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Gene-expression-based Biomarker Predicts Long-term Risk of Breast Cancer Recurrence

A comparison of three methods of predicting the risk of recurrence in women treated for estrogen-receptor (ER)-positive breast cancer finds that only the breast cancer index (BCI) – a biomarker based on the expression levels of seven tumor-specific genes – accurately identifies patients who continue to be at risk after five years of treatment with either tamoxifen or the aromatase inhibitor anastrozole. The study comparing the BCI with two other prognostic tests has been published online in Lancet Oncology.

Abcodia Licenses the ‘Risk of Ovarian Cancer Algorithm’ (ROCA) Developed at Massachusetts General Hospital and Queen Mary, University of London

Abcodia, the biomarker validation company with a focus on screening for cancer, today announced that it has entered into an agreement for an exclusive world-wide commercial license to the Risk of Ovarian Cancer Algorithm (ROCA) developed at Massachusetts General Hospital (MGH) and Queen Mary, University of London.

ROCA has the potential to be a major breakthrough for the early diagnosis of ovarian cancer. The diagnosis of ovarian cancer is usually made when the disease has spread outside the ovaries and as a result the outcome is poor. In the 80% of cases of ovarian cancer in which diagnosis occurs in the later stages, the 5-year survival rate is less than 20%. If diagnosed early, 5-year survival exceeds 85%. Hence the need for early diagnosis, in the hope that current treatments will be more effective. Around the world, an estimated 200,000 new cases of ovarian cancer are diagnosed in women each year and there are over 125,000 deaths.

ROCA is a test being validated for the screening of ovarian cancer. It was invented by Professor Ian Jacobs, Dean & Head School of Medicine, Faculty of Medical & Human Sciences, University of Manchester, and formerly of Queen Mary, University of London, and Dr Steven Skates of the Biostatistics Center, MGH, who together studied longitudinal patterns of CA125 in multiple cohorts of post-menopausal women to develop a statistical algorithm efficiently combining information in age and serial CA125 levels. ROCA has since shown excellent specificity, Positive Predictive Value (PPV) and sensitivity in large studies including UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) and UKFOCSS (UK Familial Ovarian Cancer Screening Study).

A recent study by the MD Anderson Cancer Center in normal risk postmenopausal women reported a specificity of 99.9% and a PPV of 40% for ROCA when ultrasound was used as a secondary test. This confirms, in a USA population, results previously reported by the larger UKCTOCS trial involving 202,000 normal risk postmenopausal women. The published results from UKCTOCS2 indicate that, as well as achieving high specificity and PPV, ROCA can achieve a sensitivity of 89% for screen detection of ovarian cancer. UKCTOCS is a randomised trial comparing screening with standard care, and in 2015 will provide results on the impact of screening with ROCA on mortality and survival from ovarian cancer. The final data from UKCTOCS will be of great importance in guiding future clinical use of the ROCA in clinical practice.

Commenting on the recent MD Anderson publication, Professor Ian Jacobs, also Director of the UKCTOCS trial, said: “I am delighted to see the outcome of the MD Anderson 11 year study. The results reassuringly confirm in a USA setting those reported from the UKCTOCS prevalence study published in 2009. We now await further data from UKCTOCS in 2015 to establish whether the encouraging specificity and sensitivity data translate into improvements in survival and mortality which through early detection can help women affected by ovarian cancer.”

Dr Julie Barnes, Abcodia’s CEO, said: “The licensing of ROCA is a significant opportunity for Abcodia and we now intend to work with the co-founders to actively plan a commercialisation path that will in due course enable ROCA to be made available to women in Europe, US and around the world. We are currently in active discussions with partners in different territories to support our mission. Based on the reports to date, and in particular the sensitivity, specificity and PPV data, we will begin to explore ways in which the ROCA could be implemented in clinical practice. The eventual clinical use will of course be informed and guided by the outcome of UKCTOCS and other clinical trials.”

Source: Abcodia

Biomarker Predicts Risk of Breast Cancer Recurrence After Tamoxifen Treatment

A biomarker reflecting expression levels of two genes in tumor tissue may be able to predict which women treated for estrogen-receptor (ER)-positive breast cancer should receive a second estrogen-blocking medication after completing tamoxifen treatment. In their report being published online in the Journal of the National Cancer Institute, Massachusetts General Hospital (MGH) Cancer Center investigators describe finding that the HOXB13/IL17BR ratio can indicate which women are at risk for cancer recurrence after tamoxifen and which are most likely to benefit from continuing treatment with the aromatase inhibitor letrozole (Femara).

“Most patients with early-stage, ER-positive breast cancer remain cancer-free after five years of tamoxifen treatment, but they remain at risk of recurrence for 15 years or longer after their initial treatment,” says Dennis Sgroi, MD, of the MGH Cancer Center and Department of Pathology, lead and corresponding author of the report. “Our biomarker identifies the subgroup of patients who continue to be at risk of recurrence after tamoxifen treatment and who will benefit from extended therapy with letrozole, which should allow many women to avoid unnecessary extended treatment.”

