46-gene Test Can Predict Cancer Treatment Response
Mon, 03/25/2013 - 11:39am
The first multi-gene test that can help predict cancer patients' responses to treatment using the latest DNA sequencing techniques has been launched in the NHS, thanks to a partnership between scientists at the University of Oxford and Oxford University Hospitals NHS Trust.
The test detects mutations across 46 genes in cancer cells, mutations which may be driving the growth of the cancer in patients with solid tumors. The presence of a mutation in a gene can potentially determine which treatment a patient should receive.
The researchers said the number of genes tested marks a step change in introducing next-generation DNA sequencing technology into the NHS, and heralds the arrival of genomic medicine with whole genome sequencing of patients just around the corner.
The new £300 test could save significantly more in drug costs by getting patients on to the right treatments straightaway, reducing harm from side effects as well as the time lost before arriving at an effective treatment.
The many-gene sequencing test has been launched through the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), a collaboration between Oxford University Hospitals NHS Trust and Oxford University.
The BRC Molecular Diagnostics Centre carries out the test. The lab, based at Oxford University Hospitals, covers all cancer patients in the Thames Valley area. But the scientists are looking to scale this up into a truly national NHS service through the course of this year.
"We are the first to introduce a multi-gene diagnostic test for tumor profiling on the NHS using the latest DNA sequencing technology," said Dr. Jenny Taylor of the Wellcome Trust Centre for Human Genetics at Oxford University, who is program director for Genomic Medicine at the NIHR Oxford BRC and was involved in the work. "It's a significant step change in the way we do things. This new 46-gene test moves us away from conventional methods for sequencing of single genes, and marks a huge step towards more comprehensive genome sequencing in both infrastructure and in handling the data produced."
Dr. Anna Schuh, who heads the BRC Molecular Diagnostics Centre and is a consultant haematologist at Oxford University Hospitals, added: "Patients like the idea of a test that can predict and say up front whether they will respond to an otherwise toxic treatment. What the patient sees is no different from present. A biopsy is taken from the patient's tumor for genetic testing with a consultant talking through the results a few days later. It is part of the normal diagnostic process."
Getting on the right treatment
Cancer is often described as a genetic disease, since the transition a cell goes through in becoming cancerous tends to be driven by changes to the cell's DNA. And increasingly, new cancer drugs depend on knowing whether a mutation in a single gene is present in a patient's cancer cells.
For example, a lung cancer patient may have a biopsy taken to check for changes in the EGFR gene. If there is a mutation, the patient may then be treated with a drug that works as an EGFR inhibitor. If there is no mutation, such drugs won't work and the patient would get a different drug that would be more effective for them. Knowing the presence or absence of mutations in a certain gene can choose the treatment path for that patient.
The NHS can currently test for mutations in 2 or 3 genes – genes called BRAF, EGFR or KRAS– using older sequencing technology that has been around for decades. Efforts are being made to look at increasing the number of cancer genes sequenced to nine as standard.
The Oxford scientists are the first to make such multi-gene tests possible in the NHS using the latest DNA sequencing techniques. The NHS service they have launched looks for mutations in 46 genes, and they are now working towards verifying the use of a test involving 150 genes.
The team estimates they may have used the 46 gene test with a few hundred patients since November. The Cancer and Haematology Centre at the Churchill hospital in Oxford sees perhaps 8,000 new cancer patients a year. So while this isn’t yet an automatic service for every cancer patient that comes through the door, it is ramping up quickly for many groups of patients.
There is definite clinical benefit in screening some of the 46 genes included in the test; there is probable or likely benefit in screening some of the others; mutations in further genes might be important in some cancers but not others; while with the other genes, we don’t know as yet. But having this information means researchers can investigate whether a mutation has biological significance.
Accessing clinical trials
As well as detecting mutations in the 9 or 10 genes that are already "actionable"– mutations that may help determine the course of treatment for some patients with some cancers– the 46 gene test can help in directing patients to clinical trials of new molecular therapies which depend on knowing the genetic profile of the cancer.
Jack Taylor, 71, a retired management consultant from Milton Keynes, is taking part in one of a number of such clinical trials run by the University of Oxford.
