Warfarin Dosage Requirements Affected by Common Genetic Variant in African–Americans
A new study in The Lancet has reported that the therapeutic dose of the blood thinner warfarin is affected by a commonly found genetic variant in African–Americans.
A lower dose of warfarin was needed to produce therapeutic effects in those of African ancestry who carried the rs12777823 variant when compared with those without this polymorphism.
Lead researcher Julie Johnson from the University of Florida (FL, USA) said, “Adding this genetic marker – found in more that 40% of African–American patients in the study – to standard dosing algorithms improved the predictability of warfarin dosing by 21% in these individuals, which has the potential to increase the safety and effectiveness of this notoriously hard to dose drug.”
The blood-thinning agent warfarin is used in the prevention of blood clots in individuals who have undergone major surgery, those who are affected by atrial fibrillation and those with a history of clotting. In 2011, there were 13 million prescriptions for warfarin, which is one of the most prescribed drugs around the world.
It is difficult to get the dosage of the drug correct as requirements vary widely between people. In addition, of the hospitalizations for adverse drug reactions in those over 65 years of age in the USA, a third of these were related to warfarin.
It has been elucidated by previous studies that the genes VKORC1 and CYP2CP are responsible for approximately 30% of the variation in warfarin response in those with Asian and European ancestry. Use of these genetic markers, however, is less able to predict dosing regimens in African–Americans.
The investigators of this study identified 533 African–American adults on stable doses of warfarin from the International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (AL, USA) and looked at health information and DNA samples. From this information they isolated additional genes that affect dosage requirements of warfarin in African–Americans.
The strongest signals between genetic variations and warfarin dose were observed around the previously identified VKORC1 gene and a significant association was also found between a variant on chromosome 10, named rs12777823, and warfarin dose. An independent cohort of 432 additional African–American patients was used to verify the results.
It was suggested by this study that a dose of 7–9 mg less than in standard patients was needed in African–Americans carrying one or two copies of this gene.
Mark Alberts from UTSW Medical Center in Texas, USA, stated that, “Use of genetic background to help guide warfarin dosing has been advocated for several years by the US FDA. However, the practical aspects (and limitations) have not been fully appreciated. Genetic testing has several challenges: it is not widely available in some areas; it is costly; and clinicians often can identify the correct dose before test results are available. If these problems were corrected, the actual use of such tests might increase substantially.”
Source: Perera MA, Cavallari LH, Limdi NA. Genetic variants associated with warfarin dose in African–American individuals: a genome-wide association study. Lancet doi:10.1016/S0140-6736(13)60681-9 (2013) (Epub ahead of print).
Abnormalities in HER2 Gene Found in a Wide Variety of Advanced Cancers
Overactivity of the HER2 growth factor gene is known to be involved in breast and gastroesophageal cancers. However, new research has linked 14 different advanced solid tumors with variations in the gene‘s expression, including mutations and amplifications.
The study of more than 2000 tumors, which was presented at the American Society of Clinial Oncology (ASCO) Annual Meeting 2013, was a surprise to researchers and offers the possibility that the three clinically available anti-HER2 therapies could be used against these tumors.
Massimo Cristofanilli, Professor of Medical Oncology and Director of the Jefferson Breast Center at the Kimmel Cancer Center (PA, USA) and Thomas Jefferson University Hospital (PA, USA) said, “No one ever thought that there would be such a variety of genomic alterations in HER2 in this many solid tumors.”
“But this may be good news, both clinically and scientifically,” he said. “It tells us that these tumors might benefit from treatment that we already have on hand, and, from a research perspective, it builds on the idea that it is the genomic profile of a tumor that is relevant in providing biological information for planning personalized treatments – not where the cancer is located or where it develops.”
Foundation Medicine, a cancer diagnostics company in Cambridge (MA, USA) led and paid for the study, which involved Cristofanilli and a group of coauthors from many institutions who donated tumor samples.
