Treatment of BRCA1/2-associated breast cancer and identification of mutation carriers among breast cancer patients

Abstract: The general aim of the research presented in this thesis was to contribute to the understanding of how breast cancer patients with germline BRCA1/2 mutations should be treated medically and surgically, and furthermore, to characterize the limitations and strengths of different procedures for BRCA testing. In Paper I, the long-term prognosis was assessed in a cohort of early-onset breast cancer patients (n = 221). BRCA1/2 mutation carriers (n = 20) had an inferior overall survival compared to non-carriers (HR 1.8; 95% CI 1.0-3.3), but not when the analysis was restricted to patients who received adjuvant or neoadjuvant chemotherapy (HR 1.1; CI 0.5-2.5). The results lend support to the notion that all, or almost all, patients with BRCA-associated breast cancer should be offered chemotherapy. In Paper II, breast-conserving therapy (BCT) was compared to mastectomy in a cohort of BRCA1/2 mutation carriers (n = 162). Patients treated with BCT had a high risk of local recurrence (15-year risk: 32%), some of which were probably new primary breast tumors rather than true recurrences. In Paper III, the “real world” performance (effectiveness) of the Swedish BRCA testing criteria was compared with the sensitivity (efficacy) of those criteria in a group of germline BRCA1/2 mutation carriers (n = 20), identified within a biobank research study of unselected breast cancer patients. The effectiveness was much lower than the efficacy (18% vs 65%), suggesting that currently used clinical BRCA testing routines need to be critically revised. In Paper IV, the results of a prospective, non-randomized study (BRCAsearch; ClinicalTrials.gov Identifier: NCT02557776) were reported. Patients with newly diagnosed breast cancer were offered germline BRCA testing regardless of age at diagnosis or family history of cancer. Pre-test information was provided by a standardized invitation letter instead of in-person genetic counseling. Out of 818 patients who received the invitation letter, 542 (66.2%) consented to analysis of BRCA1 and BRCA2. Eleven (2%) pathogenic mutations were found (BRCA1, n = 2; BRCA2, n = 9). Very few patients contacted us for telephone genetic counseling, suggesting that a majority felt that the written pre-test information was sufficient for them to make a decision on testing. In conclusion, the results of the work presented in this thesis indicate that germline BRCA status could contribute to personalized treatment decisions for breast cancer patients, and consequently, the results lend support to the idea that breast cancer patients should be offered BRCA testing at the time of diagnosis. The procedure for BRCA testing used in the BRCAsearch study offers an example of how genetic testing could be undertaken on a large scale in a feasible way.