Abstract P1-09-10: Molecular and genetic characterisation of contralateral breast cancers in Northern Ireland: Opportunities for personalised surgery
Authors: McIlmunn CG , Bannon FJ , Fitzpatrick D , Ervine A , Boyd C , Cameron I , Harita T , James J , Gonzalez de Castro D , Savage KI , McIntosh SA 
Published: May 2019

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 &lt;5 years between diagnoses have the poorest survival (p=0.001). In terms of receptor status, the PR status of ER positive primary and CBC tumours differed significantly (p&lt;0.001). 89.1% of ER positive primary tumours were PR positive, whilst PR positivity was only 54.4% in ER positive CBCs. Indeed, 36.6% of patients with an ER+/PR+ primary BC developed an ER+/PR- CBC, after exposure to anti-oestrogen therapy.

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.