Abstract
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. 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. 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. 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.
Highlights
Altered function of the p53 protein due to mutation or other causes leads to a cascade of transcriptional changes that play an important role in cancer development. p53 functional status can be assessed by direct DNA sequencing, yeast functional complementation assay or by tran-Authors' Affiliations: Departments of 1Breast Medical Oncology, 2Bioinformatics, and 3Pathology, The University of Texas M.D
Miller and colleagues published a seminal work to determine a P53 transcriptional signature using both U133A and U133B chips, they have shown that patients with p53 mutant cancers had a worse prognosis and most importantly a 32-gene p53 signature could identify a subset of aggressive tumors that showed transcriptional hallmarks of p53 dysfunction even in the absence of detectable p53 mutation
Patients and materials The discovery set was composed of 251 breast cancers from a publicly available data set by Miller and colleagues with known p53 mutation status including 213 ERþ and 38 ERÀ cancers [12]
Summary
Altered function of the p53 protein due to mutation or other causes leads to a cascade of transcriptional changes that play an important role in cancer development. p53 functional status can be assessed by direct DNA sequencing, yeast functional complementation assay or by tran-Authors' Affiliations: Departments of 1Breast Medical Oncology, 2Bioinformatics, and 3Pathology, The University of Texas M.D. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The prognostic, predictive, and therapeutic relevance of altered p53 status detected by any of these methods remains uncertain in breast cancer [1, 2, 6]. Most previous studies examined the clinical value of p53 abnormalities across all breast cancers and p53 transcriptional signatures were invariably derived from the entire study population including all of the different breast cancer molecular subtypes. Developing gene signatures across all breast cancers when the genomic abnormality to be predicted by a gene expression signature is not distributed evenly across the major molecular types of breast cancer will inevitably include some molecular-phenotype related probe sets that will reduce the specificity and sensitivity of the resulting predictor.
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