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

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.