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BluePrint Better Predictor of Adjuvant Chemo Response than IHC/FISH in Agendia Study

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NEW YORK (GenomeWeb) — Data from the Neoadjuvant Breast Registry Symphony Trial, led by Pat Whitworth of the Nashville Breast Center and funded by Agendia, have confirmed earlier findings supporting Agendia's BluePrint molecular subtyping assay as a more effective predictor of adjuvant chemotherapy response than classification by immunohistochemistry and FISH testing.

The study, involving several hundred patients and published last month in the journal Annals of Surgical Oncology expands on earlier NBRST data shared at this year's annual meeting of the American Society of Clinical Oncology in June, which hinted at a similar result.

In the study, researchers compared Agendia's multi-gene breast cancer classification test, BluePrint, with conventional IHC and FISH subtyping and looked at how each method fares in predicting patients' sensitivity to neoadjuvant treatment

BluePrint, part of a suite of tests Agendia markets to help guide therapeutic decision-making for breast cancer patients, classifies cancers into one of three types, Basal, Luminal, and HER2. Coupled with Agendia's other assay, Mammaprint, the suite can further distinguish Luminal patients into two subtypes — Luminal A and Luminal B.

IHC and FISH testing, meanwhile, categorize patients as either hormone receptor-positive or negative, and HER2-positive or negative, resulting in several subtypes.

According to the study's authors, among 426 total patients from the trial who had definitive surgery, Blueprint yielded a different risk classification than IHC/FISH predicted about 22 percent of the time. In many of these reclassified patients, the Agendia test appeared to better predict patients' response to neoadjuvant chemo or endocrine therapy as defined by pathological complete response.

For example, the study found that those patients BluePrint classified as Luminal A or B had pathological complete response rates of 2 percent and 7 percent respectively, compared to 10 percent for the group IHC/FISH defined as hormone receptor-positive and HER2-negative, the closest equivalent of Luminal.

BluePrint also reclassified 36 of 75 patients who were deemed HR-positive and HER2-positive (triple positive) by IHC-FISH into its Luminal, rather than HER2-positive category. This subset had a response rate of only three percent compared to 45 percent for those patients whom both classifiers deemed HER2-positive.

Overall, among patients BluePrint classified as fitting its HER2-positive subtype, pathological complete response was 53 percent, while the IHC/FISH HER2-positive subset only saw 38 percent response, the authors reported.

According to the authors, the results indicate that there are two main groups for whom these differences in classification may have significant clinical implications — first, the subset of IHC/FISH HER2-positive patients who are BluePrint HER2-negative, or Luminal — and second, the subset of IHC/FISH HR-positive/HER2-negative patients who are BluePrint Basal, rather than the expected Luminal.

In the study, BluePrint reclassified 36 out of 75 so-called triple-positive patients, those who were hormone receptor- and HER2-positive, into its Luminal group. These reclassified patients had a much lower response rate than those that both IHC/FISH and Blue Print agreed were HER2-positive — only 3 percent compared to 45 percent, respectively.

"Identification of this subset … is essential to avoid overtreatment of patients … who may be optimally treated with endocrine therapy alone, or in combination with a HER2-directed agent, thereby avoiding the use of chemotherapy," the authors wrote.

Meanwhile, about one fifth of the patients IHC/FISH classified as HER2-negative/ HR-positive — a group that should overlap with BluePrint's Luminal type — were actually classified as Basal type by the Agendia test.

"For this group of patients conventionally identified as endocrine responsive who are reclassified to the Basal subgroup, it makes sense to consider neoadjuvant chemotherapy," the authors wrote.

The study did not look at long term outcomes, only initial pathological response rates, so the question of whether BluePrint offers more accurate prediction of neoadjuvant treatment benefit in the long term is still open.

However, the authors wrote, in retrospectives analyses, initial pathologic complete response rates have correlated with distant metastasis-free survival for all but the Luminal subgroup.

Whitworth, the study's lead author, told PGx Reporter in an email that the researchers are also planning to study patients' more distant outcomes directly, following up at two- and five-years post-surgery as part of NBRST.

He said that the study has recruited its goal of about 1,000 patients, and is set to close this fall.

BluePrint is not the only molecular breast cancer classifier to enter the market. NanoString's Prosigna, which was granted 510(k) clearance by the US Food and Drug Administration last year is based on the PAM50 gene signature, which also classifies cancers into molecular subtypes.

Whitworth added that his team is also interested comparing classifications from BluePrint and the PAM50 test.

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