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UCL-AD, Sarah Cannon to Launch Cancer Panel on PGM to Select Therapy, Stratify Patients for Trials

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UCL-Advanced Diagnostics, diagnostic service provider of the University College London Cancer Institute, has opened a new molecular profiling laboratory that will offer a sequencing-based multi-gene test for cancer patients in the UK and elsewhere.

The London-based laboratory, set up by UCL-AD in partnership with the Sarah Cannon Research Institute, a US-based clinical trials organization, recently opened its doors and will start providing the new test to patients in about a month.

The test will help to select patients for existing targeted treatments, based on their tumor's mutations, but also to recruit patients for phase I clinical trials of drugs in development. "That will be a big driver," said Adrienne Flanagan, head of pathology at ULC.

Development of the test, which runs on the Life Technologies Ion Torrent PGM platform, started about a year and a half ago, according to Mike Gandy, who heads clinical and technical services at UCL-AD.

The greatest challenges, he said, have come from working with very small amounts of fragmented DNA – the scientists have tested samples with 1 nanogram of degraded DNA successfully – as well as setting up the necessary informatics and reporting infrastructure.

The lab is currently equipped with two Ion Torrent PGMs and one recently-added Ion Proton, enabling it to run at least 10,000 samples per year, about four times the number of targeted mutation tests it currently provides annually.

The first version of the panel, which addresses several common cancer types, includes 11 genes and focuses on hotspot mutations that can be targeted with existing drugs. Over the next six months or so, the panel will increase to 35 genes, including those that have been linked to approved therapies and others that could be used to place patients into clinical trials.

To prepare the genes for sequencing, the lab uses a patent-pending amplification-based method developed in-house by the team of Rifat Hamoudi, its lead molecular biologist and bioinformatician. The method works well for small formalin-fixed paraffin-embedded tissue biopsy samples, he said, and the scientists plan to publish more details about it later this year as part of a validation study of the test.

Sequencing on the PGM is done to 500x to 800x coverage, usually on the Ion 316 chip, which can fit about 40 samples per run.

The researchers chose the Ion Torrent PGM for their test because that platform allowed them to use their in-house developed library prep methods, work with small amounts of degraded FFPE samples, and because they liked the binary nature of the signal generated by semiconductor sequencing, Gandy said. They also believe the platform has a lot of potential for future development, increasing the output per run and improving mutation calling.

Gandy said issues with homopolymers, which others have reported as a concern for the PGM, have been resolved using their in-house software.

The team also built its own bioinformatics pipeline, including automated mutation calling, which is integrated with a system that generates a user-friendly report.

Physicians receive an electronic report that includes primary findings on actionable targets for which therapies are available and secondary findings in targets that could "open the door for clinical trials," Gandy said.

The lab has validated the test on a set of samples with known mutations that were previously analyzed by qPCR tests. It has shown "quite robust data" for the new test in that study, and a failure rate of less than 1 percent.

The turnaround time for the panel is five to seven days – the same as for existing targeted PCR assays – and its price will be similar to those tests as well.

The panel will be available to UCL-affiliated hospitals, other UK hospitals, and internationally. Gandy said the lab is in discussions with both public and private health insurance providers about coverage, adding that the UK's National Health Service currently reimburses for targeted genetic oncology tests.

For the first few months or so, the new test will run in parallel with existing PCR-based targeted mutation tests for EGFR, KRAS, and BRAF, but Gandy expects these will be phased out soon.

UCL-AD is not the first laboratory in the UK to develop a cancer panel: earlier this year, the Institute of Cancer Research said it is setting up a tumor profiling unit to analyze samples from cancer patients treated at The Royal Marsden, a hospital affiliated with the institute (CSN 2/20/2013).

What differentiates UCL-AD's gene panel from similar efforts by other groups is that it is embedded in an existing clinical diagnostics lab and compatible with the traditional pathology workflow, Gandy said. "We need to get this technology working on clinical samples, moving away from doing sequencing on frozen or fresh material, because that's the pathology workflow – it's formalin-fixed, paraffin-embedded material," he said, noting that FFPE samples are easier to send and safer to handle.

According to Flanagan, who is a consultant pathologist for UCL-AD, only a handful of approved targeted therapies are currently available, and the test will help select patients that will likely respond to these. For common tumors like breast cancer, the number of patients that could benefit from this is "quite large," she said.

"But I think the great benefit will be in clinical trials," she added, and the relationship with the Sarah Cannon Research Institute will help place patients into such trials.

New research results will help improve the gene panel further in the future, but studies based on the test results will also feed back into research, she said. For example, some patients may not respond to therapy, even though their tumors have a certain mutation. "They may have extra mutations, or there may be something that we just don't understand yet," she said.

"They really feed off one another, the research and the diagnostic panels."

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