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USF, Agendia Data Raise More Questions on Discordance between MammaPrint and Oncotype DX

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Researchers from the University of South Florida and Agendia shared data this month that adds to a growing collection of evidence suggesting significant discordance between results of Agendia's MammaPrint and Genomic Health's Oncotype Dx breast cancer recurrence risk tests.

The new data, presented at last week's Miami Breast Cancer Conference, expands on a study presented last year at the San Antonio Breast Cancer Conference by scientists from USF, Agendia, and Genomic Health that compared only MammaPrint, Oncotype DX, and another immunohistochemistry assay called MammoStrat.

In their presentation this month, the same USF researchers, in collaboration with Agendia, took that original data and then superimposed another set of results from Agendia's BluePrint molecular subtyping test.

According to Charles Cox, the principle investigator of the study and a professor of breast surgery at USF Health's Morsani College of Medicine, previous comparisons of MammaPrint and Oncotype DX have showed varying levels of discrepancy, such as a 2012 study by Genomic Health and a group of French researchers. That study evaluated 57 patient samples, 20 of which had different risk assessments by MammaPrint and Oncotype DX.

But without additional data following patients in the long term, it has been unclear what such evidence of discordance means about the accuracy of either test.

By also comparing BluePrint results, Cox told PGx Reporter, the group hoped to add another layer of data that could help further stratify and tease out some of the clinical implications for patients with discrepant results from the two risk tests.

"Molecular subtyping is in the guidelines of the [National Comprehensive Cancer Network] and the [St. Gallen International Breast Cancer Conference], so we thought it should play a role," he said.

Overall, the USF team compared results on tumor samples from a total of 148 patients. According to the researchers, the greatest discordance was observed in a subset of 51 patients falling in the Luminal B subtype by BluePrint analysis. Of those 51, all were stratified by MammaPrint as high risk of recurrence, while Oncotype classified 18 of them (35 percent) as low risk. MammoStrat also classified 16 of these patients as low risk.

In the BluePrint Luminal A/MammaPrint low-risk group, almost all the results were concordant with Oncotype DX, with 47 patients having a low-risk score, 12 having an intermediate score, and only 4 having a high-risk score.

MammoStrat showed a slightly higher discordance in this group, classifying 12 samples as high risk and 17 as moderate risk.

According to the researchers, although adding BluePrint into the mix doesn't reveal whether Oncotype DX or MammaPrint's results are correct or incorrect, it does hint at some of the biology behind the discordance.

Whether these Luminal B, MammaPrint high-risk, but Oncotype low-risk patients are actually at a low risk or high risk of recurrence — and what that should mean for clinicians deciding how to treat them — is a question for a longer term follow up study, which Cox said his team is planning to do in this cohort.

But in the meantime, Cox said, the fact that MammaPrint results are also borne out in the BluePrint molecular subtyping results might raise some questions about treating patients solely according to their Oncotype DX risk score.

While both tests are used clinically to assess the risk of recurrence and thus guide treatment strategy for women diagnosed with breast cancer, MammaPrint and Oncotype DX were developed very differently.

According to Cox, Oncotype DX was developed based on a set of known breast-cancer associated targets, and validated in women treated for five years with hormonal therapy.

MammaPrint utilizes a larger set of targets chosen blindly to their biological role, and based solely on their power to distinguish between women with better or worse outcomes, discovered and validated in a set of untreated women.

In light of these differences, it's possible, Cox said, that since Oncotype DX is assessing risk for women post-hormonal treatment, those patients in the Luminal B group in the study with discordant Oncotype DX results may indeed be Luminal B and at a high risk of recurrence without any post-surgical treatment at all, but still responsive enough to hormonal therapy that they sit in the Oncotype DX low-risk category, Cox said.

However, whether these patients may also benefit from, or require chemotherapy to avoid later recurrence is still in question, and something only longer-term studies can establish, Cox said.

In the meantime, he said his team hopes that being able to look at the discordance between these different tests with the added context of BluePrint molecular subtype results may add some context to future studies aiming to answer such questions.

Another study covered by PGx Reporter last year by researchers from Agendia and The Netherlands Cancer Institute — also using BluePrint — found that a small subset of discordant results between MammaPrint and Oncotype DX may be explained by the presence of a splice variant that inhibits normal ER function, yielding low-risk Oncotype DX results for patients that fit into the high-risk, Basal-like molecular subtype.

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