Abstract P4-06-13: BRCA1/2 mutations identified by screening a large unselected breast cancer cohort in Sweden
Authors: Li J , Wen SWX , Eriksson M , Kvist A , Christensen HN , Torstensson A , Easton DF , Teo S-H , Borg Å , Grönberg H , Czene K 
Published: February 2018

Abstract
Background
Treatment options for BRCA1/2 breast cancer include new therapeutic agents, such as poly (ADP-ribose) polymerase (PARP) inhibitors, which selectively target BRCA defective cells. According to current Swedish screening guidelines, eligibility for clinical BRCA1/2 hereditary mutation testing is mainly based on family history of breast or ovarian cancer and early age onset. We aimed at examining the prevalence and characteristics of BRCA1/2 mutation carriers by screening a large unselected breast cancer cohort in Sweden, and comparing our results with BRCA mutation carriers already identified through the national BRCA testing program.
Methods
Germline DNA (blood) from 5122 women diagnosed with breast cancer between 2001-2008 (LIBRO1 study) were analysed for BRCA1/2 mutations by targeted sequencing (next generation sequencing, NGS), of which 5099 samples passed quality control. All patients provided informed consent. Information on patient and tumor characteristics was collected from the LIBRO1 database. Clinical BRCA testing information was obtained from the BRCA Lab (Lund University, Sweden), which carries out mutation screening for all oncogenetic clinics in Sweden.
Multinomial logit models were used to compare tumor characteristics of BRCA1 and BRCA2 versus non-BRCA carriers. Multivariable logistic regression models were used to examine for differences between BRCA carriers identified through the national BRCA testing program and additional BRCA carriers found by sequencing the entire study population (not tested or not identified under current screening guidelines).
Results
In total, 92 (1.8%) BRCA1/2 mutation carriers were identified retrospectively by NGS. The prevalence of BRCA1/2 mutations was 1.6% (38/2363) between years 2001-2004; and 2.0% (54/2736) between years 2005-2008. After controlling for age and year of diagnosis, BRCA2 mutation carriers were in general similar to non-BRCA carriers regarding tumor characteristics (hormone receptor status, grade, tumor size and proliferation index), except for nodal involvement. BRCA1 mutation carriers, however, had more aggressive tumor characteristics than non-BRCA breast cancer patients.
Overall, 55/92 BRCA1/2 mutation carriers (59.8%) found by NGS were not already identified through the national clinical BRCA testing program. The BRCA carriers identified by clinical testing were more likely high-risk individuals, i.e. younger, less likely to have experienced menopause, and more likely to be associated with a familiar ovarian cancer compared to those not identified through clinical testing, after adjusting for year of diagnosis. A larger proportion of BRCA2 (34/42, 80%) than BRCA1 mutations (25/50, 50%) were missed by selectively testing, mainly high-risk individuals.
Conclusion
BRCA1/2 mutations were found in approximately 2.0% of unselected BC patients. Six out of ten BRCA mutation carriers were not identified through the national testing program, which follows the screening guidelines. Revised guidelines might be needed for the effective identification of BRCA1/2 germline mutations.
Citation Format: Li J, Wen SWX, Eriksson M, Kvist A, Christensen HN, Torstensson A, Easton DF, Teo S-H, Borg Å, Grönberg H, Czene K. BRCA1/2 mutations identified by screening a large unselected breast cancer cohort in Sweden [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 P4-06-13.