Personalized Medicine and Imaging Systematically Defining Single-Gene Determinants of Response to Neoadjuvant Chemotherapy Reveals Specific Biomarkers

Purpose:We sought to systematically define determinants of the response to neoadjuvant chemotherapy to elucidate predictive biomarkers for breast cancer. Experimental Design:An unbiased systematic analysis was performed inmultiple independent datasets to define genes predictive of complete pathologic response (pCR) following treatment with neoadjuvant chemotherapy. These geneswere interrogated across estrogen receptor (ER)–positive and ER-negative breast cancer and those in common across three different treatment regimens were analyzed for optimal predictive power. Subsequent validationwas performedon independent cohorts by gene expression and IHCanalyses. Results: Genes that were highly associated with the response to neoadjuvant chemotherapy in breast cancer were readily defined using a computational method ranking individual genes by their respective ROC. Such predictive genes of the response to taxane-associated therapies were strongly enriched for cellcycle control processes in bothER-positive andER-negative breast cancer and correlatedwithpCR.However, other genes that were specifically associated with residual disease were also identified under other treatment conditions. Using the intersection between treatment groups, nine genes were identified that harbored strong predictive power inmultiple contexts and validation cohort. In particular, the nuclear oncogeneDEK was strongly associated with pCR, whereas the cell surface protein BCAM was strongly associated with residual disease. By IHC staining, thesemarkers exhibited potent predictive power that remained significant in multivariate analysis. Conclusion: Systematic computational approaches can define key genes that will be able to predict the response to chemotherapy across multiple treatment modalities yielding a small collection of biomarkers that can be readily deployed by IHC analyses. Clin Cancer Res; 20(18); 4837–48. 2014 AACR. Introduction Although breast cancer is treatedwith a variety of targeted agents, conventional cytotoxic chemotherapy remains a mainstay of therapy (1–4). At present, complex chemotherapy regimens are applied in multiple distinct clinical scenarios in the treatment of breast cancer. It iswell appreciated that triple-negative breast cancer is treated largely exclusively with chemotherapy (2, 5, 6); however, other forms of breast cancer are also treatedwith chemotherapy. For example, luminal B breast cancer is often treated with adjuvant chemotherapy in conjunction with estrogen receptor (ER)– targeted therapeutics (7–10). Similarly, Her2-positive cancers are treated with trastuzumab in conjunction with taxane-based chemotherapy (11). In all of these contexts, it is critically important to elucidate determinants of the response to chemotherapy. One means to evaluate the response to chemotherapy in clinical specimens involve the analyses of the response to neoadjuvant chemotherapy (2, 12, 13). Although historically surgery has preceded treatment with adjuvant therapy, there has been a significant increase in neoadjuvant therapy (14, 15). Studies have shown that the response to neoadjuvant therapy is effective at predicting the ultimate course of tumor behavior and specific determinants of that response are being sought (2, 12, 16, 17). Importantly, pathologic response in neoadjuvant studies reveals tumor response to a given therapy independent of other prognostic features of disease, and therefore markers defined in the analyses of neoadjuvant treatment could be inferred to portend activity in the adjuvant setting as well. Several studies have analyzed the gene expression programs associated with response to neoadjuvant chemotherapy (16–18). Our group and others have analyzed specific gene expression programs associated with response to Simmons Cancer Center and Department of Pathology, UT Southwestern Medical Center, Dallas, Texas. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Authors: Erik S. Knudsen, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9072. Phone: 214-6484115; Fax: 214-648-4152; E-mail: [email protected]; and Agnieszka K. Witkiewicz, E-mail: [email protected] doi: 10.1158/1078-0432.CCR-14-0885 2014 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 4837 on April 15, 2017. © 2014 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst July 21, 2014; DOI: 10.1158/1078-0432.CCR-14-0885