The clinical and pathological characteristics of breast cancer in young women and implications for genetic testing

Abstract

This thesis explores the way in which pathological parameters of breast cancer and family history affects outcomes and the probability of being a BRCA mutation carrier in a population of young onset UK breast cancer patients. This is set in the context of the mainstreaming genetic medicine agenda, VUS knowledge and working practises of UK genetics laboratories.

Descriptive characteristics of data from the UK Prospective study of Outcomes in Sporadic versus Hereditary breast cancer study (POSH) of 3000 patients were analysed with respect to distant disease free interval (DDFI) and overall survival (OS),stratified by Estrogen Receptor (ER) status and family history(FH). Patients with ER positive tumours compared to those with ER negative tumours had a better 5 year OS (85.0% vs 75.7%, p<0.001) that became non-significant by 8 years (67.5% v 67.7%, p=0.931). There was no difference in 5-year DDFI for FH + versus FH- patients (77.4% vs 74.9%, p=0.001).

Multifocal status significantly negatively correlated with BRCA1mutation status and there was anon-significant positive association in BRCA2. In multivariate analysis multifocality was not an independent predictor for survival.

Analysis of common pathological factors (receptor status, grade and mutlifocality) in a subgroup with BRCA genetic testing results was used to derive a new predictive algorithmfor FH – patients to determining pathogenic BRCA 1/2 mutation carrier probabilities.

Knowledge of VUS results by UK breast cancer specialists and of laboratory practices reported by UK geneticists was assessed by two online questionnaire surveys. Overall 71.0% of 181 of breast cancer clinicians felt uncomfortable/
unequipped to interpret a genetics report with surgeons more confident than oncologists. To facilitate moving genetic BRCA testing into mainstream oncology, genetics laboratories need to standardise reporting and testing clinicians need additional training to interpret BRCA reports.

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Identifiers

ORCID for Diana Eccles: orcid.org/0000-0002-9935-3169

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