Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study

Anna Sofie Kappel Buhl,Trine Christensen ,Dorte Nielsen,Else Svensson,Ib Jarle Christensen,Vesna Glavicic,Anker Hansen,Knud Mejer Nelausen,Ann Knoop ,Peter Buhl Jensen,Adam Andrzej Luczak ,Sven Tyge Langkjer,Steen Knudsen,Jurij Bogovic,Erik Jakobsen ,Eva Brix ,Bent Ejlertsen,Annie Rasmussen,Søren Linnet,Eva Balslev

doi:10.1007/s10549-018-4918-4

Abstract

PurposeAnthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from > 3000 clinical tumor samples.MethodsFrom a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients’ medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line.ResultsMedian TTP was 9.3 months. The DRP was significantly associated to TTP (P = 0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI –0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases.ConclusionThe current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.

Highlights

Breast cancer (BC) is one of the most common cancers worldwide and accounts for 15% of all cancer-related deaths among females [1]
We found a significant association of the continuous drug response predictor (DRP) with time to progression (TTP) in epirubicin-treated advanced BC patients
The DRP for epirubicin has previously been evaluated on published material in a neoadjuvant setting in early BC with statistically significant findings [17]

Summary

Introduction

Breast cancer (BC) is one of the most common cancers worldwide and accounts for 15% of all cancer-related deaths among females [1]. Extended author information available on the last page of the article the time of diagnosis [3]. Most of these patients are considered non-curable and treatment is limited to a palliative focus [3]. Anthracyclines, e.g., epirubicin, doxorubicin, and pegylated doxorubicin, are widely used in the different settings of BC treatment, and are in the (neo)adjuvant setting considered standard treatment [4]. Anthracyclines are recommended in locally advanced or metastatic disease [5]. Doxorubicin is commonly used in the US, whereas the use of epirubicin is more widespread in Europe [6]. Epirubicin and doxorubicin are molecular alike with similar efficacy epirubicin potentially has a better toxicity profile particular concerning cardiotoxicity [7]

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