Gene Expression Signatures That Predict Outcome of Tamoxifen-Treated Estrogen Receptor-Positive, High-Risk, Primary Breast Cancer Patients: A DBCG Study

Maria B Lyng,Henrik J Ditzel,Karina H Gravgaard,Qihua Tan,Werner Vach,Ann Knoop,Anne-Vibeke Lænkholm,Toshi Shioda

doi:10.1371/journal.pone.0054078

Abstract

BackgroundTamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy.Methodology/Principal FindingsPost-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric bootstrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (n = 623). Three gene signatures were identified, the strongest being a 2-gene combination of BCL2-CDKN1A, exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (n = 503) confirmed the potential of BCL2-CDKN1A. The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25).Conclusions/SignificanceA novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.

Highlights

For patients with breast tumors expressing the estrogen receptor alpha protein (ER+) adjuvant anti-estrogen treatment with Tamoxifen significantly reduce the risk of recurrence and death in all age groups studied
We aimed to identify novel gene signatures that accurately predict the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy using quantitativePCR
Comparative analysis of the genes according to altered expression across the recurrent vs. non-recurrent patient samples (Table 2) identified BCL2 as the most significant (p = 0.0002), and it remained significant upon Bonferroni correction

Summary

Introduction

For patients with breast tumors expressing the estrogen receptor alpha protein (ER+) adjuvant anti-estrogen treatment with Tamoxifen significantly reduce the risk of recurrence and death in all age groups studied. A meta-analysis of 21,457 women with breast cancer included in 20 trials of adjuvant Tamoxifen therapy showed a reduction of 15-year breast cancer mortality rates by at least one third [1]. Tamoxifen remains the treatment modality for premenopausal breast cancer patients and patients resistant to AIs. In addition, the various side-effects prevent some patients from receiving AIs [6,7,8]. Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy

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Conclusion