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New Studies Validate Prognostic Value of Agendia’s MammaPrint in Breast Cancer

Agendia this week announced that newly released clinical findings support the use of its MammaPrint test in conjunction with other gene-expression assays to determine which patients’ breast cancer will recur and whether they should be treated with endocrine therapy or chemotherapy.
MammaPrint was the first in vitro diagnostic multivariate index assay to be cleared by the US Food and Drug Administration last year. The test measures the activity of 70 genes and is indicated to assess the likelihood of disease metastasis in breast cancer patients.
But now, researchers from the MD Anderson Cancer Center in Houston have presented results of a study in which they used multiple gene-expression assays, including MammaPrint, to analyze tumor samples from 198 patients with early stage, lymph-node negative breast cancer to learn if they can uncover data to predict both disease recurrence and treatment response from a single specimen.
In the study presented during the American Society of Clinical Oncology’s annual meeting in Chicago this week, Lajos Pusztai, associate professor of medicine at MD Anderson Cancer Center, and colleagues, used MammaPrint along with Affymetrix’s U133A gene chips to predict disease prognosis, and applied the Genomic Grade Index, a 200-gene endocrine sensitivity index, and a 207-gene clinical phenotype-specific chemotherapy response predictor.
Using these methods, MammaPrint results predicted that 32 percent, or 64 of the 198 patients, were at low risk for breast cancer recurrence; found that 31 percent of them would likely be highly sensitive to endocrine therapy; and claimed that 88 percent, or 56 of the 64 patients, would likely not respond to chemotherapy. More than 51 percent of the remaining 134 patients considered to be at high risk for cancer recurrence were predominantly predicted to be chemo-sensitive, Agendia said in a statement.
“These findings are exciting as they suggest that different predictive tests that evaluate the risk of recurrence and therapeutic response can be used conjunctively on a single tumor sample to help physicians gain a clearer picture of a patient’s treatment needs,” Pusztai said in a statement released by Agendia. “The information gained from multiple predictive tests can be used to help physicians make more personalized decisions related to patient management. 
“It may also be useful in helping identify additional areas for research, such as determining the best course of treatment for patients who are identified as being at high risk for breast cancer recurrence and also likely to not respond to certain treatments,” Pusztai added.
Researchers who participated in the study were employed by Agendia and owned stock in the company, according to an ASCO disclosure index.
The study also suggests that MammaPrint in conjunction with other predictive gene-expression assays can help determine the best course of treatment for early stage, node-negative breast cancer. A recent report released by an HHS advisory committee suggests that Agendia’s test is being used off-label for this purpose.

“Based on these data, Agendia does not plan to file for a label change with the FDA. However, the result of ongoing prospective studies may take us in that direction in [the] future.”

Mentioning two competing breast cancer recurrence tests — MammaPrint and Genomic Health’s Oncotype DX — the HHS Secretary’s Advisory Committee on Genetics, Health, and Society issued a report last month assessing the regulatory oversight of genetic tests and found that “some physicians use [breast cancer recurrence] tests to identify patients who will benefit from chemotherapy to avoid recurrence and overtreatment of patients who otherwise would not have a remission.
“Although physicians may use these tests to guide therapy, MammaPrint was not FDA-cleared for this intended use,” the committee states. “The studies provided to FDA to support MammaPrint’s intended use were not designed to identify women who would benefit from therapy.”
In an e-mail to Pharmacogenomics Reporter this week, Agendia CEO Bernard Sixt said that the company was not aware of any off-label use of MammaPrint.
“To our knowledge, physicians use MammaPrint results in concordance with the FDA statement on its website: ‘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,’” Sixt wrote in an e-mail.
Genomic Health’s Oncotype DX is currently the only marketed test designed to gauge both cancer recurrence and treatment benefit with tamoxifen. However, unlike MammaPrint, Oncotype DX is not FDA-cleared, but Genomic Health is currently in discussions with the agency about the regulatory status of its test.
To be sure, it would boost Agendia’s competitive edge if it could expand MammaPrint’s indication as a tool to assess treatment response. However, according to Sixt, while the study presented at ASCO “provide[s] further clinical evidence that indicate treatment effects and benefits for patients in the MammaPrint high-risk and low-risk groups … based on these data, Agendia does not plan to file for a label change with the FDA. 
“However, the result of ongoing prospective studies may take us in that direction in future,” Sixt added.
Dutch Discord
Separately, a second, prospective trial presented at ASCO looked at the clinical use of MammaPrint in 15 community hospitals in The Netherlands.  
The study, presented by Valesca Retel of the Netherlands Cancer Institute, found that of 427 MammaPrint gene profiles obtained from 812 patients with node-negative breast cancer, 30 percent of the results were discordant with the Dutch treatment guidelines. The study authors reported that in some instances, patients categorized as high risk for cancer recurrence using MammaPrint had been previously identified as low risk using the guidelines. In 54 percent of the discordant cases looked at in the study, the course of treatment was changed. 
“These studies demonstrate the clinical utility of MammaPrint in helping physicians make more informed decisions about the course of care for their patients with breast cancer,” Laura van ’t Veer, Head of Molecular Pathology at the Netherlands Cancer Institute in Amsterdam, said in a statement released by Agendia. Van ’t Veer was a researcher in both studies.
For the time being, Agendia will continue to differentiate MammaPrint from Oncotype DX by claiming Agendia’s product does not identify an intermediate group and is not treatment-dependent.
“The benefit of MammaPrint was and will remain that it gives clear results; there is no intermediate group,” Sixt said. “In addition, it has a broader indication as it is ER-independent and the results are not treatment-contaminated. 
“This means that physicians can freely decide if, and with which therapy, they want to reduce the risk of tumor recurrence,” Sixt continued. “Oncotype DX is labeled for ER positive patients, and is only valid if patients will comply to a five-year tamoxifen treatment regimen.”
However, Sixt cited a study published in JCO by Partridge et al. that found that after four years of therapy, compliance rates among patients decreased to 50 percent.
According to Genomic Health Director of Communications Emily Faucette, although Oncotype DX is not FDA-cleared, the test is fast becoming the standard of care in breast cancer diagnostics after showing the ability to predict response to chemotherapy in multiple clinical studies. It has also been recommended in ASCO and NCCN treatment guidelines and received a positive Blue Cross and Blue Shield Association technology assessment. 
“Multiple studies conducted by clinicians who use Oncotype DX in clinical practice prove the actionable nature of the test in its ability to change treatment decisions and, in many cases, help reduce unnecessary use of chemotherapy, lowering both adverse effects and cost for these patients, while increasing patient confidence in their treatment selection,” Faucette said.
The price of MammaPrint in the US is $4,200. Genomic Health’s Oncotype DX is $3,650.

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