Pharmacogenomic Predictor of Sensitivity to Preoperative Chemotherapy With Paclitaxel and Fluorouracil, Doxorubicin, and Cyclophosphamide in Breast Cancer Kenneth R. Hess, Keith Anderson, W. Fraser Symmans, Vicente Valero, Nuhad Ibrahim, Jaime A. Mejia, Daniel Booser, Richard L. Theriault, Aman U. Buzdar, Peter J. Dempsey, Roman Rouzier, Nour Sneige, Jeffrey S. Ross, Tatiana Vidaurre, Henry L. Go ´mez, Gabriel N. Hortobagyi, and Lajos Pusztai A B S T R A C T Purpose We developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and as- sessed its predictive accuracy on independent cases. Patients and Methods One hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases. Results Overall pCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant. Conclusion A 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients). J Clin Oncol 24:4236-4244. © 2006 by American Society of Clinical Oncology INTRODUCTION Despite the critical importance of selecting the most effective adjuvant/neoadjuvant chemotherapy for an individual, diagnostic tests to guide selection of the optimal regimen for a particular patient are lacking. 1-4 Estrogen receptor (ER) –negative status, high grade, and high proliferative activity are histo- logic characteristics that tend to indicate more chemotherapy-sensitive cancer. 5-7 However, these clinicopathologic variables predict general chemo- therapy sensitivity and therefore, have little potential to guide selection of a specific regimen. Neoadjuvant (preoperative) chemotherapy provides an opportu- nity to directly assess tumor response to therapy. Furthermore, complete eradication of all invasive cancer from the breast and regional lymph nodes, pathologic complete response (pCR), is associated with excellent long-term cancer-free survival. 8,9 Our goal was to evaluate gene expression profiling as a potential tool to predict who may achieve pCR to sequential anthracycline paclitaxel preoperative chemotherapy. We selected a complex multidrug regimen for study because combination chemother- apy represents the current clinical standard for pa- tients who require systemic cytotoxic treatment. Also, gene signatures that are predictive of response to individual drugs may not fully capture sensitivity From the Departments of Biostatistics and Applied Mathematics, Pathology, Breast Medical Oncology and Radiol- ogy, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Breast Cancer Unit and Unité Propre de l’Enseignement Supérieur; Equipe d’Accueil 3535 of the Institut Gustave Roussy, Villejuif, France; Albany Medi- cal College, Albany NY; Departamento de Medicina Instituto Nacional de Enfermedades Neopla ´ sicas, Lima, Peru ´. Submitted January 11, 2006; accepted May 1, 2006; published online ahead of print at www.jco.org on August 7, 2006. Supported by grants from the National Cancer Institute (RO1-CA106290), the Breast Cancer Research Foundation, the Gilder Foundation, the Dee Simmons Fund, and the Nellie B. Connally Breast Cancer Research Fund. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Lajos Pusztai, MD, DPhil, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 1354, PO Box 301439, Houston, TX 77230-1439; e-mail: lpusztai@mdanderson.org. © 2006 by American Society of Clinical Oncology 0732-183X/06/2426-4236/$20.00 DOI: 10.1200/JCO.2006.05.6861 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 24  NUMBER 26  SEPTEMBER 10 2006 4236 Downloaded from ascopubs.org by 44.200.31.66 on June 9, 2022 from 044.200.031.066 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.