He was diagnosed with a malignant melanoma on his chin in summer 2012, which was then surgically removed. It became clear that the cancer had spread to other parts of his body and a biopsy of the cancer was tested to look for mutations in the BRAF gene.
Around half of melanomas show mutations in the BRAF gene, and patients can be put on BRAF inhibitor drugs. But Jack's cancer doesn't, and he wouldn't benefit from the drugs.
But knowing his melanoma doesn't have any mutations in the BRAF gene, last month he was able to join a clinical trial led by Professor Mark Middleton in the Department of Oncology at the University of Oxford.
The PACMEL study is a phase II trial for those whose melanomas show no mutations in the BRAF gene. It is testing whether a new drug called Trametinib, in combination with chemotherapy using Taxol, offers a better prognosis with melanoma that has spread to other parts of the body.
It's too early to say whether Trametinib may have any effect on cancer progression. Jack said, "My prognosis back in August was 6 to 9 months."
He said he feels similar now: "It doesn't feel like I just have months left. Nobody can tell. Hopefully [the trial] will do something for me. If it is successful, then it has been done on me rather than waiting for someone else to do the trial. I was very happy to go into the trial. Let's go for it."
There have been side-effects of the treatment. Jack feels constantly tired, and has experienced a severe rash on his face which is painful and he is receiving treatment for it.
Jack misses playing golf three times a week and going to the gym three times a week. "I was very, very active," he said. "That's the thing I regret most. That's not the trial, the treatment. It's the cancer.
I'm hoping that once the rash clears up and I've got some energy back I'll get out on the golf course to at least play 10 holes if not 18," he said.
Changing cancer medicine
Having a diagnostic test or 'panel that can screen for mutations in multiple genes at once will be important for access to all the new cancer drugs that are coming along.
"It will be very difficult to manage in NHS diagnostic labs without gene panels," explained Schuh. "Currently, new cancer drugs tend to get approved alongside a diagnostic test specific to that drug which can determine which patients will benefit. But as more and more drugs like this come along, we can't possibly run all the many different separate tests this could mean. We need one test for a range of drugs."
Taylor added: "We wanted a test that would use the latest DNA sequencing techniques to detect a wide range of mutations in a wide range of genes. A test that would be able to cover more cancers and more treatments, all for a similar cost to conventional methods."
The test is run on a next generation sequencing platform from Life Technologies Corporation. The test and accompanying software have been substantially modified as requested by the Oxford team to fulfil diagnostic standards in their lab.
This work was co-funded by the Technology Strategy Board, the UK's innovation agency, through a grant to the NIHR Oxford BRC, Life Technologies Corporation, AstraZeneca, and Janssen Research & Development, LLC, one of the Janssen Pharmaceutical Companies.
As part of the test development, the Oxford team looked to improve the initial sample preparation in the lab, and to provide the software and infrastructure support to handle and analyse the amount of information involved. Most importantly, the Oxford group has carried out tests and comparisons to verify the robustness of the technique with cancer biopsies direct from patients.
The team compared the new 46 gene test against conventional techniques for 80 consecutive cancer biopsies in the hospital lab's workflow. The next-generation DNA sequencing method detected all the mutations the conventional method did; it detected new mutations the conventional method didn't; and detected mutations present at much lower levels in the samples. The time taken for the 46 gene test also fitted into the standard turnaround time for samples at the lab.
Schuh said: "Panel tests have significant potential while we wait for the cost of sequencing whole patient genomes to come down. Even then, panel tests may be with us for some time. After whole genome sequencing does come into use, it may be that panel tests are used first with patients’ biopsies, with only those whose panel test shows no result having their entire DNA sequenced to look for rarer genetic changes."
Lord Howe, Health Minister in the UK Department of Health, commented: "We want to be among the best countries in the world at treating cancer and know that better tailored care for patients could potentially save lives. Health research like this is incredibly important and I'm delighted we could support the work of researchers in Oxford through the National Institute for Health Research Biomedical Research Centre. By rapidly translating findings from genetics research into real benefits for patients, their work will make sure that patients get the right treatments straight away, reduce potential side effects and also help us use NHS funds more effectively."
Source: University of Oxford