Abstract OT3-01-01: Chemoprevention in BRCA1 mutation carriers (CIBRAC): A proof of concept clinical trial
Authors: Campbell AM , Savage KI , McIntosh SA 
Published: February 2018

Abstract
Introduction
Currently, risk management options for BRCA1 mutation carriers include risk-reducing mastectomies (RRM), and selective oestrogen receptor modulators (SERMs). However, the majority of BRCA1-associated tumours are oestrogen receptor negative (ER-ve). SERMs do not reduce the incidence of ER-ve tumours, therefore are unlikely to be effective in this group of women. Oestrogen and its metabolites have been shown to cause DNA damage, resulting in genomic instability in BRCA1 deficient breast cells, an early hallmark of BRCA1-related cancers. Based on this, we hypothesise that oestrogen suppression in BRCA1 carriers may reduce DNA damage in breast tissue, and thereby potentially reducing breast cancer risk.
Trial Design
The study is an interventional, non-randomised, crossover study without masking. The primary purpose is to assess the impact of these drugs on suppression of DNA damage and therefore their potential for use as chemopreventive agents in this setting.
Pre-menopausal BRCA1 mutation carriers will be recruited from the Family History Clinic at Belfast City Hospital. The proportion of women who receive information packs who progress to trial entry will be recorded, with target recruitment of twelve women to the trial. Participants will complete quality of life questionnaires, provide blood and urine samples and undergo baseline ultrasound-guided breast biopsy. Half of these women will receive a SERM (tamoxifen) for 3 months, whilst the other half receives oestrogen suppression therapy (goserelin and anastrazole), and then provide repeat questionnaires and samples (blood, urine and breast biopsy). Treatment groups will cross over for a further 3 months treatment, with a final set of questionnaires and samples taken. Compliance with treatment and adverse events will be monitored throughout the study.
Eligibility Criteria
Inclusion criteria:
· Female
· Age ≥18 years
· Premenopausal
· Known pathogenic BRCA1 mutation
· Intact ovaries
· No previous breast/ovarian/other carcinoma
· No previous use of chemoprevention
· Willingness to use non-hormonal methods of contraception
Exclusion criteria:
· BRCA1 mutation of uncertain significance
· Contraindications to study drugs or breast biopsies
· Pregnancy or breastfeeding
· Inability to give informed consent
· Patient awaiting risk reducing surgery
Specific Aims
The primary objective is to assess the feasibility of treatments by measuring successful recruitment rates and compliance. The secondary objective is to establish tolerability of interventions through quality of life measurements and adverse event occurrence.
Exploratory objectives will assess the potential of treatments to reduce DNA damage through analysis of breast biopsies using comet assays and immunohistochemistry for 53BP1 and γH2AX (markers of DNA double-strand breaks). Oestrogen and metabolite levels will be measured in blood and urine samples using UPLC-MS/MS.
Statistical Methods
Not applicable due to nature and size of pilot study
Present accrual: 1 participant
Target accrual: 12 participants
Contact information for people with specific interest in trial: aideen.campbell@qub.ac.uk or s.mcintosh@qub.ac.uk
Citation Format: Campbell AM, Savage KI, McIntosh SA. Chemoprevention in BRCA1 mutation carriers (CIBRAC): A proof of concept clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-01-01.