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New Data Support Role of Agendia BluePrint Test in Refining Breast Cancer Subtypes

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NEW YORK – Newly released data shows that molecular classifications determined by Agendia's BluePrint gene expression assay can diverge significantly from what might be expected based on other established breast cancer biomarkers, which could change how oncologists treat particular patients.

In poster presentations at the American Society of Clinical Oncology's virtual annual meeting  earlier this month, investigators presented two new studies of BluePrint classification patterns. The company highlighted both as illustrating how the test's molecular classifications can reveal different information about a breast cancer's aggressiveness or responsiveness to treatment than would be gleaned from traditional factors like HER2 and ER biomarker status.

In a statement announcing the data, the firm argued the findings offer "immediate, actionable information for doctors and patients early in the diagnosis and treatment planning process and build on research that will impact breast cancer treatment and outcomes in the future."

Agendia's Chief Medical Officer William Audeh said this week that the fact that the boundaries of BluePrint's molecular classifications don't match perfectly with HER- ER- and PR-based designations has been clear for some time, and makes sense considering the test technology.

"From the big picture view, what we are looking at with BluePrint is the expression of genes," Audeh said. The 80-gene array-based test classifies breast tumors into luminal (A or B), HER2 or basal subtypes based on the gene expression of downstream signaling pathways.

Audeh argued that because this pathway activity is what actually drives tumor behavior, BluePrint's results hew closer to the "essential biology of breast cancers" than an analysis at the level of the cell-surface receptor proteins.

As a result, he said, "what we have found is that when you look at these functional gene expression patterns in breast cancer, they don't always correlate with what we expect from the IHC categories that tumors are being placed in."

Work to uncover what these discordances mean and how they can inform clinical decision-making is now progressing as BluePrint has been implemented clinically on a wider scale, Audeh added, an effort that has generated not just the new ASCO data, but also previous complementary findings and potentially new discoveries moving forward.

In one of the ASCO studies, researchers working with Agendia evaluated the concordance between HER2 status as determined using the 2018 ASCO/CAP guidelines and molecular subtype as determined by BluePrint in a real-world diagnostic cohort of 1,453 samples.

In 2018, ASCO and the College of American Pathologists updated their HER2 IHC/ISH classification guidelines to reduce the frequency of HER2 equivocal cases, for which treatment recommendations have been ambiguous.

According to the poster's authors, previous research using BluePrint showed a substantial proportion of tumors identified as HER2 equivocal or HER2 positive by prior guidelines were not classified as HER2 subtype by the molecular assay. As such, they sought to measure whether the same might be true considering updated HER2-IHC classification cutoffs.

The team wrote that establishing HER2 positivity according to the 2018 guideline recommendations certainly led to fewer HER2 equivocal tumors overall in their cohort, "confirming the positive impact of the revisions." But the number of HER2-positive tumors that BluePrint classified as "non-HER2" subtypes was still significant.

Across the cohort, 69 percent of the definitive HER2-positive tumors, and all of the HER2 equivocal tumors, appeared as non-HER2 according to BluePrint. The assay reclassified 17 of 99 HER2-positive tumors as luminal A, 40 of 99 as luminal B, and 11 of 99 as basal.

Although the ASCO poster didn't deal with this directly, Audeh said that previous data exists, for example from the NBRST trial, showing that these IHC HER2/BluePrint non-HER2 tumors may have suboptimal responses to HER2-directed therapy. In Agendia's study of the NBRST data, the rate of pathologic complete response was significantly lower in HER2 tumors deemed luminal by BluePrint when compared to HER2 tumors that were also HER2-type by BluePrint.

In terms of clinical relevance, Audeh suggested that this data, coupled with the new evidence on BluePrint reclassification from ASCO, suggests that if an oncologist were deciding whether to apply neoadjuvant therapy seeking a pathologic complete response, their expectation of that response should be much lower in a BluePrint-luminal HER2-positive cancer.

"In that case, some patients and their physicians may choose to go directly to surgery rather than wait to see if they're in that small minority that could get a [pathologic complete response]," he said. "Whereas the true HER2-positives have honestly the highest [response] rates of any type of breast cancer and the standard of care really is to definitely take them to neoadjuvant therapy except for the smallest of tumors."

In a statement, the study's PI Adam Brufsky, professor of medicine at the University of Pittsburgh School of Medicine, said that although the findings may not have immediate relevance, they "may have the potential at some point to affect treatment decisions and patient outcomes."

To try to prove the association more definitively, Audeh said Agendia is now seeking to analyze external cohorts from large clinical trials with Agendia's MammaPrint prognostic assay and BluePrint to better define whether one can predict responsiveness to HER-2 targeted therapies and possibly combined chemotherapy.

"We think that BluePrint will help us … and we are seeking that data to determine whether it can help guide therapy in a more precise manner," he added.

