Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers

Charles Coutant, Roman Rouzier, Yuan Qi, Jacqueline Lehmann-Che, Giampaolo Bianchini, Takayuki Iwamoto, Gabriel N. Hortobagyi, W. Fraser Symmans, Serge Uzan, Fabrice Andre, Hugues De The, Lajos Pusztai

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Abstract

Purpose: Estrogen receptor-positive (ER+) and-negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers. Experimental Design: We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER-cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER-cancers, respectively. Results: External validation to predict p53 status (n= 103) showed sensitivity and specificity of 89% and 54% for the 39-gene signature, and 82% and 61% for the 30-gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n= 277, HR = 2.43, P <0.0001) but it was not prognostic in ER= cancers. It was also associated with higher chemotherapy sensitivity in ER+ but not in ER= cancers. The prognostic and predictive values remained significant in multivariate analysis. The 30-gene, ER-, p53 signature showed no prognostic or predictive values in ER+ cancers but it was associated with better prognosis in ER-cancers. It also had no chemotherapy response predictive value in ER-or ER+ cancers. Conclusions: P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer.

Original languageEnglish
Pages (from-to)2591-2601
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
Publication statusPublished - Apr 15 2011

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p53 Genes
Breast Neoplasms
Drug Therapy
Neoplasms
Genes
Mutation
Tamoxifen
Estrogen Receptors
Research Design
Multivariate Analysis
Neoplasm Metastasis
Sensitivity and Specificity

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers. / Coutant, Charles; Rouzier, Roman; Qi, Yuan; Lehmann-Che, Jacqueline; Bianchini, Giampaolo; Iwamoto, Takayuki; Hortobagyi, Gabriel N.; Symmans, W. Fraser; Uzan, Serge; Andre, Fabrice; De The, Hugues; Pusztai, Lajos.

In: Clinical Cancer Research, Vol. 17, No. 8, 15.04.2011, p. 2591-2601.

Research output: Contribution to journalArticle

Coutant, C, Rouzier, R, Qi, Y, Lehmann-Che, J, Bianchini, G, Iwamoto, T, Hortobagyi, GN, Symmans, WF, Uzan, S, Andre, F, De The, H & Pusztai, L 2011, 'Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers', Clinical Cancer Research, vol. 17, no. 8, pp. 2591-2601. https://doi.org/10.1158/1078-0432.CCR-10-1045
Coutant, Charles ; Rouzier, Roman ; Qi, Yuan ; Lehmann-Che, Jacqueline ; Bianchini, Giampaolo ; Iwamoto, Takayuki ; Hortobagyi, Gabriel N. ; Symmans, W. Fraser ; Uzan, Serge ; Andre, Fabrice ; De The, Hugues ; Pusztai, Lajos. / Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 8. pp. 2591-2601.
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abstract = "Purpose: Estrogen receptor-positive (ER+) and-negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers. Experimental Design: We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER-cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER-cancers, respectively. Results: External validation to predict p53 status (n= 103) showed sensitivity and specificity of 89{\%} and 54{\%} for the 39-gene signature, and 82{\%} and 61{\%} for the 30-gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n= 277, HR = 2.43, P <0.0001) but it was not prognostic in ER= cancers. It was also associated with higher chemotherapy sensitivity in ER+ but not in ER= cancers. The prognostic and predictive values remained significant in multivariate analysis. The 30-gene, ER-, p53 signature showed no prognostic or predictive values in ER+ cancers but it was associated with better prognosis in ER-cancers. It also had no chemotherapy response predictive value in ER-or ER+ cancers. Conclusions: P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer.",
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T1 - Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers

AU - Coutant, Charles

AU - Rouzier, Roman

AU - Qi, Yuan

AU - Lehmann-Che, Jacqueline

AU - Bianchini, Giampaolo

AU - Iwamoto, Takayuki

AU - Hortobagyi, Gabriel N.

AU - Symmans, W. Fraser

AU - Uzan, Serge

AU - Andre, Fabrice

AU - De The, Hugues

AU - Pusztai, Lajos

PY - 2011/4/15

Y1 - 2011/4/15

N2 - Purpose: Estrogen receptor-positive (ER+) and-negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers. Experimental Design: We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER-cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER-cancers, respectively. Results: External validation to predict p53 status (n= 103) showed sensitivity and specificity of 89% and 54% for the 39-gene signature, and 82% and 61% for the 30-gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n= 277, HR = 2.43, P <0.0001) but it was not prognostic in ER= cancers. It was also associated with higher chemotherapy sensitivity in ER+ but not in ER= cancers. The prognostic and predictive values remained significant in multivariate analysis. The 30-gene, ER-, p53 signature showed no prognostic or predictive values in ER+ cancers but it was associated with better prognosis in ER-cancers. It also had no chemotherapy response predictive value in ER-or ER+ cancers. Conclusions: P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer.

AB - Purpose: Estrogen receptor-positive (ER+) and-negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers. Experimental Design: We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER-cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER-cancers, respectively. Results: External validation to predict p53 status (n= 103) showed sensitivity and specificity of 89% and 54% for the 39-gene signature, and 82% and 61% for the 30-gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n= 277, HR = 2.43, P <0.0001) but it was not prognostic in ER= cancers. It was also associated with higher chemotherapy sensitivity in ER+ but not in ER= cancers. The prognostic and predictive values remained significant in multivariate analysis. The 30-gene, ER-, p53 signature showed no prognostic or predictive values in ER+ cancers but it was associated with better prognosis in ER-cancers. It also had no chemotherapy response predictive value in ER-or ER+ cancers. Conclusions: P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer.

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