Predictive Biomarkers and Personalized Medicine Distinct p53 Gene Signatures Are Needed to Predict Prognosis and Response to Chemotherapy in ER-Positive and ER-Negative Breast Cancers Charles Coutant 1,4 , Roman Rouzier 4 , Yuan Qi 2 , Jacqueline Lehmann-Che 5 , Giampaolo Bianchini 1,6 , Takayuki Iwamoto 1,7 , Gabriel N. Hortobagyi 1 , W. Fraser Symmans 3 , Serge Uzan 4 , Fabrice Andre 8 , Hugues de Th e 5 , and Lajos Pusztai 1 Abstract Purpose: Estrogen receptor-positive (ERþ) 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 ERþ and a separate 30- gene signature from 38 ER cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ERþ and ER cancers, respectively. Results: External validation to predict p53 status (n ¼ 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 ERþ cancers in two separate prognostic data sets (n ¼ 255, HR: 2.3, P ¼ 0.005 and n ¼ 198, HR: 2.17, P ¼ 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n ¼ 277, HR ¼ 2.43, P < 0.0001) but it was not prognostic in ER cancers. It was also associated with higher chemotherapy sensitivity in ERþ 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 ERþ cancers but it was associated with better prognosis in ER cancers. It also had no chemotherapy response predictive value in ER or ERþ cancers. Conclusions: P53 dysfunction is prognostically most relevant in ERþ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer. Clin Cancer Res; 17(8); 2591–601. Ó2011 AACR. Introduction 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 sequen- cing, yeast functional complementation assay or by tran- scriptional read out of p53 activity (i.e., p53 gene signature; refs. 1–5). 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 transcrip- tional signatures were invariably derived from the entire study population including all of the different breast cancer molecular subtypes. 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 iden- tify a subset of aggressive tumors that showed transcrip- tional hallmarks of p53 dysfunction even in the absence of detectable p53 mutation. 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-phe- notype related probe sets that will reduce the specificity and sensitivity of the resulting predictor. Breast cancer is no longer considered to be a single disease but a collection of molecularly and clinically distinct neoplastic diseases of the breast (7, 8). The most extensive molecular and clinical Authors' Affiliations: Departments of 1 Breast Medical Oncology, 2 Bioin- formatics, and 3 Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 4 Department of Gynecology and Obstetrics, University Pierre et Marie Curie, Paris 6 and UPRES EA 4053, Tenon Hospital, Assistance Publique des Hôpitaux de Paris; 5 Department of Biochemistry and INSERM U944, University Rene Diderot, Paris 7, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; 6 Division of Medical Oncology, Fondazione IRCCS Istituto Tumori di Milano, Milan, Italy; 7 Department of Gastroenterological Surgery and Surgical Oncology, Okayama, University Graduate School of Medicine and Dentistry, Okayama, Japan; and 8 The Translational Research Unit, Institut Gustave Roussy, Villejuif, France Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Lajos Pusztai, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439. Phone: 713-792-2817; Fax: 713- 794-4385; E-mail: lpusztai@mdanderson.org doi: 10.1158/1078-0432.CCR-10-1045 Ó2011 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 2591 Research. on July 31, 2017. © 2011 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst January 19, 2011; DOI: 10.1158/1078-0432.CCR-10-1045