The second ASCO study also compared BluePrint classification patterns to breast cancer designations determined by traditional biomarkers, but in this case it analyzed the distribution of Blueprint-determined basal-like status against so-called triple negative status — cancers that are negative for HER2, ER, and PR.

The company suggested that the findings from this analysis might have more immediate implications for how a patient's treatment could or should change in light of BluePrint data versus legacy biomarker status.

The study analyzed a small cohort recruited to a larger ongoing registry trial called FLEX, which aims to enroll a minimum of 10,000 patients 18 years or older with histologically proven invasive stage I-III breast cancer tested with Agendia's MammaPrint prognostic assay with or without BluePrint subtyping.

The FLEX poster at ASCO evaluated the distribution of triple-negative breast cancer subtypes in a set of 143 genomicaly basal-type cancers across self-reported patient ethnicities (Caucasian, African American, and Latin American) and showed, overall, that these basal tumors are heterogeneous and include all defined TNBC subtypes, independent of ethnicity.

In addition, investigators looked at the prevalence of IHC-determined estrogen receptor status in the basal-type cohort, finding that approximately a third of BluePrint basal-type tumors in the group were ER+ by IHC.

According to the researchers, this suggests that a subset of the tumors oncologists might expect to be Luminal based on their ER status are actually basal-type.

Akin to the findings of the first study, Audeh said that this complexity in the distribution of basal, luminal, triple-negative and ER-positive tumors is something Agendia has observed before. "We've known for some time that when you look at triple negative breast cancers genomicaly, they are not all basal," he said. "There's a proportion that appear to have other pathways active in them. And then the opposite is also true, that some tumors that turned out to be genetically basal aren't always triple negative."

Audeh added that the most important aspect of the analysis is that it adds to the knowledge about this unique subset of estrogen-positive cancers that turn out to be genomicaly basal.

"They behave very differently than most estrogen-positive breast cancers," he said. "They're far more chemotherapy-sensitive and they essentially behave just like other basal cancers or the majority of triple-negative breast cancers. And I think clinically that's quite important today because many oncologists will indeed treat a triple-negative breast cancer quite differently than an estrogen-positive breast cancer."

In a statement accompanying the data, Cathy Graham, director of breast surgery at Emory St. Joseph's Hospital and an author of the poster, said that this evidence of Blueprint's potential to reclassify a subset of ER+ tumors "identifies an urgent and actionable situation."

"From a clinical perspective, when these patients are first diagnosed, they appear to have luminal breast cancer," she said. "But [with comprehensive genomic testing] a large subset of these breast cancers is reclassified to basal-type, which is high risk." This suggests that such knowledge could allow oncologists to enact more personalized treatment approaches, she noted.

Audeh said that the NBRST study also yielded data in this vein, demonstrating that BluePrint identifies "a group of patients that is hidden in the estrogen-positive population, but has much higher chemotherapy sensitivity as well as much higher aggressiveness."

The group of tumors that were ER-positive and HER2-negative but turned out basal by BluePrint in that trial had a much higher pathologic complete response rate than estrogen-positive cancers that turn out to be luminal and the difference was quite striking, Audeh said. Among Luminal B cancers, which are considered high-risk despite being estrogen receptor-positive, pathologic complete response was only about 6 percent. In contrast, ER-positive Basal tumors showed a response rate of about 34 percent, Audeh said, similar to what was seen in triple negatives.

Audeh added that the way clinicians address triple-negative can be significantly different than what they'd choose not knowing a tumor fell into this category or its BluePrint equivalent basal-type subset.

"When I ask oncologists if they're going to give the same chemotherapy [regimen] to an estrogen-positive cancer versus a triple-negative cancer, in many cases they will say no," he said. "They tend to use three or four drug regimens or aggressive regimens containing anthracyclines for triple negative. And they'll tend to use two drug regimens in ER-positive cancers."

"We also know that triple negative breast cancers are very often treated with neoadjuvant chemotherapy as the standard of care except for the smallest tumors," Audeh added. "There's been data … showing that if you delay adjuvant therapy more than about eight weeks the outcomes start to get worse, so you don't want to delay that therapy. But it's not the same for ER-positive cancers where time to starting chemo can be delayed somewhat without a detrimental outcome."

The findings, if Agendia can further establish them, forewarn a potentially complex future for breast oncologists, where established practices in regard to therapeutic decisions for HER2-, ER-, and PR-based subtypes might require increasing subdivision and reassessment based on further molecular classification, but Audeh argued that greater personalization only stands to benefit patients.

He didn't provide detailed adoption numbers for BluePrint but said that uptake has paralleled the company's MammaPrint assay, with about 90 percent of samples sent to the company now including requests for both tests in parallel.

"We really believe that the total output ... is really providing the most comprehensive genomic profiling of early-stage breast cancer that one can get right now," he said. "And what we're uncovering in these posters ... and in more data to come ... is that this genomic diversity has clinical implications."

"The next step is to find the best therapy to apply to the subtypes that we are finding," he concluded.

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