Cancer Therapy: Preclinical Gene Expression Profiles Associated with Response to Chemotherapy in Epithelial Ovarian Cancers Amir A. Jazaeri,1Christopher S. Awtrey,4 Gadisetti V.R. Chandramouli,1 Ya o E r i c Chu a n g, 2 Javed Khan,3 Christos Sotiriou,1Olga Aprelikova,1Cindy J. Yee,4 Kristin K. Zorn,6 Michael J. Birrer,6 J. Carl Barrett,1andJeff Boyd4,5 Abstract Purpose: The goal of this study was to determine whether distinct gene expression profiles are associated with intrinsic and/or acquired chemoresistance in epithelial ovarian carcinoma. Experimental Design: Gene expression profiles were generated from 21primary chemosensi- tive tumors and 24 primary chemoresistant tumors usingcDNA-based microarrays. Gene expres- sion profiles of both groups of primary tumors were then compared with those of 15 ovarian carcinomas obtained followingplatinum-based chemotherapy (‘‘postchemotherapy’’ tumors). A theme discovery tool was used to identify functional categories of genes involved in drug resistance. Results: Comparison of primary chemosensitive and chemoresistant tumors revealed differential expression of 85 genes (P < 0.001). Comparison of gene expression profiles of primary chemo- sensitive tumors and postchemotherapy tumors revealed more robust differences with 760 genes differentiatingthe two groups ( P < 0.001). In contrast, only 230 genes were differentially expressed between primary chemoresistant and postchemotherapy groups (P < 0.001). Common to both gene lists were 178 genes representing transcripts differentially expressed between post- chemotherapy tumors and all primary tumors irrespective of intrinsic chemosensitivity.The gene expression profile of postchemotherapy tumors compared with that of primary tumors revealed statistically significant overrepresentation of genes encoding extracellular matrix ^ related proteins. Conclusions: These data show that gene expression profiling can discriminate primary chemo- resistant from primary chemosensitive ovarian cancers. Gene expression profiles were also identi- fied that correlate with states of intrinsic and acquired chemoresistance and that represent targets for future investigation and potential therapeutic interventions. Platinum-based combination chemotherapy is the standard resistant to this treatment and subsequently show low response first-line treatment for advanced-stage epithelial ovarian carci- rates to other second-line agents (1–3). Early identification of noma. For the f75% of patients diagnosed with advanced- this group of patients could lead to their enrollment in clinical stage disease, 20% to 30% progress on or rapidly become trials or treatment with other experimental therapeutics because standard treatment affords them little benefit. Among initially chemosensitive patients, the vast majority will eventually relapse. Thus, chemoresistance may be present at the outset 1 2 Authors’Affiliations: Laboratory of Biosystems and Cancer and Radiation of treatment (intrinsic resistance) or may develop during Biology Branch, Center for Cancer Research, and 3Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland; 4Gynecology and Breast Research treatment (acquired resistance). In practice, ovarian cancers Laboratory, Department of Surgery, and 5Department of Medicine, Memorial are considered ‘‘platinum sensitive’’ if the clinical progression Sloan-KetteringCancer Center, New York,New York; and 6Department of Cell and free interval is >6 months, and evidence suggests that the longer Cancer Biology, Center for Cancer Research, National Cancer Institute, Rockville, this interval, the higher the subsequent response rates to Maryland Received 12/27/04; revised 5/31/05; accepted 6/16/05. additional chemotherapy (4–6). Grant support: NIH grant U01 CA88175 (J. Boyd) and Gynecologic Cancer Understanding the biological mechanisms underlying che- Foundation, National Cancer Institute Gynecologic Oncology Fellowship Program moresistance is of utmost importance for improving the (A.A. Jazaeri and K.K. Zorn). treatment and outcome of ovarian cancer. This topic has been The costs of publication of this article were defrayed in part by the payment of page the subject of intense research, and previous studies on charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. chemoresistance in ovarian cancer have investigated potential Note: Supplementary data for this article are available at Clinical Cancer Research involvement of molecules involved in drug transport, apopto- Online (http://clincancerres.aacrjournals.org/). sis, DNA repair, and detoxification pathways (7–11). Much of Requests for reprints: Jeff Boyd, Department of Surgery, Memorial Sloan- this research has been done