Medical Device Daily

The FDA yesterday reported marketing clearance for a new genetic test used to determine the likelihood of breast cancer returning within five to 10 years after a women's initial cancer.

But the day when doctors can tell a patient, with exact confidence, that she does not need adjuvant therapy may still be in the distant future.

The MammaPrint test, developed by Agendia (Amsterdam, the Netherlands), uses the latest in molecular technology to predict whether existing cancer will metastasize (spread to other parts of a body). The test relies on microarray analysis, a powerful tool for studying, simultaneously, the patterns of behavior of large numbers of genes in biological specimens, the FDA said.

It is not the first such predictor to hit the U.S. market, but the FDA said it is the first cleared molecular test that profiles genetic activity.

The recurrence of cancer is partly dependent on the activation and suppression of certain genes in the tumor. Prognostic tests like the MammaPrint can measure the activity of these genes, and help physicians understand their patients' odds of the cancer spreading, the agency said.

Bernhard Sixt, PhD, Agendia's CEO, told Medical Device Daily that, for now, because the test is so complex, it will only be done in Agendia's lab in Amsterdam rather than sold to hospitals and physicians.

Sixt said the test could benefit future breast cancer patients by determining high or low risk for recurrence. But he said the test would not benefit women who have already had surgery to remove their cancer because the technology requires fresh tissue to work with.

Len Lichtenfeld, MD, deputy chief medical officer for the American Cancer Society (Atlanta) told MDD that while this type of test is an important first step in being able to reduce the number of breast cancer patients who unnecessarily receive adjuvant therapy after surgery, science is still a long way from being able to accurately predict which women are at greatest risk for cancer return.

Thus, he called the new test "a step in that direction, but it's only a first step."

MammaPrint has been on the market in the Netherlands since 2005.

"Clearance of the MammaPrint test marks a step forward in the initiative to bring molecular-based medicine into current practice," said Andrew von Eschenbach, FDA commissioner. "MammaPrint results will provide patients and physicians with more information about the prospects for the outcome of the disease. This information will support treatment decisions."

In developing the test, Agendia compared the genetic profiles of a large number of women suffering from breast cancer and identified a set of 70 genes whose activity confers information about the likelihood of tumor recurrence. The MammaPrint test measures the level of activity of each of these genes in a sample of a woman's surgically removed breast cancer tumor, then uses a specific algorithm formula to produce a score that determines whether the patient is deemed low risk or high risk for spread of the cancer to another site.

The result may help a doctor in planning appropriate follow-up for a patient when used with other clinical information and laboratory tests.

"The FDA's focus on the emerging field of molecular diagnostics underscores the growing importance of personalized medicine," Sixt said. "In Europe Agendia's service has already demonstrated its technical robustness and reliability, adding significant clinical value for physicians and breast cancer patients."

The MammaPrint is the first cleared in vitro diagnostic multivariate index assay (IVDMIA) device.

Several months ago, the FDA issued a draft guidance document concerning the need for these complex molecular tests to meet pre-market review and post-market device requirements, even when the tests are developed and used by a single laboratory. Although the FDA regulates diagnostic tests sold to laboratories, hospitals and physicians, it says it uses discretion when regulating tests developed and performed by single laboratories.

The FDA has scheduled a public meeting for Thursday to discuss its draft guidance document describing its regulatory approach to this type of test.

"There have been rapid advances in microarrays and other pioneering diagnostics, and a corresponding increase in the use and impact of these complex tests," said Steven Gutman, MD, director of In Vitro Diagnostic Device Evaluation for the agency. "This has prompted the FDA to take a closer look at the potential risks as well as the benefits associated with such tests when they are developed and used in laboratories. This test clearance takes into account the development of these innovative technologies and ensures public health by carefully evaluating their performance."

Prior to clearance, the FDA requested evidence that the MammaPrint had been properly validated for its intended use. Agendia submitted data from a study using tumor samples and clinical data from 302 patients at five European centers.

These studies confirmed that the test was useful in predicting time to distant metastasis in women under age 61 and in the two earliest stages of the disease and who have tumor size equal to or less than five cm and no evidence that the cancer has spread to nearby lymph nodes (lymph node negative).

The MammaPrint analysis cannot be performed on formalin-fixed paraffin-embedded tumor tissue because this fixation procedure causes the RNA to degrade, and the accuracy of the test depends on keeping the tumor RNA intact, the company noted.

The FDA said it plans to publish a special controls guidance document within the next 60 days describing types of data that should support claims for genetic profiling for breast cancer prognosis.

According to the American Cancer Society, an estimated 178,480 new cases of invasive breast cancer will be diagnosed among women in the U.S. in 2007, and more than 40,000 women are expected to die from the disease this year.