BioEd Online

US regulators have approved a new diagnostic tool to help target treatment for breast cancer patients.

The test, called MammaPrint and produced by the Dutch company Agendia, uses the expression of 70 genes in tumour samples to help determine whether a woman with early-stage cancer is likely to suffer from a recurrence, and so whether she will benefit from chemotherapy or not. It was approved for use in some patients by the US Food and Drug Administration (FDA) on Tuesday.

The approval is a breakthrough for both patients, as it helps to fill a large gap in determining cancer prognosis, and for the FDA: it is the first test to be approved under a regulatory scheme that the agency is considering putting in place for all such genetic diagnostics.

Although chemotherapy reduces the chance of cancer recurrence for some breast cancer patients, an estimated 70-80% of patients who received the drugs would have never had a recurrence anyway, and so would have survived without them¹. Genetic tests can help identify these patients beforehand, saving them the discomfort of chemotherapy.

Another test already on the US market, called Oncotype DX, also helps to determine the necessity of chemotherapy in breast cancer patients. But this is only useful for classifying breast cancer tumours that can sense the hormone oestrogen — and nearly half of all breast cancers in premenopausal women are oestrogen-insensitive, notes Patricia Ganz, a breast cancer specialist at the University of California, Los Angeles. MammaPrint, which can be used for both types of tumour, should therefore fill an important niche, Ganz says.

MammaPrint has been available in Europe since 2004. Agendia charges roughly 2,500 euros (US$3,000) per test and claims to have conducted more than 5,000 tests so far.

Personalized approaches are important, especially when deciding how to treat cancer, says Richard Simon, chief of the Biometric Research Branch at the US National Cancer Institute's Division of Cancer Treatment and Diagnosis. "Most treatments only benefit a minority of the patients," says Simon. "And many of those treatments are also expensive, toxic, or inconvenient."

Gaining trust

The regulation of such complex genetic tests has been up in the air at the FDA, and the agency has yet to officially adopt guidelines for how to deal with them. They released a draft guidance plan for this last September, which was shaped in part using MammaPrint as a test case, says René Bernards, Agendia's chief scientific officer.

Although the FDA regulates medical diagnostics that are commonly used in laboratories and hospitals, complicated tests performed only by a single company have not previously required FDA approval. Instead the FDA monitors the labs in which such tests are conducted on a case-by-case basis, and does not require clinical data about the diagnostic itself.

Oncotype DX, produced by Genome Health of Redwood City, California, for example, has not been directly approved by the FDA. Instead, the FDA approved the lab.

This system does not reflect the fact that these tests could have an important impact on public health, says Steve Gutman, director of the Office of In Vitro Diagnostic Device Evaluation and Safety at the FDA. It is better, he says, to take the more rigorous approach of regulating the test itself, as done with MammaPrint. "To get the trust of the medical community, the FDA has to step in," says Bernards.

Not so simple

Although such tests help clinicians to personalize medicines, they also come with complications. Because they are based on the expression of many genes, they can be very difficult to interpret, for example.

"Whenever you do a clinical test, you really want a plus or minus answer and you want it to be clear," says Raphael Bueno, a thoracic surgeon and cancer researcher at Brigham and Women's Hospital in Boston, Massachusetts. Diagnostic companies must often devise proprietary algorithms to calculate the meaning of their results.

Some patients will still feel more secure choosing chemotherapy even if a test tells them it isn't best for them, says Ganz. "I think one of the problems is that we've oversold chemo in the United States," says Ganz. If MammaPrint classifies a patient into the low-risk category, that patient still has around a 10% chance that the cancer will resurface over the next ten years.

The test has been validated in 300 patients, and a larger randomized trial evaluating the predictive ability of MammaPrint in 6,000 patients is ongoing. Ganz hopes that the results of that study will clarify the benefits or risks of relying on the diagnosis.