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After Moving MammaPrint to FFPE Format, Agendia Sees Revenue Boost, Increasing Adoption


Migrating its testing platform from analyzing fresh-tissue samples to formalin-fixed paraffin-embedded biopsies has bolstered sales of Agendia's MammaPrint breast cancer recurrence test, according to company officials.

For the first quarter of this year, test sales grew by 93 percent year over year, Agendia CEO David Macdonald told PGx Reporter earlier this month.

MammaPrint, the lead product in the privately held company's pipeline, received clearance from the US Food and Drug Administration in 2007 as a prognostic assay that analyzes the expression of 70 genes and helps doctors discern whether their patients' breast cancer will recur within five to 10 years.

MammaPrint, which operates on an Agilent microarray-based platform, initially analyzed fresh tissue samples. However, starting in January, Agendia began accepting FFPE samples for MammaPrint and other breast cancer-related diagnostics in its Symphony suite of products.

According to Macdonald, the company was starting to see increasing adoption rates for MammaPrint and other diagnostics in 2011, but introducing FFPE analysis this year has further bolstered sales.

"We almost doubled our sales in 2011, even as we were selling our test in the fresh tissue format," Macdonald said. Then, "in 2012, we've doubled our sales again. If you look at Agendia on a consolidated basis, we've more than doubled our volume from first quarter last year to first quarter this year."

Agendia did not provide exact sales figures for MammaPrint. However, in response to increased demand for the test, Agendia has more than doubled its sales team, from 10 reps to 26 reps in the US.

Reimbursement prospects for MammaPrint also appear to be improving in line with growing product sales. Medicare has been reimbursing MammaPrint since 2010 and Agendia has netted contracts with several private payors, including Humana and UnitedHealthCare. Macdonald estimated that Agendia currently has more than 200 million lives covered in the US for MammaPrint.

Agendia recently reported data from a prospectively designed outcomes trial, called RASTER, which showed reduced use of adjuvant chemotherapy in 20 percent of study participants deemed at low risk of breast cancer recurrence by MammaPrint. "The RASTER data may help us on [the reimbursement] front," Macdonald added.

Although RASTER was a prospectively designed investigation, it wasn't a randomized study. In order to update MammaPrint's label with a predictive claim, which would validate that the test can be used to guide treatment with specific chemotherapies, Agendia will need data from a prospective, randomized-controlled trial.

In this regard, the company is investigating MammaPrint in a prospective, randomized study called MINDACT, which will assess the accuracy of the diagnostic to gauge patient outcomes based on whether they are at high or low risk of recurrence. For those patients in the trial who receive chemotherapy based on clinical factors and MammaPrint results, the researchers will track whether they respond better to anthracycline-based chemotherapy regimens or to a docetaxel-capecitabine regimen.

"Once we have outcome data on the MINDACT trial, we'll be able to get a predictive claim," Macdonald said.

While increasing its marketing muscle and expanding reimbursement coverage have certainly contributed positively to greater uptake of the company's tests, MammaPrint's ability to analyze FFPE appears to be the main growth driver.

In the US, most labs preserve tissue from biopsies in formalin, so by the time medical oncologists see patients, their tumor biopsies are already in FFPE format. As a consequence, when MammaPrint was only available in fresh tissue format, oncologists couldn't readily use the test to guide treatment strategies for their patients.

Stefan Glück, a professor and oncologist at the University of Miami's Sylvester Comprehensive Cancer Center, told PGx Reporter that he began using MammaPrint after Agendia began analyzing FFPE samples.

"I'm a medical oncologist who normally sees patients a couple weeks after they have had surgery" to remove their breast tumor, Glück explained. "Now that the test is available on archived tissue … I can order the test even a year later if I wish."

George Sledge, a professor of oncology at the Indiana University School of Medicine and former president of the American Society of Clinical Oncology, told PGx Reporter via e-mail that the "biggest barrier" to MammaPrint adoption in the past was "the paraffin vs. frozen section" issue.

Benefit of a Binary Result?

Patients with early-stage estrogen receptor-positive breast cancer usually receive surgery to remove the tumor and then are treated with a combination of chemotherapy and hormonal therapy to reduce the chances that their cancer will return. However, patients who are at low risk of recurrence can potentially avoid the toxicities of chemotherapy, and be treated just with hormonal therapy.

In order to determine the likelihood of cancer recurrence and decide whether to treat with adjuvant chemotherapy, doctors can use a number of molecular diagnostics — such as MammaPrint, Genomic Health's Oncotype DX, General Electric Healthcare/Clarient's MammoStrat, and NanoString's PAM50 — in conjunction with tools such as Adjuvant!Online, which assesses recurrence risk based on age, tumor size, nodal involvement, and histologic grade.