Previous research by Sgroi’s team, in collaboration with investigators from bioTheranostics Inc., discovered that the ratio between levels of expression of two genes – HOXB13 and IL17BR – in tumor tissue predicted the risk of recurrence of ER-positive, lymph-node-negative breast cancer, whether or not the patient was treated with tamoxifen. The current study of patients from MA.17, the highly successful clinical trial of letrozole, was designed to evaluate the usefulness of the HOXB13/IL17BR ratio for both prognosis – predicting which tamoxifen-treated remained patients at risk of recurrence – and for identifying who could benefit from continued treatment with letrozole.

To answer those questions the investigators analyzed primary tumor samples and patient data from the placebo-controlled MA.17 trial, which confirmed the ability of extended letrozole therapy to improve survival after the completion of tamoxifen treatment. Tissue samples were available from 83 patients whose tumors recurred during the study period – 31 who had received letrozole and 52 in the placebo group – and 166 patients with no recurrence, 91 of whom had received letrozole, with 75 getting the placebo. Analysis of the tumor samples revealed that a high HOXB13/IL17BR ratio – meaning the expression level of HOXB13 is greater than that of IL17BR – predicts an increased risk for tumor recurrence after tamoxifen therapy, but that elevated risk drops significantly if a patient receives letrozole

Paul E. Goss, MD, PhD, director of the Breast Cancer Research Program at the MGH Cancer Center and a co-author of the report, explains, “This discovery means that about 60 percent of women with the most common kind of breast cancer can be spared unnecessary treatment with the concommitant side effects and costs. But more importantly, the 40 percent of patients who are at risk of recurrence can now be identified as needing continued therapy with letrozole, and many will be spared death from breast cancer.” He and Sgroi note that their findings need to be validated by additional studies before they can be put into clinical practice.

Source: Massachusetts General Hospital

Third-generation Device Significantly Improves Capture of Circulating Tumor Cells

A new system for isolating rare circulating tumor cells (CTCs) – living solid tumor cells found at low levels in the bloodstream – shows significant improvement over previously developed devices and does not require prior identification of tumor-specific target molecules. Developed at the Massachusetts General Hospital (MGH) Center for Engineering in Medicine and the MGH Cancer Center, the device rapidly delivers a population of unlabeled tumor cells that can be analyzed with both standard clinical diagnostic cytopathology and advanced genetic and molecular technology. The MGH team’s report has been published in Science Translational Medicine.

“This new technology allows us to follow how cancer cells change through the process of metastasis,” says Mehmet Toner, PhD, director of the BioMicroElectroMechanical Systems Resource Center in the MGH Center for Engineering in Medicine, the paper’s senior author. “Cancer loses many of its tissue characteristics during metastasis, a process we have not understood well. Now for the first time we have the ability to discover how cancer evolves through analysis of single metastatic cells, which is a big step in the war against cancer.”

The new device – called the CTC-iChip – is the third microchip-based device for capturing CTCs developed at the MGH Center for Engineering in Medicine. The first two systems relied on prior knowledge of a tumor-specific surface marker in order to sort CTCs from whole blood and required significant adjustment for each different type of cancer. The systems also required four to five hours to process a single blood sample.

The only U.S. Food & Drug Administration-cleared, commercially available device for capturing and enumerating CTCs – the CELLSEARCH® system developed by Veridex, LLC – relies on magnetic nanoparticles that bind to the same epithelial protein used in the MGH -developed microchip-based devices and cannot always find CTCs present at very low numbers. In January 2011 the MGH entered into a collaborative agreement with Veridex and its affiliate Janssen Research & Development, LLC, to establish a center of excellence in research on CTC technologies.

Combining elements of both approaches – magnetic labeling of target cells and microfluidic sorting – the CTC-iChip works by putting a blood sample through three stages. The first removes from the sample, on the basis of cell size, all blood components except for CTCs and white blood cells. The second step uses a microfluidic process developed at the MGH to align the cells in a single file, allowing for extremely precise and rapid sorting. In the third stage, magnetically labeled target cells – either CTCs tagged via the epithelial marker or white blood cells tagged on known blood-cell antigens – are sorted out. Tagging white blood cells instead of CTCs leaves behind a population of unlabeled and unaltered tumor cells and doesn’t rely on the presence of the epithelial marker or other known tumor antigens on the cell surface.

The new system was able to process blood samples at the extremely rapid rate of 10 million cells per second, handling a tube of blood in less than an hour. Both the mode of sorting out tagged CTCs, called tumor-antigen-dependent, and the technique that depletes white blood cells, called tumor-antigen-independent, recovered more than 80 percent of tumor cells from different types of cancer that had been added to blood samples. Comparison of the antigen-dependent-mode CTC-iChip with existing commercial technology for processing blood samples from patients with prostate, breast, pancreatic, colorectal and lung cancer showed the CTC-iChip to be more sensitive at detecting low levels of CTCs.

