Abstract B02: Influence of germline BRCA mutation on response to oral cyclophosphamide in relapsed heavily pretreated ovarian cancer
Authors: Spiliopoulou Pavlina , Zubairi Ishtiaq , Gibson Sarah , Brown Jennifer , McNeish Iain , Glasspool Ros 
Published: August 2018

Abstract
Background: Continuous, metronomic administration of the alkylating agent cyclophosphamide (MC) has antitumor activity that may depend upon antiangiogenic and immune-stimulatory effects. In retrospective, mainly single-center clinical studies, objective response rate is reported as 20-25% in solid tumors. Its DNA-damaging potential could be potentiated in patients with BRCA-deficient tumors, a relatively common occurrence is ovarian cancer (OC). Here, we present efficacy and toxicity data of MC in patients with recurrent OC. We also investigate the influence of germline BRCA1/2 mutation status on outcome.
Methods: Patient records at a large regional UK cancer center were retrospectively reviewed. BRCA status was tested using Sanger sequencing, Gehan-Breslow-Wilcoxon and Fisher’s exact test for statistical analysis.
Results: Between 2012-2016, forty-nine patients with recurrent OC, median age 68 years (range 44-86), received 2 cycles of MC. Starting dose was 50mg/day in 45 patients and 100mg/day in 4 patients. Forty patients (82%) had acquired platinum-resistant disease. Ninety-two percent (92%) of patients had received 2 lines of previous treatment (median=3, range 1-10 lines).
Main toxicities were myelotoxicity (37% Grade 1-2) and gastrointestinal adverse events (20% Grade 1-2). There was 1 case of Grade 3 myelotoxicity and 1 case of Grade 3 transaminitis. There were no treatment-related deaths.
Median number of cycles was 3 (range 2-16 cycles). Eighteen patients (37%) showed a CA125 response. Radiologic responses were seen in 3/42 (7.1%) evaluable patients; 12/42 (28.6%) showed stable disease (SD). Median progression-free survival (PFS) and overall survival (OS) were 2.9 and 9 months, respectively. The rate of disease stabilization (PR or SD or Ca125 response) beyond 4 months was 18/49 (36.7%). PFS for this patient group achieving stable disease was 7.2 months.
Germline BRCA status was known for 35/49 patients. Patients with germline BRCA1/2 mutations had improved radiologic responses compared to wild-type patients (33% vs 0%; p=0.0128), longer PFS (8.3m vs 2.5m, p=0.013) and a trend towards longer OS (16m vs 6m, p=0.10).
Conclusions: Metronomic cyclophosphamide has overall modest activity in recurrent, platinum-resistant OC. However, it can achieve meaningful disease stabilization for some patients and offer a safe and easy to administer treatment in heavily pretreated cases. Patients with germline BRCA1/2 mutations have improved response rate and progression-free survival. Within the limitations of this small study, cyclophosphamide could be considered an option for this subset of patients.
Citation Format: Pavlina Spiliopoulou, Ishtiaq Zubairi, Sarah Gibson, Jennifer Brown, Iain McNeish, Ros Glasspool. Influence of germline BRCA mutation on response to oral cyclophosphamide in relapsed heavily pretreated ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B02.