Approximately 50 tumor samples for the analysis were donated by Cristofanilli. A HER2 mutation was found in one of these tumor samples from a patient with triple negative breast cancer. Cristofanilli said, “My patient was treated with Herceptin® as well as chemotherapy, and derived clinical benefit. No one looks for HER2 mutations in this form of breast cancer. To me, this makes the case for the value of genome-driven therapy.”
A total of 2223 tumor samples were analyzed by Foundation Medicine, which involved a genetic screen of over 182 genes and 14 genetic rearrangements that have been associated with cancer. The samples included 20 different advanced solid cancers.
HER2 variations were observed in 14 types of solid tumors, including 29% of esophageal, 20% of uterine, 14% of breast, 12% or stomach and 6% of lung cancer samples.
It was also found that the HER2 alterations showed wide variation. A total of 116 different irregularities were found in 4.9% of specimens. Amplifications were seen in 58%, substitutions in 25%, indels in 14%, splice site variants in 2%, translocations in 2%, multiple alterations in 5% and two tumors were found to have both a substitution and amplification.
Anti-HER2 therapies such as Herceptin could also be used to block HER2 that is affected in the ways observed in the study as it can also treat HER2 mutations.
“This study highlights the need to study a broad range of genes at a high level of sensitivity and specificity when searching for novel targets of therapy. Widespread use of this approach could provide more treatment options and enable more rapid accrual to ongoing and planned trials of agents targeting pathways under study.”
Source: Medical News Today: www.medicalnewstoday.com/articles/261362.php
Light Shed on Markers of Drug Resistance in Head and Neck Cancers
Research revealing biomarkers that could potentially be used to guide treatment for head and neck cancer by identifying patients whose tumors are unlikely to respond to treatment with the monoclonal antibody cetuximab has been presented at the 49th annual meeting of American Society of Clinial Oncology (ASCO) by scientists from the Fox Chase Cancer Center (PA, USA). This drug was approved by the US FDA in 2006 when combined with radiotherapy or as a second-line treatment after chemotherapy had failed.
“Targeted therapies should optimally be used in patients who are selected for sensitivity or the absence of sensitivity and we‘ve been handicapped by not knowing the resistance in head and neck cancers”, said Barbara Burtness, chief of head and neck medical oncology at Fox Chase and chair of the Eastern Cooperative Oncology Group (ECOG), as a team of researchers who organize and carry out clinical trials funded by the National Cancer Institute.
Burtness states that prior to the development of cetuximb, conventional platinum-based chemotherapy and radiation were the only treatments available to head and neck cancer patients. However, patients do not show the same responses to treatment, as tumors in different patients show different biologies. As a consequence of this, some patients are exposed to the side effects of the drug without showing any clinical benefit. In order to match treatments to tumors, biomarkers can be utilized and may also help resensitize tumors to treatment with cetuximab.
The biology of cetuximab-resistant and nonresistant tumors is being studied by Burtness and her colleagues from the ECOG head and neck committee with the aim of finding molecular signatures that highlight whether a particular cancer will respond to the drug. Two potential biomarkers have been elucidated.
In cancerous cells, cetuximab targets the EGFR, which sends signals throughout the cell when activated using various pathways. It was hypothesized by Burtness and her coworkers that cetuximab resistance may be mediated by abnormalities in one of these pathways. Their search for molecules related to the pathways uncovered the protein PTEN and the gene PIK3CA. They predicted that the likelihood of being unresponsive to cetuximab may be increased in cells that do not express PTEN, or which have mutations in PIK3CA.
Tumor samples from a small randomized Phase III trial of head and neck cancer comparing chemotherapy with cetuximab and chemotherapy alone were used to test the biomarkers. Improved responses were seen in patients with metastatic/recurrent head and neck cancer when cetuximab was added to chemotherapy. A significant survival benefit in patients treated with cetuximab was seen in a subsequent larger study (EXTREME). In these studies, patients who were most likely to respond to the drug were not identified.
