Friday, April 16, 2010

Foundation Medicine: a new genomic approach to cancer diagnosis

[Reposted from Times Online]


On June 25, 2000, Bill Clinton welcomed Francis Collins and Craig Venter to the White House to announce the completion of the first draft of the human genome. Ten years on, scientists have taken many important steps towards understanding what this sequence means for human health, yet most of the medical benefits still lie in the future. Except, that is, in one important disease. Cancer.

Cancer is at root a disease of the genes, caused when mutations trigger uncontrolled cell division. Understanding the genome is thus a highly valuable weapon against tumours, as a knowledge of the molecular defects that drive them can allow doctors to attack them with targeted therapies. In the past decade, several of these smart drugs have hit the market, often transforming the prognosis for patients.

Imatinib (Glivec or Gleevec), for instance, has turned chronic myeloid leukaemia into a controllable disease. Patients with colon cancer can benefit from cetuximab (Erbitux) only if their tumours do not carry a mutation in a gene called KRAS. Trastuzumab (Herceptin) is often highly effective against breast cancers with a HER2 mutation, while gefitinib (Iressa) and erlotinib (Tarceva) work against lung tumours with an EGFR mutation. And most recently,an experimental drug called PLX4032 has had hugely promising results against melanomas with a particular mutation of the BRAF gene, offering hope for treatment of a cancer with a terrible prognosis.

The move towards such targeted therapies is certain to be a dominant theme of oncology over the next decade. But if they are truly to transform patient care, they need to be accompanied by simple diagnostics -- the tests that identify the genetic subtype of a patient's tumour, so that doctors can choose the appropriate therapy. As Sir John Bell has pointed out, access to such tests is currently patchy, particularly on the NHS.

That is where an exciting new company may soon come in. Foundation Medicine, based in Boston, has today announced it has raised $25 million in funding to develop a one-stop-shop service for genomic diagnosis of cancer. It is going to be a while before it has a product to offer doctors -- its executives are currently engaged in a "listening tour" while they develop their services. But its idea is one that has great potential to help patients to benefit from advances in genomic science.

Foundation is advised by several luminaries in this field, including Eric Lander, director of the Broad Institute, a pioneer of the Human Genome Project, and an adviser to President Obama. Other consultants include Levi Garraway, Matthew Meyerson and Todd Golub, of the Dana Farber Cancer Institute and Harvard Medical School.

Its goal is to broaden significantly the scope of genomic cancer diagnosis, so that samples of each patient's tumours can be analysed not just for one or two genes that might be salient to their treatment, as can happen at present, but for dozens.

A few leading-edge cancer centres, such as Dana Farber and Massachusetts General Hospital (which I visited recently), are starting to do this sort of testing already. Foundation, though, will offer an outsourced service that is suitable for any hospital, to widen access to such diagnosis to patients being treated at ordinary centres that lack the facilities or expertise to do such tests themselves.

Alexis Borisy, Foundation's chief executive, described the idea to me as follows:

"The vision that motivates us at Foundation is that we believe more and more cancer patients are going to benefit from an understanding of the core molecular aberrations that are driving their specific tumours. The technology has moved to a point where it's feasible to decipher those in an individual, patient-specific manner, and to do that in day-to-day oncology practice.

"Our aim is to make that technology available to oncologists, to have an off-the-shelf service for oncologists that they can have complete confidence in."

Dr Meyerson told me:

"Through Foundation Medicine, we’re going to make genomic testing available to all cancer patients. It will, if you like, democratise access to this sort of thing. That is our goal. My hope is we will be doing comprehensive testing on every patient’s cancer."

The notion of testing tumours for multiple mutations is important because of the pace at which scientists are unravelling cancer genomics. It is already emerging that some mutations that are common in one cancer type, such as BRAF in melanoma, also occur at lower frequencies in others -- in this case, in lung cancer. That means that a BRAF inhibitor, though designed for melanoma patients, might also work against lung cancers with the same mutation.

The problem is that while testing lung tumours for EGFR mutations alone makes sense, as that gene is commonly defective in that cancer type, it is not cost-effective to perform the BRAF test in isolation to catch perhaps 1 per cent of patients who might carry it. A reasonably-priced "multiplex text" that covers dozens of genes, however, could be applied to every tumour to provide useful diagnostic clues.

As Borisy put it:

"Some mutations might have been validated in one type of tumour, but could also be relevant and actionable in other settings. In the next couple of years, literally tens of thousands of cancer genomes are going to be analysed. We're going to discover actionable genes that are present in maybe 1 per cent, 0.5 per cent of tumours. At this low frequency, we won't be able to find these by testing one aberration at a time."

Many more rare mutations of this sort are going to emerge as projects like the International Cancer Genome Consortium examine the genomic architecture of cancer over the coming years. Standardized tests that look at dozens, hundreds even, of mutations are going to be necessary if we're to make full clinical use of these insights -- and services like Foundation's are likely to make those accessible.
There's another issue here: gene patenting. As I wrote when a US court last month struck down Myriad Genetics' patent on the breast cancer risk genes BRCA1 and BRCA2, broad patent rights over genes have the power to severely restrict multiplex testing of the type Foundation intends to offer. It just isn't practical to pay royalties to dozens of different patent holders over dozens of different mutations for which you might test.

Posted by Mark Henderson on April 15, 2010 in Cancer , Genetics |

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