering,” said Sanjiv Suri, Chief Executive Officer, Pharm-Olam International. “That’s why Julia is such a great addition. Her record is enviable and formidable. I’m confident she’ll be successful in helping us further develop our strategy, create efficiencies, and expand our Biostatistics business unit.” Pharm-Olam operates in more than 60 countries worldwide, offering end-to-end clinical trial support for Phase I-IV clinical trials. More information about Pharm-Olam and its full-service capabilities and offerings are available at www.Pharm-Olam.com, or by request via email (firstname.lastname@example.org). Pharm-Olam International is a multinational Contract Research Organization (CRO) offering comprehensive clinical research services to the pharmaceutical, biotechnology and medical device industries. From Phase I to Phase IV, Pharm-Olam focuses on delivering the highest quality data, achieving targeted enrollment and meeting projected timelines, making clinical research as Easy As I, II, III, IV™. For more information about Pharm-Olam, visit www.Pharm-Olam.com.
News Article | February 19, 2017
Questions about health screenings -- Whether to screen? How often? At what age? At what cost? -- seem to readily breed conflicting opinions and public confusion. What's needed is rigorously produced evidence. That's where Constantine Gatsonis, chair of the Department of Biostatistics at Brown University, comes in. In a talk and panel discussion at the 2017 annual meeting of the American Association for the Advancement of Science on Sunday, Feb. 19, Gatsonis, a veteran researcher on many large cancer screening studies, will discuss how such trials are designed and conducted to ensure that researchers can evaluate not only the accuracy of a test, but also its cost-effectiveness, its effect on doctor and patient decision-making and its effect on health outcomes. After all, screening is not just about detection, Gatsonis said, but about health. Patients definitely want their cancers found, but not all accurate, positive diagnoses should lead to treatment. "There is a growing concern of this notion of over-diagnosis," he said. "Screening is finding small lesions that would not hurt you. Generally speaking with screening, especially as the modalities become more and more accurate and can see smaller and smaller things, the question is, is that good for you? It's not a foregone conclusion." In his talk, "Evaluating the Impact of Diagnostic Modalities Used in Screening for Disease," and the panel, "Medical Decision-Making: To Screen or Not to Screen?" in Room 309 of Hynes Convention Center at 8 a.m., Gatsonis will outline how large studies and statistical analysis bring data to bear on the many questions that swirl around screenings. Definitive screening trials feature huge sample sizes to ensure the highest degree of certainty when comparing one method against another. But even when the sample is large and the question is straightforward, the answers won't always be obvious. Gatsonis was the lead statistician of the Digital Mammographic Imaging Screening Trial, which sought to compare the accuracy of digital vs. film mammograms for detecting breast cancer in a sample of more than 49,000 women. The primary paper from that study was published in the New England Journal of Medicine in 2005. The two technologies turned out to have similar accuracy overall, but with a huge sample and carefully gathered data, the study was able to also show that digital mammography had significantly greater accuracy in women younger than 50 years, women with radiographically dense breasts, and premenopausal or perimenopausal women. The evidence of some clear advantages gave digital mammography a strong foothold, Gatsonis said: "That study is the study that essentially put digital mammography in every hospital." Well-structured, thoughtfully designed trials can answer multiple questions. Gatsonis was co-lead statistician for the National Lung Screening Trial, which produced the 2010 finding that among 53,454 current or former heavy smokers aged 55 to 74, those who received low-dose helical CT scans had a 20 percent lower risk of dying from lung cancer than participants who received chest X-rays. The study therefore answered the question of which screening method was better based on health outcomes. The trial also kept track of costs and so was able to assess that CT screening was cost-effective, at least given certain specific assumptions. The study also gathered the data needed to analyze another pertinent question that isn't always asked: Did false positives -- CT scans that inaccurately detected cancer -- trouble patients? An analysis led by Gatsonis's Brown colleague Ilana Gareen found that such results did not cause serious concern, at least in part because the study's informed consent procedures were clear about the possibility of the unduly dire-seeming result. Gatsonis is now leading the statistical side of a new breast cancer screening study, the Tomosynthesis Mammography Imaging Screening Trial, which will compare the 3D technology of tomosynthesis with standard, 2D digital mammography. Rather than just assessing accuracy, the trial, which is set to begin recruiting a whopping total of 165,000 U.S. and Canadian women between the ages of 45 and 74, will also focus on a specific clinical outcome that will be readily apparent within four and a half years from their entry into the study. At that point the research team will assess in which group -- tomosynthesis or digital mammography -- it was more frequent for a woman to be diagnosed with an advanced, aggressive cancer. The data will help to discern the health impact of each kind of screening, without the team having to wait until there was a sufficient number of breast cancer deaths to allow for a comparison based on mortality. "We're actually trying to bridge the span between accuracy and ultimate outcome," Gatsonis said, and "do so within a reasonably short study." In addition to using this innovative endpoint for the primary comparison, the trial is promoting a new approach to screening, which incorporates knowledge of breast cancer risk factors and tailors screening to these factors. For example, Gatsonis said, postmenopausal women will be screened annually or biennially depending on their risk profile. Big screening trials are expensive and logistically complicated. They generate massive amounts of data that must be expertly interpreted to accomplish their goals. But Gatsonis said that's all still better than the alternative of speculative opining. "Nobody said screening is a simple process," he said.
News Article | February 21, 2017
Pfizer Director of Biostatistics to deliver key presentation at the 9th Adaptive Designs in Clinical Trials conference in London.