Gene expression signatures that predict outcome of tamoxifen-treated estrogen receptor-positive, high-risk, primary breast cancer patients: a DBCG study

TY - JOUR

T1 - Gene expression signatures that predict outcome of tamoxifen-treated estrogen receptor-positive, high-risk, primary breast cancer patients

T2 - a DBCG study

AU - Lyng, Maria B

AU - Lænkholm, Anne-Vibeke

AU - Tan, Qihua

AU - Vach, Werner

AU - Gravgaard, Karina H

AU - Knoop, Ann

AU - Ditzel, Henrik

PY - 2013/1/16

Y1 - 2013/1/16

N2 - BACKGROUND: 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.METHODOLOGY/PRINCIPAL FINDINGS: Post-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/SIGNIFICANCE: A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.

AB - BACKGROUND: 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.METHODOLOGY/PRINCIPAL FINDINGS: Post-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/SIGNIFICANCE: A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.

KW - Aged

KW - Breast Neoplasms

KW - Cyclin-Dependent Kinase Inhibitor p21

KW - Female

KW - Humans

KW - Middle Aged

KW - Polymerase Chain Reaction

KW - Proto-Oncogene Proteins c-bcl-2

KW - Receptors, Estrogen

KW - Tamoxifen

U2 - 10.1371/journal.pone.0054078

DO - 10.1371/journal.pone.0054078

M3 - Journal article

C2 - 23342080

SN - 1932-6203

VL - 8

SP - e54078

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 1

ER -