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Agendia, Genomic Health Present New MammaPrint, Oncotype DX Data at Breast Cancer Symposium

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By Turna Ray

Agendia and Genomic Health both presented data last week on the ability of their gene-expression tests to characterize breast cancer based on nodal status and to determine which patients will yield a survival advantage with chemotherapy treatment.

At the San Antonio Breast Cancer Symposium, Genomic Health presented data suggesting that anthracycline-based chemotherapy (CAF) is unlikely to benefit patients with either 1-3 or 4 or more positive nodes, if their tumors have a low recurrence score based on its Oncotype DX breast cancer diagnostic. Separately, Agendia also reported data at the meeting showing that women 65 years or older who are deemed to be at low risk for breast cancer recurrence by its 70-gene profile assay, MammaPrint, survived without chemotherapy treatment for up to 10 years.

Genomic Health's Oncotype DX assesses the expression of 21 genes in a patient's tumor sample and yields a recurrence score between 0 and 100 that translates into high risk, low risk, or intermediate risk for patients. Previous studies have shown that a low 21-gene recurrence score identifies patients with estrogen receptor-positive breast cancer who do not appear to benefit from CAF plus tamoxifen treatment despite positive axillary lymph nodes.

Oncotype DX was initially validated for use in women with early-stage, node-negative, ER-positive breast cancer. However, Genomic Health has been trying to expand the test's indication into node-positive women. Additionally, the company plans to launch its real time PCR-based platform for Oncotype DX in colon cancer next year. It is also looking to apply it to kidney cancer under a collaboration with Pfizer, and to help determine which women will benefit from treatment during a precancerous breast condition called ductal carcinoma in situ [see PGx Reporter 01-16-2008].

Meanwhile, Agendia's MammaPrint — a breast cancer recurrence test cleared by the US Food and Drug Administration as an in vitro diagnostic multivariate index assay in 2007 — gauges the expression of 70 genes on a microarray-based platform. The test has been validated in early-stage breast cancer patients at risk of recurrence following surgery, despite ER status and any prior treatment. Based on patients' genomic profile, MammaPrint stratifies them into either low risk or high risk of distant recurrence.

Agendia is also slated to launch an array-based diagnostic in colon cancer, called ColoPrint, this year or next [see PGx Reporter 06-03-2009].

Although the indications for Agendia's and Genomic Health's multi-gene assays differ in highly specific forms of breast cancer, the two companies are competitors in the overall breast cancer molecular diagnostics space, and are racing to expand their platforms into other cancer types. The competition is particularly heating up between the two companies as they continue to validate the sensitivity of their tests in terms of nodal status and survival benefit.

Oncotype DX: Survival Benefit in N+ Cancer

At SABCS last week, Genomic Health presented data on 10-year disease-free survival analyses within nodal categories 1-3 and 4 by the Oncotype DX recurrence score on 148 patients on tamoxifen in a previous Southwest Oncology Group trial and from 219 patients on CAF followed by tamoxifen. Researchers from Loyola University and the Breast Cancer InterGroup also looked at patients' breast cancer specific survival, which only accounted for deaths due to breast cancer, not other causes such as cardiovascular events.

"As with the previously reported five-year disease-free survival analysis by nodal status and linear recurrence score, there was no apparent disease-free survival benefit to CAF in the lower recurrence scores over 10 years for either the 1-3+ or 4+ nodal groups," the researchers reported in the abstract. "Any clinically meaningful CAF benefit for disease-free survival was not evident until much higher recurrence scores."

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Furthermore, researchers found "no breast cancer specific survival benefit from CAF in either the low recurrence score or intermediate recurrence score categories, but CAF resulted in superior breast cancer specific survival in the high recurrence score category," the researchers concluded.

The 10-year estimates for breast cancer-specific survival for the low recurrence score group were 92 percent for patients on tamoxifen and 87 percent for those on CAF and follow-on tamoxifen. In the intermediate recurrence score group, 10-year breast cancer specific survival estimates were 70 percent for the tamoxifen arm and 81 percent for the CAF/tamoxifen arm. For the high recurrence score group, 10-year breast cancer specific survival estimates were 54 percent for tamoxifen and 73 percent for CAF/tamoxifen.

"These additional exploratory analyses reinforce our initial interpretation that anthracycline-based chemotherapy does not appear to benefit patients with either 1-3 or 4 or more positive nodes over 10 years, if their tumors have a low recurrence score," the study authors concluded. The researchers suggest conducting a prospective trial to confirm these results. The study presented at SABCS was funded by the National Cancer Institute and Genomic Health, and was an update to a Southwest Oncology Group trial (INT0100).

"New adjuvant treatment strategies for tumors with this distinct biology should be a high research priority," the researchers suggest.

MammaPrint: Patients 65 or Older

Agendia, meantime, released new data at SABCS on MammaPrint's ability to determine that breast cancer patients 65 years or older, who are deemed "high risk" by the test, should forego adjuvant chemotherapy.

"One-half of all new breast cancer diagnoses occur in women age 65 years or older," researchers from Agendia and other institutions note in the abstract. "In this age group, the use of adjuvant chemotherapy is largely influenced by co-morbidity and little is known about the applicability of prognostic multi-gene assays."

Agendia's study enrolled 204 women 65 years or older diagnosed with primary breast cancer that had spread to as many as three lymph nodes and who were treated with either no adjuvant systemic therapy or adjuvant hormonal therapy alone. Researchers enrolled patients presenting to the Jules Bordet Institute and the Netherlands Cancer Institute between 1987 and 2003. Patients' MammaPrint test results were compared with clinical-pathological risk assessment using Adjuvant!Online.

