Gene-Based Test Identifies Breast Cancer with Low Risk for Late Metastasis

Charles Bankhead

March 2013, Highlights - Prognostic Tests

An 8-gene panel has demonstrated potential for identifying patients with estrogen receptor (ER)-positive and HER2-negative breast cancer at low risk for late metastasis. Patients classified as low risk by the EndoPredict panel had a significantly lower rate of distant metastasis after 5 and 10 years of follow-up compared with patients who did not meet the test’s criteria for low risk, according to Peter Dubsky, MD, of the Breast Health Center, Associate Professor of Sur­gery, Medical University of Vienna, Austria.

In a multivariate analysis, only the EndoPredict classification and nodal status emerged as independent predictors of the likelihood of late metastasis. Adding the gene test results to clinical variables (EPclin) significantly improved prognostic performance versus the clinical factors alone, Dr Dubsky said. Exploratory investigation of individual genes included in the panel revealed various effects on pathogenesis.

The EndoPredict Test

“The EndoPredict score identifies early and late recurrences and offers independent prognostic information beyond what can be achieved with all common clinical parameters,” he said.

“Proliferation genes add prognostic information for identifying early recurrences, whereas genes associated with estrogen receptor signaling are important for late events,” he explained.

ER-positive breast cancers remain at risk for late metastasis beyond 5 years, whereas most ER-negative tumors do not. Consequently, ER-positive cancer is associated with higher breast cancer–specific mortality after 5 to 10 years of follow-up, Dr Dubsky said.

The risk for late metastatic recurrence increases with nodal positivity and tumor size. Several molecular tests have been developed as aids to clinical decision-making, but no test with published data has outperformed the combination of hormone receptor status, HER2 status, and the proliferation factor Ki67.

EndoPredict is an RNA-based genetic test consisting of 8 cancer-related genes (BIRC5, UBE2C, DHCR7, RBBP8, IL6ST, AZGP1, MGP, and STC2) and 3 reference genes. Dr Dubsky presented results from a retrospective validation study involving 1702 patients from 2 clinical trials of adjuvant endocrine therapy for patients with ER-positive and HER2-negative tumors.

Study Results

The primary objectives of the study were to evaluate the test’s ability to predict the risk for late metastasis and to determine whether the test plus the clinical variables of tumor size and nodal status improved prediction of late metastasis.

In addition, the investigators explored the contributions of genes associated with ER signaling and differentiation from pro­liferation in early and late metastases.

The test classified 49% of the patients as low risk. After 5 years of follow-up, patients who did not have low-risk scores had almost a 3-fold greater risk for distant metastasis compared with the low-risk group (hazard ratio [HR], 2.80; P <.001). Beyond 5 years, the risk remained significantly increased in patients who were not classified as low risk (HR, 2.91; P = .002).

Multivariate analyses showed that the gene test was a predictor of early distant recurrence (HR, 1.20; P <.001) and late metastases (HR, 1.28; P = .001). Nodal status was the strongest predictor of early and late metastases (HR, 2.15; P <.001; HR, 2.45; P <.001, respectively). Age, tumor size, Ki67 level, tumor grade, and treatment assignment did not predict metastasis.

The EPclin Score

The investigators also evaluated the prognostic performance of the EPclin score—a combination of the EndoPredict and the clinical risk factors of nodal status and tumor size— with regard to the risk of metastasis beyond 5 years.

The addition of the gene-based test significantly improved the prognostic value of all common clinical parameters that were evaluated. The EPclin score demonstrated better performance than any other clinical parameters that were added to the EndoPredict test.

“The EPclin score identified a low-risk subgroup containing 64% of all patients at risk after 5 years,” said Dr Dubsky. “Results showed that 98% of these women remained free of distant metastases 10 years after diagnosis. The risks and side effects of extended therapy should be weighed against this projected outcome.”