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01.04.2014 | Research article | Ausgabe 2/2014 Open Access

Breast Cancer Research 2/2014

Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2− breast cancer patients: results from the GEICAM 9906 trial

Zeitschrift:
Breast Cancer Research > Ausgabe 2/2014
Autoren:
Miguel Martin, Jan C Brase, Lourdes Calvo, Kristin Krappmann, Manuel Ruiz-Borrego, Karin Fisch, Amparo Ruiz, Karsten E Weber, Blanca Munarriz, Christoph Petry, Cesar A Rodriguez, Ralf Kronenwett, Carmen Crespo, Emilio Alba, Eva Carrasco, Maribel Casas, Rosalia Caballero, Alvaro Rodriguez-Lescure
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​bcr3642) contains supplementary material, which is available to authorized users.

Competing interests

JCB declares receiving salary from Sividon Diagnostics GmbH and holding a patent application related to the content of this article. KK and KF declare receiving salary from Sividon Diagnostics GmbH. KEW, RK and CP declare receiving salary from Sividon Diagnostics GmbH, holding shares in Sividon Diagnostics GmbH and holding a patent application related to the content of this article. The rest of the authors declare that they have no competing interests.

Authors’ contributions

MM was involved in the conception and design of the study; acquisition, assembly analysis and interpretation of data; and drafting the manuscript. JCB participated in the conception and design of the study, designed the gene expression experiments, participated in the analysis and interpretation of data as well as statistical analysis and drafted the manuscript. KK designed and carried out the gene expression experiments, participated in the analysis and interpretation of data and was involved in drafting the manuscript. KF participated in the design of the study and in the statistical analysis and revised the manuscript critically. KEW participated in the design of the study and in the statistical analysis and revised the manuscript critically. RK participated in the conception and design of the study, participated in the analysis and interpretation of data and helped with drafting the manuscript. CP participated in the conception and design of the study, participated in the interpretation of data and helped with drafting the manuscript. LC, MRB, AR, BM, CR, CC, EA and ARL were involved in the acquisition and assembly of data and in the critical revision of the manuscript. MC completed statistical analyses and interpretation of data and critically revised the manuscript. EC and RC participated in the design and coordination of the study and helped with drafting the manuscript. All authors read and approved the final manuscript.

Abstract

Introduction

EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2− BC patients in the GEICAM 9906 trial.

Methods

The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor–positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression.

Results

The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2− cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant.

Conclusions

EP is an independent prognostic parameter in node-positive, ER+/HER2− BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone.
Zusatzmaterial
Additional file 1: Figure S1: Participating centers in the GEICAM 9906 phase III clinical trial. (PDF 76 KB)
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Additional file 2: Figure S2: Diagram of the CONSORT study. (PPTX 57 KB)
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Additional file 3: Figure S3: Kaplan-Meier overall survival curves for ER+/HER2− breast cancers by EndoPredict score and combined molecular and clinical EndoPredict test score risk groups. Cutoff points for EndoPredict (EP) and combined molecular and clinical EndoPredict test (EPclin) were prespecified at 5 and 3.3, respectively. Numbers in parentheses indicate the 95% confidence interval of the hazard ratio. EP: EndoPredict score. EPclin: combined molecular and clinical score. ARR: Absolute risk reduction estimated at 10 years. (A) Overall (OS) in EP low risk was 92% vs 67% in the EP high risk. (B) OS in EPclin low risk was 99% vs 69% in the EPclin high risk. (PPTX 101 KB)
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Additional file 4: Figure S4: Kaplan-Meier metastasis-free survival curves for breast cancer patients with ER+/HER2− tumors. Analysis by treatment arm (FEC vs FEC-P). ER, Estrogen receptor; MFS, Metastasis-free survival. (PPTX 72 KB)
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Additional file 5: Figure S5: Kaplan-Meier metastasis-free survival curves for ER+/HER2− tumors by treatment arm in EndoPredict clinical score (A) low-risk and (B) high-risk group. EPclin: combined molecular and clinical score. Cutoff point for EPclin was prespecified at 3.3. Numbers in parentheses indicate the 95% confidence interval of the hazard ratio. ER, Estrogen receptor; MFS, Metastasis-free survival. (PPTX 96 KB)
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Authors’ original file for figure 1
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Authors’ original file for figure 5
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Authors’ original file for figure 8
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