Comparison of EndoPredict and EPclin With Oncotype DX Recurrence Score for Prediction of Risk of Distant Recurrence After Endocrine Therapy

Richard Buus; Ivana Sestak; Ralf Kronenwett; Carsten Denkert; Peter Dubsky; Kristin Krappmann; Marsel Scheer; Christoph Petry; Jack Cuzick; Mitch Dowsett

Disclosures

J Natl Cancer Inst. 2016;108(11) 

In This Article

Abstract and Introduction

Abstract

Background: Estimating distant recurrence (DR) risk among women with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2 (HER2)–negative early breast cancer helps decisions on using adjuvant chemotherapy. The 21-gene Oncotype DX recurrence score (RS) is widely used for this. EndoPredict (EPclin) is an alternative test combining prognostic information from an eight-gene signature (EP score) with tumor size and nodal status. We compared the prognostic information provided by RS and EPclin for 10-year DR risk.

Methods: We used likelihood ratio χ2 and Kaplan-Meier survival analyses to compare prognostic information provided by EP, EPclin, RS, and the clinical treatment score (CTS) of clinicopathologic parameters in 928 patients with ER+ disease treated with five years' anastrozole or tamoxifen. Comparisons were made for early (0–5 years) and late (5–10 years) DR according to nodal status. All statistical tests were two-sided.

Results: In the overall population, EP and EPclin provided substantially more prognostic information than RS (LRχ2: EP = 49.3; LRχ2: EPclin = 139.3; LRχ2: RS = 29.1), with greater differences in late DR and in node-positive patients. EP and EPclin remained statistically significantly prognostic when adjusted for RS (ΔLRχ2: EP+RS vs RS = 20.2; ΔLRχ2: EPclin+RS vs RS = 113.8). Using predefined cut-offs, EPclin and RS identified 58.8% and 61.7% patients as low risk, with hazard ratios for non-low vs low risk of 5.99 (95% confidence interval [CI] = 3.94 to 9.11) and 2.73 (95% CI = 1.91 to 3.89), respectively.

Conclusions: EP and EPclin were highly prognostic for DR in endocrine-treated patients with ER+, HER2-negative disease. EPclin provided more prognostic information than RS. This was partly but not entirely because of EPclin integrating molecular data with nodal status and tumor size.

Introduction

Breast cancer is the most common cancer in women. About 80% of primary breast cancers are estrogen receptor (ER)– positive disease. Patients with ER-positive disease receive adjuvant endocrine therapy after surgery that markedly improves their prognosis.[1] A large proportion of patients receiving endocrine therapy have sufficiently low risk to safely avoid chemotherapy. Differentiating these patients from higher-risk patients who may benefit from adjuvant chemotherapy is a priority for breast cancer management.[2]

Multigene expression prognostic assays may be used to estimate residual risk of recurrence following surgery and endocrine treatment to aid decisions on the appropriateness of chemotherapy treatment. The most widely used test is the Oncotype DX 21-gene recurrence score (RS).[3] Other prognostic scores to estimate residual risk in endocrine-treated patients include the PAM50 risk of recurrence (ROR) score,[4] the Breast Cancer Index (BCI),[5] and the IHC4 test that is immunohistochemically based and is combined with the clinical treatment score (CTS) to integrate clinicopathological parameters.[6] The amount of prognostic information provided for early (0–5 years) and late (beyond five years) recurrence varies across these tests.[7]

The EndoPredict (EP) assay combines the expression of three proliferative and five ER-signaling/differentiation-associated genes and is normalized by three housekeeping genes.[8] EP may be measured in formalin-fixed, paraffin-embedded tissue sections by quantitative real-time polymerase chain reaction (qRT-PCR) in decentralized laboratories[9] and provides a score that ranges between 0 and 15 after scaling. EPclin was derived from EP by incorporating nodal status and tumor size to create an integrated diagnostic algorithm for clinical decisions.[8] Both EP and EPclin were trained on a cohort of 964 patients with ER-positive, human epidermal growth factor receptor 2 (HER2)–negative carcinomas treated with adjuvant endocrine therapy only.[8] Thresholds for EP and EPclin to differentiate between patients at low or high risk corresponding to a 10% probability of distant recurrence (DR) at 10 years were set at 5 and 3.3, respectively. Both EP and EPclin were shown to be prognostic for early and late distant recurrence in the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6 and -8 trials.[10]

TransATAC, the translational substudy of the Arimidex, Tamoxifen, Alone or in Combination trial (ATAC), served as a validation study for the Oncotype DX RS,[11] PAM50 ROR,[12] and BCI[13] scores and as a training set for a definition of PAM50 ROR cut-off values and for CTS and IHC4 scores.[6]

Our aims were to assess the prognostic value of EP and EPclin for DR in postmenopausal women with hormone receptor–positive, HER2-negative primary breast cancer in TransATAC and to compare their prognostic ability with that of the Oncotype DX RS.

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