This pilot study will evaluate the feasibility of a NGS-based tumour BRCA1/2 mutation testing pathway initiated in the oncology clinic for patients with HGSEC, either at primary diagnosis or first relapse, whereby only patients with a positive germline BRCA1/2 mutation test will be referred to clinical genetics. Germline BRCA1 and BRCA2 MLPA will be carried out to ensure accurate detection of BRCA1/2 LGRs. Patients with a high clinical risk of being germline mutation carriers and a negative germline BRCA1/2 mutation test should also be referred to clinical genetics. The investigators believe an upfront tumour testing pathway would be more cost-effective, as it would involve testing all patients for tumour BRCA1/2 mutations, followed by a single site germline test to clarify somatic/germline status of this mutation in approximately 25% of patients. In contrast, an upfront germline testing pathway would involve germline BRCA1/2 testing for all patients, followed by tumour BRCA1/2 tests in those 80 - 82% patients who do not have a germline BRCA1/2 mutation.
Systematic testing of patients in the oncology clinic for tumour BRCA1/2 mutations should not only ensure that all patients who are eligible for and agreeable to testing receive it, but also improve the quality of referrals to the clinical genetics team. Moreover, this approach is likely to significantly improve the identification rate of HGSEC patients with germline BRCA1/2 mutations, with resultant benefits for these patients in terms of cancer treatment and prevention, and their families in terms of opportunities for cancer prevention. The identification of patients with BRCA1/2 mutant HGSEC may facilitate treatment with effective maintenance therapies, or participation in clinical trials targeted at patients with BRCA1/2-mutated HGSEC. The incorporation of a health economics analysis relating to the introduction of this proposed testing pathway will further inform on the feasibility of its adoption into routine clinical practice on study completion. Finally, this study will also report on the currently unknown frequency, characteristics, disease course, and treatment patterns of germline and somatic BRCA1/2 mutations in an Irish population with HGSEC.
