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


METHODS
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.
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1439, USA.
Charles
C
Coutant
Roman
R
Rouzier
Yuan
Y
Qi
Jacqueline
J
Lehmann-Che
Giampaolo
G
Bianchini
Takayuki
T
Iwamoto
Gabriel N
GN
Hortobagyi
W Fraser
WF
Symmans
Serge
S
Uzan
Fabrice
F
Andre
Hugues
H
de Thé
Lajos
L
Pusztai
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000706:statistics & numerical data*; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D011237:Predictive Value of Tests; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53