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Agendia Breast Cancer Tests Show Promise for Improved Therapy Prediction

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NEW YORK (GenomeWeb) – New results from an ongoing trial support expanded utility of Agendia's breast cancer tests for stratifying patients and personalizing their treatment.

The data, from the I-SPY 2 trial, were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland on Wednesday by Laura van 't Veer, chief research officer of Agendia and a professor at the University of California, San Francisco.

I-SPY 2 is a phase II randomized clinical trial that is testing a variety of different drugs, alone or in combination, alongside standard chemotherapy in women with newly diagnosed breast cancer who have an elevated risk of recurrence.

Previous reports from the trial have included data on how phosphoproteins can help identify patient subgroups likely to respond to specific therapies. But every patient also receives Agendia MammaPrint and BluePrint testing, which might also predict their response to treatment.

In her presentation this week, van 't Veer shared results from two analyses of I-SPY 2 genomic data — one focused on the ability of the MammaPrint assay to predict patient response to different treatments, the other looking at the ability of Agendia's BluePrint subtyping test to forecast responses that might not be expected based on the readout from other molecular biomarkers.

MammaPrint measures the expression of 70 genes and classifies patients as either high risk or low risk of recurrence. But in the analysis shared this week, investigators looked at narrower definitions within the high-risk group, classifying the I-SPY 2 cohort as either "high risk" (MP1) or "ultra-high risk" (MP2).

Van 't Veer and colleagues set out to test the hypothesis that MP1/2 results might be associated with treatment response, analyzing a group of 986 patients in the trial.

Of the 986 subjects, 483 (49 percent) had an MP2 result, and this group was more than twice as likely to have a pathologic complete response to therapy compared to MP1 patients.

When the results were adjusted according to a patient's HER2 status and treatment received, the MP2 response rate remained significantly higher than the MP1 response rate across eight of 10 analyzed therapy arms.

Ultra-high risk patients with HR-positive and HER2-positive disease were 3.6 times more likely to have a pathologic complete response than high-risk patients, while those who were HR-positive and HER2-negative were 3.2 times more likely to respond.

In a second presentation, van 't Veer shared an analysis of data from Agendia's BluePrint, an 80-gene signature that classifies patient as having either basal, luminal, or HER2 subtypes of breast cancer.

The researchers analyzed results from 375 HR-positive and HER2-negative patients, aiming to see if differences in tumor biology, as indicated by a BluePrint score, might supersede or alter the prognostic or predictive information that is implied by single biomarkers like HR and HER2.

Luminal tumors, for example, are understood to represent ‘typical’ HR-positive and HER2-negative disease, while basal cancers resemble triple-negative tumors, van 't Veer said during a press conference to discuss the study results. But it is unclear what divergent results for a cancer mean, where biomarkers suggest one attribute and the BluePrint assay another.

The Agendia investigators asked in their I-SPY 2 analysis whether HR-positive HER2-negative tumors classified as basal by BluePrint might be more responsive to targeted chemotherapy than those classified as the more typical, or more expected, luminal type.

And indeed, they saw that patients with basal subtype cancers were approximately four times more likely to achieve a pathologic complete response than patients with luminal cancer, regardless of which therapy they were receiving.

In addition, the researchers found an association between subtypes assessed by BluePrint and the MammaPrint MP1 or MP2 classes: about 77 percent of the HR-positive HER2-negative basal patients were also marked as ultra-high risk or MP2 by MammaPrint, compared to only 9 percent of the luminal patients.

According to van 't Veer, the findings are a strong demonstration that BluePrint can identify a subset of patients with HR-positive HER-negative basal tumors who are more likely to respond to neoadjuvant chemotherapy.

The MammaPrint data, meanwhile, suggest that this test — initially used to predict good outcomes in patients with a low-risk signature — could now also be used "to predict response in high-risk signature patients who receive chemotherapy or targeted therapies," she said in a statement.

"The clinical implications will need to be further developed … [but] in short, this is a prognostic signature that is also predictive," she added.

Other Agendia officials also hailed the data as evidence that the firm's tests have therapy-predictive and not just prognostic value for patients.

The firm has been at a disadvantage compared to its competitor Genomic Health because advisory groups and guidelines bodies have recognized the Genomic Health Oncotype Dx test as chemo-predictive and MammaPrint as well as other competing tests as only prognostic.

But William Audeh, Agendia's chief medical officer, said in a statement that the new data from I SPY 2 suggest a "continuing and constantly expanding utility" for the firm's assays.

Endorsement of either test as predictive by outside groups may depend on whether the company can follow up these retrospective results with a prospective demonstration.

Van 't Veer said that this is already in the works. Based on the findings so far, investigators will now be using these and other potentially qualifying biomarkers to prioritize treatment in a follow-up trial, called I-SPY 2.2, which is slated to begin in the fall of 2019.

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