Burtness first developed methods to analyze if a test sample carried the mutation or lacked PTEN using tumor samples from Fox Chase Cancer Center. The samples were then tested for PTEN and, of the 67, 23 (34%) were found to not express the protein. Samples were also analyzed for the PIK3CA mutation, and mutations were seen in two samples (4%). When samples that either did not express PTEN or that had the PIK3CA mutation were grouped together, no significant difference in overall survival or progression-free survival was seen when compared with the rest of the sample population.
The study does however suggest that cetuximab increased progession-free survival and overall survival each by a month in patients who expressed PTEN and lacked the PIK3CA mutation, compared with patients lacking these two markers.
Burtness said that these results are promising, but they are still early. “It‘s a small sample, and clearly more work need to be done on larger sample sets. But we do think that this combination biomarker – the signature of PTEN loss and/or PIK3CA mutation – might point the way to those patients who are resistant to cetuximab”.
A better understanding of the biology of tumors that do not respond to treatment with cetuximab could be provided by a critical biomarker, as the information could indicate the use of other new or existing treatments to resensitize a tumor to cetuximab.
“If you find a molecule that can be targeted that seems to produce resistance, it would make sense to look at cetuximab in combination with something that turns off the abnormality in the chemical pathway,” said Burtness.
Source: Medical News Today: www.medicalnewstoday.com/releases/261294.php
Existing Compounds could be Used to Target Solid Tumors With Genetic Changes
Research from Fox Chase Cancer Center (PA, USA) presented at the 49th annual meeting of American Society of Clinial Oncology (ASCO) suggests that currently available compounds could be used to target genetic mutations in nearly two-thirds of solid tumors. This could lead to the possibility that doctors will sequence tumors before deciding on which treatment to use.
“Extending sequencing of a patient‘s tumor is not something that‘s routinely done now” explains Patrick Boland, a hematology/oncology fellow at Fox Chase Cancer Center and author of the study. “Our ultimate hope is that, if we determine testing is worthwhile, it becomes routine for a doctor to send off a tumor sample to look for mutations before deciding on a course of treatment.”
Doctors do already check for a limited number of mutations in some cancers, for example lung cancer. However, treatment for a only a small number of patients is guided as a result of mutations found with this focused testing. It is probable that most tumors have many mutations and that drugs already available or in development could be used to target these.
In this study genetic profiling to identify nearly 200 mutations associated with cancer was carried out on 77 patients with solid tumors, mainly inflammatory breast cancer and colon cancer. The results of DNA sequencing were studied to establish the effects of testing and the potential impact this may have on patient care.
One mutation or more was found in 96% of patients. At least one mutation that could be targeted by a drug that is currently available or in development was found in nearly two-thirds of patients. These ‘actionable‘ mutations were often amplifications, where multiple copies of a single gene are present, which increases its effects on the body.
It was, however, pointed out by Boland that in many cases, although these genetic alterations are present, it is difficult to elucidate which, if any, are driving the cancers. “Even if we find a [change], we don‘t know if it‘s something that‘s driving the tumor to grow, or something that just happened along the way.” The fact that more research to understand the basic biology of tumors is needed is highlighted by this study Boland said. “We need our colleagues in the basic sciences to continue investigating the underpinnings of cancer, so we can determine which mutations are most important to target.”
However, the list price of the sequencing test from Foundation Medicine used in this study is nearly US$6000, which is a major limiting factor in the sequencing of tumors. Boland said, “We hope that, once sequencing tumors becomes the standard of care, it will be routinely covered by insurance.”
Genetic sequencing is, however, becoming more affordable, notes Boland. When analysis of tumor DNA can be carried out more readily, doctors will be able to use this information to target treatment to particular mutations with benefits for patients. It may become standard practice for sequencing of tumors to occur before a doctor decides how to treat them. “The expectation is that, sometime soon, these kinds of tests will be done on a routine basis,” predicts Boland. He added, “We‘re not there yet.”
Source: Medical News Today: www.medicalnewstoday.com/releases/261294.php
– All stories written by Sarah Jones