using cell culture models and far KetteringCancer Center, Box 201, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8608; Fax: 212-717-3538; E-mail: [email protected]. fewer data are available on the relevance of these studies to, and F 2005 American Association for Cancer Research. biomarkers and potential mechanisms of drug resistance for, doi:10.1158/1078-0432.CCR-04-2682 clinical samples. Clin Cancer Res 2005;11(17) September 1, 2005 6300 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2005 American Association for Cancer Research. Molecular Profile of Drug Resistance in Ovarian Cancer The availability of new high-throughput screening techniques associated with both intrinsic and acquired chemoresistance in has allowed for more global investigations of molecular profiles ovarian cancer. The first aim of this investigation was to deter- associated with chemoresistance. In the present study, cDNA mine if intrinsically chemoresistant and chemosensitive tumors microarrays were used to investigate gene expression patterns could be distinguished based on their gene expression profiles. Ta b l e 1. Clinicopathologic features of primary ovarian cancer cases c Case no. Age* Histology Stage Grade Chemotherapy DFE Primary chemoresistant R1 49 Clear cell IIIC 3 Carboplatin/paclitaxel 0 R2 6 1 Endometrioid IIIC 3 Carboplatin/paclitaxel 0 R3 6 1 Serous IV 3 Carboplatin/paclitaxel 0 R4 49 Serous IIIC 2 Carboplatin/paclitaxel 0 R5 77 Serous IIIC NAb Carboplatin/paclitaxel 0 R6 49 Serous IIIC 2 Carboplatin/paclitaxel 0 R7 55 Serous IV 3 Carboplatin/paclitaxel 0 R8 56 Serous IIIC 2-3 Carboplatin/paclitaxel 0 R9 6 1 Serous IIIC 3 Carboplatin/paclitaxel 0 R10 73 Serous IV 3 Carboplatin/paclitaxel 0 R11 78 Serous IIIC 3 Carboplatin/paclitaxel 0 R12 7 1 Serous IV 2 Carboplatin/paclitaxel 0 R13 52 Serous IV 2 Carboplatin/paclitaxel 0 R14 64 Serous IIIA 1 Carboplatin/paclitaxel 0 R15 49 Serous IIIC 2 Carboplatin/paclitaxel 0 R16 47 Serous IV 3 Carboplatin/paclitaxel 0 R17 66 Serous IIIC 3 Cisplatin/cyclophosphamide 0 R18 69 Serous IV 2 Cisplatin/cyclophosphamide 0 R19 4 4 Serous IV 2 HD x cisplatin/cyclophosphamide 0 R20 35 Serous IV 2 Cisplatin/cyclophosphamide 0 R21 67 Serous IIIC 2-3 Cisplatin/cyclophosphamide 0 R22 63 Endometrioid IIIC 3 Carboplatin/paclitaxel 0 R23 76 Serous IIIC 3 Carboplatin 0 R24 65 Serous IIIC 2 Carboplatin/paclitaxel 0 Primary chemosensitive S1 5 1 Serous IV 2 Carboplatin/paclitaxel 35 S2 45 Endometrioid IIIC 2-3 HDCarboplatin/paclitaxel 41 S3 65 Mixed IIIC 3 Carboplatin/paclitaxel 13 S4 77 Serous IIIC 2-3 Carboplatin/paclitaxel 3 1 S5 53 Serous IIIC 3 Carboplatin/paclitaxel 32 S6 71 Serous IIIC 3 Carboplatin/paclitaxel 30 S7 55 Serous IIIC 3 Carboplatin/paclitaxel 19 S8 78 Endometrioid IIIC 2-3 Carboplatin/paclitaxel 24 S9 46 Endometrioid IIIC 3 Carboplatin/paclitaxel 2 1 S10 69 Serous IIIC 2 Carboplatin/paclitaxel 14 S11 54 Serous IV 1 Carboplatin/docetaxel 18 S12 53 Serous IIIC 2 Carboplatin/paclitaxel 18 S13 77 Serous IIIB 3 Carboplatin/paclitaxel 2 1 S14 56 Serous IIC 2 Carboplatin/paclitaxel 16 S15 44 Serous IIIC 2 Carboplatin/paclitaxel 16 S16 59 Carcinoma IIIC 3 Carboplatin/paclitaxel 16 S1744Serous IIICNACarboplatin/paclitaxel 13 S18 69 Serous IIIC 2 Carboplatin/paclitaxel 2 1 S19 70 Carcinoma IIIC 3 Carboplatin/paclitaxel 36 S20 74 Serous IIIC 2 Carboplatin/paclitaxel 2 1 S21 57 Serous IIIC 2 Carboplatin/paclitaxel 18 *Age at time of surgery. cDisease-free interval followingcompletion of chemotherapy (months). bNot available. xHigh-dose chemotherapy with bone marrow transplant. www.aacrjournals.org 6301 Clin Cancer Res 2005;11(17) September 1,2005 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2005 American Association for Cancer Research. Cancer Therapy: Preclinical Ta b l e 2 . Clinicopathologic features of postchemotherapy ovarian cancer cases Case no. Age* Histology Stage Grade Clinical hx Chemotherapy PC1 57 Serous IIIC 2 NC/IDc Carboplatin/paclitaxel  3 PC2 74 Serous IIIB 3 NC/ID Carboplatin/paclitaxel  3 PC3 59 Serous IIIC 3 NC/ID Carboplatin/paclitaxel  3 PC4 77 Serous IIIC 2 NC/ID Carboplatin/paclitaxel  6 PC5 73 Serous IIIC 2 NC/ID Carboplatin/paclitaxel  6 PC6 68 Undifferentiated IV 3 NC/ID Carboplatin/paclitaxel  6 PC7 22 Serous IIIC 1 NC/ID Carboplatin/paclitaxel  6 PC8 71 Serous IV 3 NC/ID Carboplatin/paclitaxel  6 PC9 71 Serous IIIC 3 NC/ID Carboplatin/paclitaxel  6 PC10 45 Endometrioid IIIC 2 PSLb HDx Carboplatin/paclitaxel PC11 56 Serous IIIC 3 PSL Carboplatin/paclitaxel  6 PC12 58 mixed IIIC 3 PSL Carboplatin/paclitaxel  6 PC13 66 Serous IIIC 3 PSL Carboplatin/paclitaxel  6 PC14 42 Serous IIIC 3 PSL Carboplatin/paclitaxel  6 PC15 28 Serous IIIC 2 PSL Carboplatin/paclitaxel  6 *Age