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*, Troels Dreier Christensen, Ib Jarle Christensen, Knud Mejer Nelausen, Eva Balslev, Ann Søegaard Knoop, Eva Harder Brix, Else Svensson, Vesna Glavicic, Adam Luczak, Sven Tyge Langkjer, Søren Linnet, Erik Hugger Jakobsen, Jurij Bogovic, Bent Ejlertsen, Annie Rasmussen, Anker Hansen, Steen Knudsen, Dorte Nielsen, Peter Buhl Jensen

*Kontaktforfatter for dette arbejde

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Resumé

Purpose: Anthracyclines 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. Methods: From 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. Results: Median 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. Conclusion: The 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.

OriginalsprogEngelsk
TidsskriftBreast Cancer Research and Treatment
Vol/bind172
Udgave nummer2
Sider (fra-til)391–400
ISSN0167-6806
DOI
StatusUdgivet - nov. 2018

Fingeraftryk

Epirubicin
Prospective Studies
Pharmaceutical Preparations
Messenger RNA
Informed Consent
Proportional Hazards Models
Paraffin
Formaldehyde
Medical Records
Multivariate Analysis

Citer dette

Buhl, Anna Sofie Kappel ; Christensen, Troels Dreier ; Christensen, Ib Jarle ; Nelausen, Knud Mejer ; Balslev, Eva ; Knoop, Ann Søegaard ; Brix, Eva Harder ; Svensson, Else ; Glavicic, Vesna ; Luczak, Adam ; Langkjer, Sven Tyge ; Linnet, Søren ; Jakobsen, Erik Hugger ; Bogovic, Jurij ; Ejlertsen, Bent ; Rasmussen, Annie ; Hansen, Anker ; Knudsen, Steen ; Nielsen, Dorte ; Jensen, Peter Buhl. / 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. I: Breast Cancer Research and Treatment. 2018 ; Bind 172, Nr. 2. s. 391–400.
@article{91c25852698349d3b82d88b102da14da,
title = "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",
abstract = "Purpose: Anthracyclines 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. Methods: From 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. Results: Median 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. Conclusion: The 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.",
keywords = "Advanced breast cancer, Epirubicin, Precision medicine, Predictive biomarker",
author = "Buhl, {Anna Sofie Kappel} and Christensen, {Troels Dreier} and Christensen, {Ib Jarle} and Nelausen, {Knud Mejer} and Eva Balslev and Knoop, {Ann S{\o}egaard} and Brix, {Eva Harder} and Else Svensson and Vesna Glavicic and Adam Luczak and Langkjer, {Sven Tyge} and S{\o}ren Linnet and Jakobsen, {Erik Hugger} and Jurij Bogovic and Bent Ejlertsen and Annie Rasmussen and Anker Hansen and Steen Knudsen and Dorte Nielsen and Jensen, {Peter Buhl}",
year = "2018",
month = "11",
doi = "10.1007/s10549-018-4918-4",
language = "English",
volume = "172",
pages = "391–400",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer",
number = "2",

}

Buhl, ASK, Christensen, TD, Christensen, IJ, Nelausen, KM, Balslev, E, Knoop, AS, Brix, EH, Svensson, E, Glavicic, V, Luczak, A, Langkjer, ST, Linnet, S, Jakobsen, EH, Bogovic, J, Ejlertsen, B, Rasmussen, A, Hansen, A, Knudsen, S, Nielsen, D & Jensen, PB 2018, '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', Breast Cancer Research and Treatment, bind 172, nr. 2, s. 391–400. https://doi.org/10.1007/s10549-018-4918-4

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

I: Breast Cancer Research and Treatment, Bind 172, Nr. 2, 11.2018, s. 391–400.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort

T2 - a retrospective-prospective blinded study

AU - Buhl, Anna Sofie Kappel

AU - Christensen, Troels Dreier

AU - Christensen, Ib Jarle

AU - Nelausen, Knud Mejer

AU - Balslev, Eva

AU - Knoop, Ann Søegaard

AU - Brix, Eva Harder

AU - Svensson, Else

AU - Glavicic, Vesna

AU - Luczak, Adam

AU - Langkjer, Sven Tyge

AU - Linnet, Søren

AU - Jakobsen, Erik Hugger

AU - Bogovic, Jurij

AU - Ejlertsen, Bent

AU - Rasmussen, Annie

AU - Hansen, Anker

AU - Knudsen, Steen

AU - Nielsen, Dorte

AU - Jensen, Peter Buhl

PY - 2018/11

Y1 - 2018/11

N2 - Purpose: Anthracyclines 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. Methods: From 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. Results: Median 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. Conclusion: The 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.

AB - Purpose: Anthracyclines 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. Methods: From 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. Results: Median 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. Conclusion: The 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.

KW - Advanced breast cancer

KW - Epirubicin

KW - Precision medicine

KW - Predictive biomarker

U2 - 10.1007/s10549-018-4918-4

DO - 10.1007/s10549-018-4918-4

M3 - Journal article

C2 - 30099635

AN - SCOPUS:85051496722

VL - 172

SP - 391

EP - 400

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 2

ER -