Of the women enrolled, more than 63 percent were classified as genomic low risk and nearly 37 percent were deemed genomic high risk by MammaPrint. After a median follow-up of 8.6 years, the five- and 10-year breast cancer-specific survival rates for the genomic low risk group were 96 percent and 86 percent versus 82 percent and 66 percent for the genomic high risk group.

"In univariate analysis, MammaPrint was prognostic for five-year breast cancer specific survival and 10-year breast cancer specific survival," the researchers reported. "In a multivariate model adjusted for 10-year risk predicted by Adjuvant!Online, MammaPrint was independently prognostic for five-year breast cancer-specific survival and 10-year breast cancer-specific survival."

These findings led researchers to conclude that while MammaPrint identifies a smaller proportion of women in the 65 year or older age bracket as high risk, the genomic prognosis indicates that this segment of patients may safely "forego chemotherapy."

"If these data are confirmatory, the ongoing prospective MINDACT trial will be amended to include older women," the researchers said.

Oncotype DX: N+ Treatment Impact

Until last week, Oncotype DX was validated only in node-negative patients. At SABCS, Genomic Health not only presented data on the ability of Oncotype DX to assess chemotherapy benefit on lymph node-positive breast cancer patients, but the company simultaneously published this data in The Lancet Oncology and presented a poster on how this data stands to impact current treatment guidelines.

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"Results of recent Oncotype DX studies indicate that the recurrence score can identify node-positive, estrogen receptor-positive (N+/ER+) patients who may not benefit from chemotherapy and have a low risk of distant recurrence with hormonal therapy alone," researchers from Genomic Health, New York University School of Medicine, and others, wrote in an abstract. However, acknowledging that there are no data on the impact of Oncotype DX on adjuvant treatment planning in node-positive patients, researchers surveyed doctors who have used the test in this setting to "characterize the effect of the … breast cancer assay on adjuvant treatment recommendations in N+/ER+ breast cancer."

The researchers analyzed 160 web-based surveys from community and academic oncologists in the US who had ordered Oncotype DX for at least one patient with node-positive, ER-positive breast cancer. The median patient age was 61 years. One, two, three, or four positive nodes were reported in 69 percent, 18 percent, 6 percent, and 3 percent of patients, respectively. Fifty-four percent of N+/ER+ patients had a low recurrence score; 38 had an intermediate recurrence score, and 8 percent had a high recurrence score.

Ahead of obtaining the recurrence score with Oncotype DX, chemotherapy was planned in 56 percent of patients, endocrine therapy was planned in 29 percent, and there was no recommendation for 14 percent, while 1 percent was slated for other types of therapies. After obtaining the recurrence score, doctors' treatment recommendations were changed from hormonal therapy plus chemotherapy to hormonal therapy alone in 35 percent of patients and from hormonal therapy to hormonal therapy plus chemotherapy in 10 percent of patients.

"These findings indicate that for N+/ER+ patients, the recurrence score is used more often (but not exclusively) in patients with 1–3 positive nodes and [early-stage] disease," the researchers concluded. "Treatment recommendations for these patients with N+ disease were frequently changed by the recurrence score results, with an overall reduction in the recommendation for chemotherapy treatment."

"There are now five studies involving more than 1,000 patients that support the clinical utility of Oncotype DX in guiding treatment selection for node-positive breast cancer," said Steven Shak, Genomic Health chief medical officer, in a statement. "With this suite of clinical evidence, recently expanded Medicare coverage, and clinical experience with more than 5,500 patients with node-positive breast cancer, we believe we can arm node-positive patients and their physicians with the same accurate, standardized genomic information that node-negative patients and their doctors have been using to help guide treatment plans over the past five years."

MammaPrint: Genomic Profiling In N+ Patients

Researchers from Agendia and other institutions presented data at SABCS on the need for stronger treatment strategies for patients who have node-positive cancer and are classified as having high recurrence risk by MammaPrint, since this subset of patients has very poor outcomes.

"It has previously been shown that the 70-gene profile (MammaPrint), which was developed in node-negative patients, is excellent in predicting disease outcome in patients with 1-3 positive nodes and similarly in patients with 4-9 positive-nodes," the researchers said in their abstract. "Further analysis based on adjuvant treatment received and pooled analysis of the 2 lymph node-positive series was performed in order to assess the prognostic added value of genomic profiling in lymph node-positive patients."

Researchers analyzed frozen tumor samples from 519 patients; 346 had 1-3 positive lymph nodes, and 173 had 4-9 positive nodes. Of these patients, approximately 41 percent had the 70-gene good prognosis profile and 59 percent had the 70-gene poor prognosis profile. After 10.3 years median follow-up, distant metastases occurred in 141 patients, while 103, or 20 percent, of patients died of their disease.

"Our data show that the 70-gene profile is a strong prognostic marker of distant recurrence and breast cancer specific death in breast cancer patients with positive lymph nodes," the researchers conclude in their abstract. "Combining nodal status (1-3 nodes vs. 4-9 nodes) and 70-gene profile (good vs. poor) allows stratifying patients among subgroups for whom tailored treatment strategies should be designed and assessed based on their very different outcome.

"Patients with elevated number of lymph nodes and high genomic risk have a very poor prognosis and might need to be considered for stronger treatment strategies," the researchers concluded.

The array of abstracts presented at SABCS by Agendia shows that the company is also investing in gathering clinical outcomes data on MammaPrint that will convince payors to reimburse for the test. While MammaPrint is not as widely covered as Oncotype DX, Agendia representatives have said the company has ramped up discussions with payors.

Earlier, this month, Agendia announced that Palmetto GBA, California’s Part B Medicare administrator, had established coding guidelines for MammaPrint. The coding guidelines for healthcare providers are available at the Centers for Medicare and Medicaid Services website.

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