Abstract 1192: Triple negative breast cancer: BRCAness and concordance of clinical features and treatment response with BRCA1 mutation carriers.
Authors: Lips Esther H. , Mulder Lennart , van der Kolk Lizet E. , Oonk Anne M.M. , Imholz Alex L.T. , Hogervorst Frans B.L. , Wesseling Jelle , Rodenhuis Sjoerd , Nederlof Petra M. 
Published: August 2014

Abstract
Introduction
Previous work from our group and other groups has shown that triple negative breast cancers (TNBC) frequently show BRCAness, the phenotype that some sporadic tumors share with BRCA-mutated cancers. We propose the use of a BRCA1-like genomic profile and of BRCA1 promoter methylation as indicators of BRCAness. In a randomized trial, tumors with this BRCA1-like profile responded more favorably to intensified alkylating chemotherapy. We now assessed the frequency of BRCAness in a large cohort of TNBCs. In addition, we determined the association with clinicopathological variables and treatment response.
Methods
A total of 388 TNBCs were included in this study. These were obtained from three different sources: a neoadjuvant chemotherapy trial (n=152), a series of patients from breast cancer families but without germline mutations (n=145), and a series of patients treated with adjuvant chemotherapy (n=91). Two assays for BRCAness were employed: array Comparative Genomic Hybridization (aCGH) to asses a BRCA1-like profile and methylation specific Multiplex Ligation-dependent Probe Amplification (MLPA) to determine BRCA1 promoter methylation. BRCA1 germline mutation status was known for half of the patients. Clinicopathological characteristics were available for most patients, and chemotherapy response data was available for the neoadjuvant series.
Results
In the three series, 66% to 69% of the tumors had an aCGH BRCA1-like profile and 27% to 37% showed BRCA1 promoter methylation. 87% of the tumors with promoter methylation showed a BRCA1-like aCGH profile. A germline mutation in BRCA1 and somatic BRCA1 promoter methylation did not occut together (n=155; p = 10-6). Patients with aCGH BRCA1-like or BRCA1 methylated tumors were younger than patients with non-BRCA1-like or unmethylated tumors (p=0.02 and p&lt;0.01, respectively). BRCA1 mutated tumors and aCGH BRCA1-like tumors were more often of histological grade 3 (97% vs. 74% (p&lt;0.01) for BRCA1-mutated vs. BRCA1 wildtype and 86% vs 67% (p&lt;0.01) for aCGH BRCA1-like vs. non-BRCA1-like tumors). BRCA1-mutated tumors had a higher response rate to neoadjuvant chemotherapy than BRCA1 wildtype tumors (71% vs. 37% (p=0.04) pathological complete remission rate). For aCGH BRCA1-like and BRCA1 methylated tumors, a non-significant trend for a better chemtherapy response was observed.
Conclusion
The majority of the TNBCs in this study show signs of BRCAness, and these tumors share clinicopathological characteristics with BRCA1 mutated tumors. Somatic BRCA1 promoter methylation and BRCA1 germline mutations are mutually exclusive events. A better characterization of TNBC and the presence of BRCAness will not only have consequences for treatment, but also for hereditary breast cancer screening.
Citation Format: Esther H. Lips, Lennart Mulder, Lizet E. van der Kolk, Anne M.M. Oonk, Alex L.T. Imholz, Frans B.L. Hogervorst, Jelle Wesseling, Sjoerd Rodenhuis, Petra M. Nederlof. Triple negative breast cancer: BRCAness and concordance of clinical features and treatment response with BRCA1 mutation carriers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1192. doi:10.1158/1538-7445.AM2013-1192