Oncotype DX, which has been available since 2004, is currently the market leader. However, Agendia believes that one of the main factors swaying some oncologists toward MammaPrint is the fact that the test provides a binary result, placing patients at either high risk of recurrence or low risk of recurrence, while Oncotype DX provides patients a recurrence risk score that is associated with either high-risk, low-risk, or intermediate-risk categories.

A 2010 study published in Cancer by Kelly et al. estimated that, depending on the specific cutoff used to denote "intermediate risk," between 40 percent and 66 percent of hormone receptor-positive, node-negative breast cancer patients receive equivocal results from Oncotype DX.

In light of this, many oncologists "don’t know what do with an intermediate score," Sledge said. He noted that TAILORx, an ongoing 10,000-patient study investigating whether chemotherapy helps patients deemed to be at intermediate risk by Oncotype DX, should "answer the question definitively."

In the meantime, some oncologists are turning to MammaPrint, preferring to have a "yes" or "no" answer when deciding whether to give patients chemotherapy. Glück, a primary investigator in TAILORx, said that after the trial finished enrolling patients, he began looking into other molecular diagnostics on the market and was impressed with the science underlying MammaPrint's development.

"This annoying thing with intermediate test results is just not a problem with MammaPrint," he said.

"Usually, I know when a patient is at high risk or low risk of recurrence. But sometimes we are not sure, and that's when we need these [molecular] tests," Glück said. "Then, I send the patient samples to Genomic Health, and I get an intermediate result, and I'm still not sure" whether to treat the patient with chemotherapy.

Glück is on Agendia's medical advisory board and previously worked with Genomic Health in an advisory capacity and conducted research on Oncotype DX.

The benefit of a binary result versus a recurrence score is not exactly clear cut, however. Whether physicians are using MammaPrint and Oncotype Dx, they use results from these tests to treat patients along the continuum of their disease. "Whether you dichotomize or split in three or look at it as a continuous variable is basically a statistical question," Sledge said.

In response to criticism about intermediate test results with Oncotype DX, Genomic Health has previously said that most oncologists using the test know how to use the more nuanced risk groupings in light of patients' disease characteristics. "Ultimately, we've learned in studying breast cancer that there is a continuous biology in luminal breast cancer," said Steve Shak, Genomic Health's chief medical officer, explaining that doctors treat patients at the low end of the intermediate recurrence score range very differently than patients who receive a very high intermediate recurrence score.

Similarly, oncologists using tests that just indicate if patients are at high or low risk of recurrence don't uniformly treat patients with or without chemotherapy if they fall in one or the other category, he pointed out. "Are all the patients who are deemed at low risk treated the same way? Are all those at high risk treated the same? What about patients who are right near the cut off? And which patients might benefit from hormonal therapy alone and no longer be at high risk?"

However, given the pressures of busy community practices, the simpler MammaPrint result might have traction with doctors who see many patients, not just breast cancer patients. In the community setting, "anything that can simplify the discussion is useful, and a 'yes/no' takes a lot less time to explain to a patient than what a '14' means," said Howard McLeod, director of the University of North Carolina's Institute for Pharmacogenomics and Individualized Therapy.

"Based on the studies that have been done, it seems that regardless of what assay you use, you clump people in the same box," he added. "If that indeed is true, the test that allows you to convey the test results in the most straightforward manner is the way to go."

Overall, however, McLeod hasn't noted a big shift away from Oncotype DX. "It has definitely been around longer and has been analyzing FFPE for longer, so Genomic Health seems to be maintaining its market share in the US."

Regulatory Reassurance

Oncotype DX is currently the most widely used and reimbursed test for gauging breast cancer recurrence. According to Genomic Health, physicians in 60 countries have ordered nearly 250,000 Oncotype DX tests to date. Furthermore, it is the only gene expression test recommended for node-negative breast cancer patients in treatment guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

However, Oncotype DX is a laboratory-developed test and Genomic Health has not signaled plans to seek US Food and Drug Administration approval any time soon. While this fact hasn't hampered Oncotype DX adoption, some doctors who are choosing MammaPrint over the market leader seem reassured by the fact that Agendia's test has been green-lighted by the FDA.

For example, Stephanie Akbari, medical director of the Reinsch Pierce Family Center for Breast Health in Arlington, Va., used to test patients on Oncotype DX, but starting in 2010, she switched to MammaPrint after receiving discordant results from Genomic Health for a patient.

In this instance, which, according to Akbari, was "the straw that broke the camel's back," her patient had two tumors in the same breast and samples from both tumors were to be sent for analysis to Genomic Health. However, the pathologist mistakenly sent two tissue samples from the same tumor for analysis.

When the test results came back to Akbari, she realized that testing by Oncotype DX had yielded two different scores — 14 and 23 — for samples from the same tumor. "The problem with that is medical oncologists treat a recurrence score of 14 very differently from a 23," said Akbari.

