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Contralateral breast cancer (CBC) incidence is reported as 0.4-0.7% per year, equating to an approximate 10-15% 20 year risk after primary cancer diagnosis. Young age at primary diagnosis and a strong family history are consistently cited as significant risk factors for CBC development. Requests for contralateral prophylactic mastectomy (CPM) are rising, despite a lack of evidence that CPM significantly improves breast cancer specific survival. Therefore, a method to stratify CBC prognosis and risk at an individual level is required to allow us to personalise surgical decision-making for individual patients. This study aims to: 1. Explore prognostic factors following CBC diagnosis; 2. Investigate metastatic CBC prevalence by determining clonal relationships between primary and CBC tumours; 3. Assess the rate of germline predisposition gene mutations in a large cohort of Northern Irish CBC cases. A cohort of 403 CBC patients and 1:1 matched unilateral breast cancer controls (matched for age, year of diagnosis, nodal positivity and tumour morphology) were identified from the Northern Ireland Cancer Registry. Archival primary, CBC and normal lymph node tissue from these CBC patients were obtained for somatic and germline sequencing of a custom 94-gene panel, comprising genes most commonly mutated in breast cancer and all known predisposition genes. CBC patients had a significantly increased risk of breast cancer specific mortality when compared with 1:1 matched unilateral breast cancer controls (HR 6.45, CI 4.27-9.77). Within the CBC cohort, a shorter time interval between primary and CBC diagnosis is associated with increased breast cancer mortality, whereby women with Targeted next generation sequencing of 42 cases to date has provided evidence of shared somatic mutations suggestive of metastatic clonality between primary and CBC in four cases (9.5%). Germline pathogenic predisposition gene mutations were identified in five (11.9%) patients and a further ten (23.8%) patients were noted to have germline predisposition variants of unknown significance. Breast cancer specific mortality risk was significantly higher in CBC patients compared with matched unilateral cancer controls, in excess of what would be expected from two primary cancer events. This finding suggests that there are as yet unquantified factors contributing to this excess hazard. Poorer outcome with shorter inter-tumour diagnostic intervals, in addition to evidence of primary-CBC clonality in some cases, suggests that metastatic CBC may play a role in excess risk. Additionally, the significant reduction in PR positivity of ER positive CBC tumours after ER+/PR+ primary tumours, could suggest that acquired hormonal resistance following primary anti-oestrogen therapy exposure may contribute to this additional mortality hazard. Citation Format: McIlmunn CG, Bannon FJ, Fitzpatrick D, Ervine A, Boyd C, Cameron I, Harita T, James J, Gonzalez de Castro D, Savage KI, McIntosh SA. Molecular and genetic characterisation of contralateral breast cancers in Northern Ireland: Opportunities for personalised surgery [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-10.

Background The evaluation of circulating tumour DNA (ctDNA) from clinical blood samples, liquid biopsy, offers several diagnostic advantages compared with traditional tissue biopsy, such as shorter processing time, reduced patient risk and the opportunity to assess tumour heterogeneity. The historically poor sensitivity of ctDNA testing, has restricted its integration into routine clinical practice for non-metastatic disease. The early kinetics of ctDNA during radical radiotherapy for localised NSCLC have not been described with ultra-deep next generation sequencing previously. Materials and methods Patients with CT/PET-staged locally advanced, NSCLC prospectively consented to undergo serial venepuncture during the first week of radical radiotherapy alone. All patients received 55Gy in 20 fractions. Plasma samples were processed using the commercially available Roche AVENIO Expanded kit (Roche Sequencing Solutions, Pleasanton, CA, US) which targets 77 genes. Results Tumour-specific mutations were found in all patients (1 in 3 patients; 2 in 1 patient, and 3 in 1 patient). The variant allele frequency of these mutations ranged from 0.05–3.35%. In 2 patients there was a transient increase in ctDNA levels at the 72 h timepoint compared to baseline. In all patients there was a non-significant decrease in ctDNA levels at the 7-day timepoint in comparison to baseline (p = 0.4627). Conclusion This study demonstrates the feasibility of applying ctDNA-optimised NGS protocols through specified time-points in a small homogenous cohort of patients with localised lung cancer treated with radiotherapy. Studies are required to assess ctDNA kinetics as a predictive biomarker in radiotherapy. Priming tumours for liquid biopsy using radiation warrants further exploration.

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.

Tissue microarray (TMA) is a high throughput analysis tool to identify new diagnostic and prognostic markers in human cancers. However, standard automated method in tumour detection on both routine histochemical and immunohistochemistry (IHC) images is under developed. This paper presents a robust automated tumour cell segmentation model which can be applied to both routine histochemical tissue slides and IHC slides and deal with finer pixel-based segmentation in comparison with blob or area based segmentation by existing approaches. The presented technique greatly improves the process of TMA construction and plays an important role in automated IHC quantification in biomarker analysis where excluding stroma areas is critical. With the finest pixel-based evaluation (instead of area-based or object-based), the experimental results show that the proposed method is able to achieve 80% accuracy and 78% accuracy in two different types of pathological virtual slides, i.e., routine histochemical H&E and IHC images, respectively. The presented technique greatly reduces labor-intensive workloads for pathologists and highly speeds up the process of TMA construction and provides a possibility for fully automated IHC quantification.