BRCA1 is both a prognostic and predictive biomarker of response to chemotherapy in sporadic epithelial ovarian cancer ☆ Judith E. Carser a, 1 , Jennifer E. Quinn a, 1 , Caroline O. Michie b , Eamonn J. O'Brien c , W. Glenn McCluggage d , Perry Maxwell a, d , Elisabeth Lamers a , Tong F. Lioe e , Alistair R.W. Williams f , Richard D. Kennedy a, c , Charlie Gourley b , D. Paul Harkin a, c, ⁎ a Centre for Cancer Research and Cell Biology, Queens University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, N. Ireland, UK b University of Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XR, Scotland, UK c Almac Diagnostics, Seagoe Industrial Estate, Craigavon, BT63 5QD, N. Ireland, UK d Department of Pathology, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BL, N. Ireland, UK e Department of Pathology, Belfast City Hospital, 51 Lisburn Road, Belfast, BT9 7AB, N. Ireland, UK f Department of Pathology, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, Scotland, UK abstract article info Article history: Received 23 April 2011 Accepted 16 August 2011 Available online 13 September 2011 Keywords: BRCA1 Chemotherapy Ovarian cancer Prognostic Predictive Biomarker Objectives. We investigated the relationship between BRCA1 protein expression by immunohistochemis- try (IHC) and clinical outcome following platinum and platinum/taxane chemotherapy in sporadic epithelial ovarian cancer (EOC). Methods. BRCA1 IHC was performed on a cohort of 292 ovarian tumours from two UK oncology centres. BRCA1 protein expression levels were correlated with overall survival (OS), progression free survival (PFS) and clinical response to chemotherapy by multivariate analysis. Results. EOC patients with absent/low BRCA1 protein expression (41%) had a better chance of clinical re- sponse following chemotherapy as compared to patients with high BRCA1 expression (odds ratio 2.47: 95%CI 1.10–5.55, p = 0.029). Patients with absent/low BRCA1 had a higher probability of clinical response following single agent platinum compared to high BRCA1 expressing patients (68.5% vs. 46.8%), while addition of a tax- ane increased response rates independent of BRCA1. Overall, patients with absent/low BRCA1 had a better clinical outcome compared to patients with high BRCA1 protein expression in terms of both OS (HR = 0.65: 95%CI 0.48–0.88, p = 0.006) and PFS (HR = 0.74, 95%CI 0.55–0.98, p = 0.040). Conclusions. We confirm that absent/low BRCA1 protein expression is a favourable prognostic marker. However, we also provide the first evidence that absent/low BRCA1 protein expression in sporadic EOC pa- tients predicts for an improved clinical response to chemotherapy. © 2011 Elsevier Inc. All rights reserved. Introduction Epithelial ovarian cancer (EOC) is a major cause of mortality worldwide with estimates for new cases diagnosed in the USA and UK per annum, of 21,880 and 6,537 respectively [1,2]. Despite ad- vances in cytoreductive surgery and chemotherapy over the last de- cade, the five year relative survival rate is 46% [1]. Platinum and taxane combination chemotherapy is accepted as the international standard of care based on the Gynecologic Oncology Group 111 and OV-10 studies. These observed a significant increase in both PFS and OS in favour of platinum/taxane combinations over platinum/non- taxane regimens [3–5]. However, two later studies failed to demon- strate a survival advantage upon the addition of taxanes resulting in debate over the additional clinical benefit of taxanes to platinum che- motherapy [6,7]. Currently, there are no clinically validated predictive molecular biomarkers in routine use to help guide chemotherapy treatment decisions in EOC. The most important risk factor for developing EOC is a family his- tory of breast and/or ovarian cancer associated with germline muta- tions in BRCA1 or BRCA2, accounting for 5–15% of cases [8]. Somatic mutations are rare in sporadic disease, occurring in less than 10% of patients [9]. However, BRCA1 is reported to be downregulated in 15–72% of sporadic EOC cases via epigenetic and transcriptional mechanisms [10–12]. Therefore, BRCA1-deficiency is significant in the pathogenesis of both sporadic and hereditary EOC. Gynecologic Oncology 123 (2011) 492–498 ☆ Funding: Cancer Research UK (DPH), The HPSS R&D Office Northern Ireland (JEC), Breast Cancer Campaign (JEQ&EL), The Almac Trust and Invest Northern Ireland (RDK), The Melville Trust for the Care and Cure of Cancer (COM), The Charon Fund, The Scottish Chief Scientists Office (CG). ⁎ Corresponding author at: Centre for Cancer Research and Cell Biology, Queens University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. Fax: +44 28 9097 2776. E-mail address: d.harkin@qub.ac.uk (D.P. Harkin). 1 These authors contributed equally to this manuscript. 0090-8258/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2011.08.017 Contents lists available at SciVerse ScienceDirect Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno