Background: Ipilimumab was the first immune checkpoint inhibitor to demonstrate a survival benefit for metastatic melanoma patients and has been available in Northern Ireland (NI) since 2012. With the advent of more novel checkpoint inhibitor options and combinations, single-agent Ipilimumab use has declined, but evidence indicates it may continue to have a role after PD-1 inhibitor monotherapy failure. We investigated our clinical outcomes in the earlier era of this treatment. Methods: Ipilimumab-treated patient data were retrospectively collected using electronic record systems and clinical notes. Descriptive and inferential statistics using Microsoft Excel® and SPSS® were employed to evaluate outcomes, including objective response rates (RR) according to RECIST criteria, disease control rates (DCR), progression free survival (PFS) and overall survival (OS). Results: 70 patients were treated with Ipilimumab in NI between November 2012 and December 2015. 57 patients had a cutaneous or unknown primary, and of these, 40.3% harboured a BRAF mutation. 56.4% of all patients had received prior systemic therapy. Median follow-up duration was 12 months (range 0.63 to 51.2 months), and median number of cycles administered was 4, with 65.7% completing 4 cycles. RR and DCR were 10.1% and 31.9% respectively, and the median PFS was 2.9 months and OS 11.7 months. 50.7% of patients with disease progression received subsequent systemic therapy but 52% of deaths occurred prior to access to PD-1 inhibitor and BRAF/MEK targeted therapy in NI. Grade 3-4 toxicities occurred in 31.4% of patients. The 30-day mortality was 5.7% (4 patients), with only 1 suspected treatment-related death. Serum LDH>upper limit of normal, serum neutrophil:lymphocyte ratio>4, M1c disease, uveal primary, presence of brain metastases and ECOG performance status 2 were identified as clinical factors which correlate with worse PFS and OS, and all early mortality cases had two or more of these factors. Conclusions: Efficacy and toxicity data, and prognostic indicators for our cohort, are similar to other published data. Ipilimumab is deliverable in a non-clinical trial setting with acceptable outcomes, and may remain relevant as a viable treatment option. Patient selection is key to optimal results. Legal entity responsible for the study: Belfast Health and Social Care Trust Funding: None Disclosure: O. Oladipo: Served on advisory boards for MSD and BMS and supported for travel to educational meetings by both companies. V. Coyle: Almac Diagnostics, Craigavon, UK, Corporate Research Collaboration. All other authors have declared no conflicts of interest.

OBJECTIVES:We investigated the relationship between BRCA1 protein expression by immunohistochemistry (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 response 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 taxane 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 patients predicts for an improved clinical response to chemotherapy.

5527 Background: Reduced expression of BRCA1 is observed in a substantial proportion of sporadic EOC. First line management of EOC involves platinum and taxane based chemotherapy. In vitro studies demonstrate that reduction in BRCA1 protein expression leads to enhanced sensitivity to platinum but relative resistance to taxane chemotherapy. We investigated the relationship between BRCA1 protein expression by immunohistochemistry (IHC) and survival in EOC patients, correlating outcome with type of chemotherapy received. Methods: 97 archival formalin-fixed, paraffin embedded tumour samples were identified from the Edinburgh Cancer Centre ovarian database. All patients received platinum based chemotherapy (platinum only n = 50, platinum/taxane n = 47). Tumour sections were stained for BRCA1 protein and scored by two independent reviewers. Tumours were graded from 0 (no BRCA1 protein) to 4 (>90% cells positive). BRCA1 protein expression was correlated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis. Results: Overall, patients with no detectable BRCA1 protein had a significantly improved PFS compared to those with positive staining (17.4 months vs 12.2 months, p = 0.04). Specifically, patients receiving platinum only regimens had a significantly improved PFS if they had no detectable BRCA1 protein compared to those with positive staining (14.5 months vs 10.8 months, p = 0.035).In contrast, patients positive for BRCA1 protein (grades 1–4) had a significant increase in both OS (43.7 months vs 20.4 months, p = 0.03) and PFS (12.7 months vs 10.9 months p = 0.02) if they received platinum/taxane combination over platinum alone. Patients with no detectable BRCA1 protein (grade 0) had no significant difference in OS or PFS whether they were treated with combination or platinum only chemotherapy. Conclusions: This study provides initial evidence that BRCA1 protein expression may be a predictive marker of chemotherapy response in sporadic EOC. Specifically, patients with positive BRCA1 staining demonstrate a better clinical outcome with platinum/taxane based chemotherapy over platinum alone whereas no such difference was seen in those with no BRCA1. Further prospective clinical studies are required to validate these findings. No significant financial relationships to disclose.

Objectives. Treatment of epithelial ovarian cancer (EOC) remains a challenge, despite advances in surgery and chemotherapy. Hereditary ovarian cancer is primarily due to germline mutations in the BRCA1 turnout suppressor gene. In addition, sporadic EOC tumours display significant of loss of BRCA1 function due to epigenetic inactivation of the BRCA1 gene. This article reviews the preclinical and clinical evidence to support a role for BRCA1 as a potential predictive biomarker of response to both platinum and taxane based chemotherapy in EOC.Methods. We conducted a Medline and Pubmed search for reports between 1990 and 2008 using the search terms: BRCA1 and hereditary ovarian cancer, BRCA1 and sporadic ovarian cancer, ovarian cancer and chemotherapy, ovarian cancer and taxanes, ovarian cancer and platinums, ovarian cancer and clinical response, BRCA1 and DNA damage, BRCA1 and DNA repair, BRCA1 and mitotic checkpoint. If reports identified by these criteria referred to other papers not in the initial search, then these were also reviewed if relevant to BRCA1 and ovarian cancer.Results. The BRCA1 pathway plays a significant role in the development of both hereditary and sporadic EOC. Evidence suggests that BRCA1 is a potential biomarker of response to platinum chemotherapy in EOC with BRCA1 deficiency predicting for enhanced response. In contrast, initial evidence suggests that loss of BRCA1 function results in reduced response to antimicrotubule-based chemotherapy. The ability of BRCA1 to differentially modulate response to these agents involves loss of BRCA1 mediated DNA repair and mitotic checkpoint control, respectively.Conclusions. Standard first line treatment of EOC consists of a combination of platinum and taxane chemotherapy, however clinically useful biomarkers for predicting response to these agents have yet to be established. BRCA1 may prove useful as a biomarker in EOC for assigning chemotherapy treatments based on the presence or absence of BRCA1 function. (C) 2008 Elsevier Inc. All rights reserved