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Agendia Nets Highest Level Evidence for MammaPrint Use to Predict Breast Cancer Chemotherapy Benefit


NEW YORK (GenomeWeb) – Based on the results of a large, prospective, randomized trial, researchers have found that women with early-stage breast cancer can forgo chemotherapy after surgery if they are deemed low risk by Agendia’s 70-gene signature test MammaPrint.

The results of the so-called MINDACT (Microarray in Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy) trial suggest that among women who have early-stage disease and are high risk by clinical parameters, using MammaPrint could reduce the use of chemotherapy by half. The study, which involved researchers from more than 100 centers around the world, provides the highest level of evidence that MammaPrint is a clinically useful tool for predicting adjuvant chemotherapy benefit in breast cancer patients, according to Agendia.

Study leader Martine Piccart from the Jules Bordet Institute in Brussels presented data from the nearly 7,000-patient study at the American Association for Cancer Research annual meeting in New Orleans today, showing that nearly 95 percent of women who were classified as low risk by MammaPrint, but high risk according to the standard risk assessment tool Adjuvant! Online — and did not receive chemotherapy — survived for five years without their disease coming back. Importantly, patients in this same group who were randomized to receive adjuvant chemotherapy fared just as well, providing strong evidence that women who are low risk by MammaPrint can avoid chemotherapy without a negative impact on outcomes.

Once breast cancer progresses to an advanced stage, it is largely incurable. By giving early-stage breast cancer patients adjuvant chemotherapy, doctors hope to wipe out metastatic lesions that might have spread to other parts of the body but are too small to detect. There are downsides to this, including the risk of secondary cancers and leukemia, as well as congestive heart failure.

"[MINDACT] is now the first trial that shows in a randomized way that for the patients who are clinically high risk, it is really to their benefit to use MammaPrint to determine if they need or do not need chemotherapy," Laura van ’t Veer, inventor of MammaPrint and an investigator in the present study, told GenomeWeb. Based on this data, she said, many thousands of women in the US who are clinically high risk for recurrence could potentially avoid the toxicities of chemotherapy.


Agendia launched MammaPrint in Europe in 2004, but introduced it in the US market in 2007 after garnering 510(k) clearance from the US Food and Drug Administration, becoming the first complex genomic breast cancer recurrence test to achieve this. Although oncologists now increasingly use genomic tests, such as MammaPrint and Genomic Health’s Oncotype DX, to gain insights into whether early-stage breast cancer patients are likely to experience recurrence, the standard is Adjuvant! Online — an online tool that helps doctors assess the risks and benefits of giving patients chemotherapy after surgery based on clinical factors.

In MINDACT, researchers screened more than 11,000 women, and enrolled nearly 6,700 early-stage breast cancer patients, who all received testing with MammaPrint and were evaluated by Adjuvant! Online. Approximately 2,700 women who were deemed low risk by both tools received no chemotherapy, while around 1,800 women who were high risk by both measures received chemo. The five-year, distant metastasis-free survival in patients who were low risk by both MammaPrint and Adjuvant! Online was 98 percent, and for patients who were high risk by both tools, it was 90.6 percent.

Meanwhile, more than 2,100 patients had discordant results — 592 patient were considered high risk by MammaPrint and low risk by Adjuvant! Online; and 1,550 were low risk by MammaPrint and high risk by Adjuvant! Online. These patients were randomly assigned to receive adjuvant chemo or forgo it. Patients assigned to receive chemotherapy in the trial could receive adjuvant hormone therapy if they had hormone receptor-positive cancer, and could be randomized to two different types of endocrine therapy.

In the subset of patients who were high risk by the clinical assessment tool but low risk by MammaPrint, and went without chemo, Piccart and colleagues hypothesized that 92 percent would achieve five year, distant metastasis-free survival. At AACR, they reported that women fared even better in MINDACT, since 94.7 percent went for five years without distant metastasis.. Moreover, there was no clinically meaningful difference in the five-year survival of women in this group — low risk by MammaPrint but high risk by Adjuvant! Online — who were randomized to receive chemotherapy.

Ultimately, whether chemotherapy would improve  outcomes of patients in the discordant group is a difficult question to answer from MINDACT, since it wasn't powered to answer this question, Piccart said. "What I'm showing you here is an intent-to-treat analysis, which is most robust from a statistical point of view," she said during a press conference at AACR, which was webcast. She explained that while the statistical analysis suggests there could be a "very small" absolute benefit from the addition of chemotherapy, this benefit is so small that it "would not justify the risk of chemotherapy."

Practice changing data

The results of MINDACT, Piccart hopes, will go a long way in improving access to MammaPrint for women with early breast cancer in European countries, where many healthcare systems still don't reimburse gene expression testing. (In the UK, Oncotype DX is reimbursed for breast cancer patients who meet certain criteria.)

"This is the highest rigor evidence you can achieve, when you compare your diagnostic with standard assessment in the randomized way," Van 't Veer told GenomeWeb. Van 't Veer is Agendia's chief research officer and heads the Breast Oncology Program at the University of California, San Francisco.

The results from MINDACT provide level 1A clinical evidence that will enable guidelines bodies, such as the National Comprehensive Cancer Network, to update their recommendation to doctors regarding MammaPrint as a useful tool for predicting which early-stage breast cancer patients can do well without chemotherapy.

Agendia has previously published retrospective analyses on patients with 10-year outcome data, which had findings similar to MINDACT. Based on that, European guidelines bodies for a number of years have recommended MammaPrint as a tool that can be used to guide treatment decisions in early-stage breast cancer patients. But to date, expert groups in the US have held off for more definitive evidence.

"The NCCN hasn’t gone that far," said Van 't Veer. "They were awaiting this prospective randomized trial from MINDACT to make that decision."

The American Society of Clinical Oncology now recommends in its guidelines for women with early-stage invasive breast cancer and known hormone and HER2 receptor status that doctors use a number of biomarkers, as well as Oncotype DX, EndoPredict, PAM50, and Breast Cancer Index tests, but not MammaPrint, to determine which patients should receive adjuvant systemic therapy.

"Level 1A evidence hasn’t ever been achieved by other tests," Van 't Veer pointed out. Agendia has also performed economic modeling on MammaPrint’s use, and has published data showing the test is more cost effective than Adjuvant! Online and Oncotype DX.

The US market for genomic breast cancer recurrence testing has become competitive in recent years, although Genomic Health has maintained its leading position with Oncotype DX since launching the test in 2004. According to an estimate from Barclays last year, the company holds 90 percent market share in the invasive breast cancer space.

Genomic Health has historically marketed its test as the only one that can not only gauge disease recurrence in early-stage breast cancer patients but also predict whether they will benefit from adjuvant chemotherapy. Guidelines bodies in the US support the company's claims for the test, which analyzes the expression of 21 genes and provides a recurrence score between 0 and 100 (a score below 18 is low risk, 18 to 30 is intermediate risk, and 31 or over is high risk).

Genomic Health last year published some data from the prospective TAILORx study involving more than 10,000 women with hormone-receptor positive, HER2-negative, node-negative breast cancer. Five years after treatment, in approximately 1,600 women with the lowest recurrence risk — Oncotype DX scores between zero and 10 — 99.3 percent had no distant recurrence after receiving just hormonal therapy, even if they would have met clinical criteria to receive chemotherapy based on age, tumor size, and tumor grade. 

TAILORx was designed, however, to investigate the extent to which patients with an intermediate Oncotype DX score — defined in the study as those with scores between 11 and 25 — can safely do without chemotherapy, but these data aren’t yet available because patients in this category have done so well that there haven’t been enough recurrences. Still, for doctors, these data would provide definitive guidance as to how to treat patients that Oncotype DX has given intermediate risk scores, especially when other tests deem them high or low risk, as studies have shown (see stories here and here).

Van 't Veer emphasized that unlike TAILORx, MINDACT compares MammaPrint against Adjuvant! Online, and noted that this is essential for advancing the standard of care. "MINDACT was a courageous trial when we designed it," nearly a decade ago, "to really put a molecular diagnostic to the test [against] the clinical standard," she said.

MammaPrint's adoption has suffered from the fact that it was developed on frozen tissue material, which made it difficult to evaluate the test in paraffin-embedded biopsies collected in prospective studies. Although MammaPrint can now be performed on fixed-paraffin blocks, and will likely become more widely used in Europe and parts of Asia based on the MINDACT results, Piccart acknowledged that the US "is still a question mark," given Oncotype DX's hold on the market.

Nancy Davidson, director of the University of Pittsburgh Cancer Institute, said during the AACR press conference that colleagues at her institution use both Oncotype DX and MammaPrint, although the former is more frequently ordered. "But there are folks who are big fans of MammaPrint, and they are going to be very excited to see these major results from this trial," Davidson said.

Patients will be followed in MINDACT to gauge their 10-year survival without cancer recurrence, and even up to 15 years for the low-risk group. Van 't Veer noted it is remarkable that patients in the study were 90 percent compliant with their randomization assignment to be treated with or without chemotherapy. "That contributed to making the trial a success," she said.

Piccart highlighted that through MINDACT, researchers have built a biobank of patient samples with full gene expression data, beyond the 70 genes assessed by MammaPrint, which can fuel future research. Ultimately, MINDACT has demonstrated that "genomics can provide important information in order to treat patients with early breast cancer in a more optimal way," she said.