According to Genomic Health's website, an Oncotype DX recurrence score below 18 places patients at low risk of recurrence and makes them eligible for potentially forgoing chemotherapy. Patients with a score between 18 and 30 are at intermediate risk and the treatment strategy is for this group is unclear.

Meanwhile, the exact recurrence score range for intermediate risk is currently in flux. In the TAILORx trial, the range for intermediate risk is between 11 and 25.

Akbari said that Genomic Health informed her that the two different risk scores she received for the same tumor fell within the confidence intervals for Oncotype DX scores. Nevertheless, she said that after this experience, she lost confidence in Oncotype DX and began to investigate other molecular diagnostics.

The fact that MammaPrint has FDA clearance was a plus for Akbari. In garnering the agency's stamp of approval, Agendia had to show that the test reported consistent results from the same tumor sample. However, because Oncotype DX isn't FDA cleared, Akbari didn't have the same confidence about the analytical validity of the test.

"I don't know if anyone knows [how often this type of discordant result occurs] because most of the time you wouldn't knowingly send two samples from the same tumor for analysis," she noted. "Because Genomic Health hasn't applied for FDA clearance for Oncotype DX and shown that [this kind of discordance] doesn't normally occur, one can't comment one way or another."

After this incident with Genomic Health occurred in May 2010, Akbari began consulting for Agendia in October of the same year.

Upon hearing about this example, Genomic Health's Shak suggested that retesting the patient's sample could have resolved the issue for Akbari. "Simply switching testing platforms based on this one example, doesn't seem credible," he said, noting that Genomic Health has sufficient controls in place to account for this type of variability and provides confidence intervals with reported recurrence risk scores that include the contribution of tumor heterogeneity.

"Our studies show that when we look at the variability that exists in Oncotype DX recurrence score results between tissue blocks from the same tumor… the standard deviation for the variability is on the order of plus or minus three to four recurrence score units," Shak said.

Treatment Strategies

Although oncologists in the US have more experience using Oncotype DX recurrence scores to guide treatment decisions, there is no data from prospective randomized-controlled studies yet on the chemopredictive features of Oncotype DX. MammaPrint, meanwhile, isn't indicated as a predictive test.

In the long run, the molecular diagnostic that stands to prevail in the breast cancer recurrence market will be the one that can help physicians personalize treatment strategies with specific drugs. Several ongoing prospective trials, such as TAILORx and MINDACT, promise to shed light on the chemopredictive aspects of Oncotype DX and MammaPrint, but these studies won't be completed for several years.

In the meantime, experts at the St. Gallen International Breast Cancer Conference last year recommended the use of Oncotype DX to predict which breast cancer patients should receive chemotherapy. The majority of experts from the same panel agreed that the chemopredictive properties of MammaPrint "were not yet sufficiently established" (PGx Reporter 7/27/2011).

Although Oncotype DX is the molecular diagnostic most readily used to make breast cancer treatment decisions, a common criticism is that the chemopredictive aspects of the test were retrospectively validated on patients who were treated with a chemo regimen that is no longer part of the standard treatment.

Genomic Health has cited retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project B20 trial to assert that Oncotype DX can be used to predict "the magnitude of chemotherapy benefit" in patients. In the original B20 study, node-negative breast cancer patients were treated with a chemo regimen containing cyclophosphamide/methotrexate/fluorouracil or just methotrexate/fluorouracil. However, these regimens aren't readily used in medical practice.

"CMF is extremely rarely used," Glück said, asserting that doctors who are using Oncotype DX test results to decide whether to administer newer chemotherapies are doing so with insufficient clinical evidence.

Ahead of data from MINDACT and a subsequent FDA labeling update, Agendia cannot make any claims about MammaPrint's ability to predict whether patients will respond to a specific chemotherapy. However, some doctors adopting the test cited as a benefit the fact that its prognostic gene set was derived from an analysis of tumor samples from women who weren't treated with any adjuvant chemotherapy.

The MammaPrint prognostic score isn't "influenced by any kind of chemo," Glück said. "It's biased only by 10 years outcome, nothing else. And then, as a medical oncologist I can decide what treatment to give."

Besides MammaPrint, Agendia sells other breast cancer diagnostics in its Symphony suite of tests that further help doctors guide treatment strategies. The company estimates that between 90 percent and 95 percent of the time when doctors order MammaPrint, they also order other tests in the Symphony suite, which includes TargetPrint and BluePrint.

TargetPrint provides information about the receptor status of a tumor, which doctors can use to guide hormonal therapy. BluePrint analyzes tumor subtypes, which are also critical for discerning the best treatments for patients. These tests aren't FDA approved, but Agendia has said it plans to seek regulatory clearance for BluePrint.

"Physicians are really interested in getting the whole picture" when it comes to treating breast cancer, Macdonald said.

For further perspective on the MammaPrint test, please check out our video interview with Agendia CEO David Macdonald.