In the antigen-independent mode, the CTC-iChip successfully identified CTCs from several types of cancers that had lost or never had the epithelial marker, including triple-negative breast cancer and melanoma. CTCs isolated through this mode were put through standard cytopathological analysis, which revealed structural similarities to the original tumor, and detailed molecular genotyping of CTCs from a single patient found significant differences in gene expression patterns among individual CTCs.

“We’re only beginning to identify potential applications of the ability to analyze how tumors mutate as they spread, but this should help improve our understanding of the fundamental genetic principles of metastasis,” says Toner, the Benedict Professor of Surgery at Harvard Medical School (HMS). “We hope to develop this technology to the point where it could be used for early diagnosis, which is the ‘Holy Grail’ that all of us working on CTC technology have been striving for.”

Ravi Kapur, PhD, of the Center for Engineering in Medicine, leader of the innovation team within the MGH Circulating Tumor Cell Center, says, “The CTC-iChip provides a first-in-class device for high-efficiency, high-speed tumor cell sorting from a clinically relevant blood volume. The chip is designed for mass manufacturing, and simple automation for clinical translation.” The team is working with collaborators at Veridex and Janssen to refine the system for commercial development.

Study co-author Daniel Haber, MD, PhD, director of the MGH Cancer Center and Isselbacher/Schwartz Professor of Oncology at HMS, adds, “The study of cancer metastasis has been limited by the inability to quickly and reliably isolate tumor cells in transit in the blood. This new approach is likely to be a game changer in the field.”

Study: Inertial Focusing for Tumor Antigen–Dependent and –Independent Sorting of Rare Circulating Tumor Cells

Source: EurekAlert!

Next-Generation Circulating Tumor Cell Test Demonstrates High Efficiency and Accuracy in New Study

Veridex, LLC (Veridex) recently announced that the first study of the company’s next-generation circulating tumor cell (CTC) technology, developed in collaboration with researchers at Massachusetts General Hospital (MGH), has been published in Science Translational Medicine. The collaboration, initially announced in January 2011, has led to the development of a next-generation CTC (or “liquid biopsy”) technology that offers enhanced specificity and sensitivity and enables more extensive characterization of captured cells.

The new technology tests for CTCs from the blood of cancer patients using advanced microfluidic separation techniques integrated with innovative magnetic sorting to isolate a broad spectrum of rare circulating cancer cells. This technology will allow physicians to get information about a patient’s cancer at the time treatment is being administered, one of the key components to enabling personalized medicine.

Results from the in vitro study showed the integrated system enabled the processing of large blood volumes with high throughput and efficiency, and also allowed for the ability to isolate CTCs from both epithelial and non-epithelial cancers.

In the study, the technology was used to identify the presence of CTCs in patients with cancers of the lung, prostate, pancreas, breast, as well as melanoma.

“Veridex is proud to have introduced CELLSEARCH®, the first and only FDA-cleared CTC test, and we’re excited to work with the team at Massachusetts General Hospital on our next-generation test,” said Nicholas C. Dracopoli , Ph.D., Vice President and Head of Oncology Biomarkers, Janssen Research & Development, LLC. “Together, Veridex and the MGH team bring more than 25 years of experience in rare cell technology to this project. We’re encouraged by the positive results from this study and the potential role this technology may play in helping to advance physicians’ ability to monitor their patients and develop more personalized treatment approaches.”

“These results show the possibility of its use for patients in ‘real time’ as they are receiving treatment. We hope that this next-generation CTC technology will become an everyday tool for doctors treating patients with cancer,” said Mehmet Toner , Ph.D., director of the BioMicroElectroMechanical Systems Resource Center in the Massachusetts General Hospital.

How It Works

The system used two modes of immunomagnetic sorting to isolate CTCs: a positive selection mode to identify and tag target CTCs based on expression of the epithelial surface marker EpCAM (“epithelial cell adhesion molecule”), and a negative selection mode, in which the blood sample is depleted of leukocytes by tagging them with specific antibodies. The test’s ability to isolate CTCs in this manner allows for RNA-based, single cell molecular characterization and expression analysis of CTCs. It will also allow for the test to be used in a broader range of cancers, including cells undergoing epithelial-mesenchymal transition (EMT) and cancer stem cells.

The technology integrates three sequential processes in a single automated system to capture clinically significant CTCs. First, after whole blood samples have been labeled with magnetic beads, the system separates nucleated cells, including CTCs and white blood cells, from red blood cells and platelets with minimal cell loss. Next, the system aligns nucleated cells in a single file within a sorting channel. Finally, the magnetically tagged cells are deflected into a collection channel for identification. These three integrated functions replace the need for separate cell lysis (break down), centrifugation and sorting steps.

About Circulating Tumor Cells

Circulating tumor cells are cancer cells that have detached from the tumor and are found at extremely low levels in the bloodstream. The value of capturing and counting CTCs is evolving as more research data is gathered about the utility of these markers in monitoring disease progression and potentially guiding personalized cancer therapy.

Study: Inertial Focusing for Tumor Antigen–Dependent and –Independent Sorting of Rare Circulating Tumor Cells

Source: PR Newswire