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BioTheranostics Study Suggests BCI Test May Outperform Oncotype for Long-term Risk and HER2-neg Subset

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In a recent validation study, researchers involved in developing Biotheranostics' Breast Cancer Index test have found that the BCI outperformed Genomic Health's Oncotype DX in predicting longer-term recurrence risk, as well as early recurrence risk in a subgroup of HER2-negative patients.

The team published the results, an extension of work presented last year at the San Antonio Breast Cancer Conference (PGx 12/12/2012), in the Lancet last month.

The study's lead author Dennis Sgroi, director of breast pathology at Massachusetts General Hospital, told PGx Reporter that the ER+, node-negative, HER2-negative population the study drilled down to represents a subset for whom risk stratification to guide anti-hormonal and chemotherapy is especially beneficial.

"If [patients] are HER2-positive, we know how to treat them: pretty uniformly. They are going to get chemotherapy, hormonal therapy, and Herceptin, so there really isn’t a need for a prognostic biomarker in [that group,]" Sgroi said.

"But the subset of ER-positive, node-negative, HER2-negative patients, that’s really the population you are targeting with this type of testing. That’s who you really want to decide whether they need hormonal therapy alone or chemotherapy … and the study showed that the BCI has a significant performance difference [for this subgroup] compared to Oncotype," he said.

BioTheranostics' BCI, which Sgroi and his colleagues developed and validated, is a combination of two gene expression biomarkers — HOXB13/IL17BR, and a five-gene "molecular grade index" or MGI — that the team originally developed separately and then discovered could add predictive value to each other.

In the study — which compared risk scores according to the BCI with risk scores from Oncotype DX and another classifier, IHC4 — Sgroi and his colleagues found that BCI and IHC4 performed equally well and better than Oncotype DX in determining risk of distant recurrence for the first five years after diagnosis in the HER2-negative subset of patients. However, all three assays had significant prognostic ability for early distant recurrence if the results were not restricted to HER2-negative patients, according to the study authors.

The team also found that in predicting prognosis from five to 10 years post-diagnosis, the BCI far outperformed either competing test.

Sgroi said BCI's performance specifically gauging this five- to 10-year distant recurrence risk bodes well for the clinical potential of the test, because it suggests that the assay may be unique in its ability to offer critical prognostic information specific to the post-five-year period.

"We were very excited by that because there are two therapeutic decision points for patients — first is the time of diagnosis, and then secondly, if a patient undergoes hormonal therapy for five years and is tumor-free you have another decision to make [as to] whether to put them on longer-term hormonal therapy or not."

"In those patients who have had hormonal therapy for five years and are disease free, BCI is prognostic and provides a risk estimate for late recurrence. IHC4 and OncotypeDx were not prognostic in this setting," Sgroi said.

The study looked, overall, at a retrospective sample set from the TransATAC study representing all postmenopausal patients in the trial with estrogen-receptor-positive, node-negative breast cancer who had already been scored using Oncotype DX's 21-gene recurrence test as well as IHC4 values.

The researchers did BCI analysis on 665 matched samples that had sufficient remaining RNA and assessed the ability of the test to predict distant recurrence over 10 years, as well as early recurrence up to five years after diagnosis. They also assessed the test's ability specifically for the period of five to 10 years, comparing these predictions to risk scores given by Oncotype and IHC4 in a multivariate analysis, measuring improvement in prediction by the change in the likelihood ratio χ² value, which measures the amount of information added by the gene signatures compared with clinical treatment score.

For ER-positive, node-negative patients overall, the three tests all offered significant prognostic power in the timeframe of zero to five years. But when looking specifically at HER2-negative patients, the researchers found that the BCI and IHC4 tests had higher prognostic ability — a likelihood ratio χ² value change of 13.65 and 13.83 respectively — than Oncotype, which had a LR-Δχ² of 8.37.

For both HER2-positive and HER2-negative patients, only the BCI was strongly prognostic for recurrence from five to 10 years in the multivariate analysis, the authors reported.

Neither Agendia's Mammaprint nor NanoString's PAM50, another multi-gene assay that gauges the risk of 10-year distant recurrence in breast cancer, were included in the comparison because neither had been performed on the ATAC cohort at the time BioTheranostics performed its analysis.

An interesting additional result of the analysis, Sgroi said, was that although the BCI is designed to split patients into three risk groups — low-, intermediate-, and high-risk — in the ATAC cohort, the intermediate risk group tended to track extremely closely to either the low-or high-risk group, depending on which timeframe the researchers were looking at.

So, for the first five years after diagnosis, the intermediate-risk group was extremely close in its risk of recurrence to the low-risk group, while from five to 10 years, the intermediate-risk group showed a risk very close to the high-risk group — essentially meaning that for each time period there were only two real risk categories: low and high.

According to the study authors, this might mean an advantage for the BCI over other contemporary gene-expression signatures, since having only two distinct risk groups "potentially eliminates the less-actionable intermediate-risk category that can account for as many as 40 percent of patients with estrogen-receptor-positive breast cancer."

"All these patients were treated with anastrozol or tamoxifen for five years, and at the end of those five years they came off these anti-hormonal agents," Sgroi explained. "So, what one can hypothesize, is that this [intermediate group] is the group that was responding to hormonal agents during the first five years."

Sgroi said that his team hopes to follow up the study and other recent validation research they have published with efforts to demonstrate that the BCI can predict not only patients' risk of recurrence, but also how they may respond to chemotherapy.

However, he said he sees the current validation results as strong enough for the test to be used to guide treatment decisions even without this additional evidence.

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