Abstract 1755: The fate of germline BRCA related mutations in breast tumor tissues
Authors: Kotoula Vassiliki , Fostira Florentia Fostira , Papadopoulou Kyriaki , Apostolou Paraskevi , Tsolaki Eleftheria , Lazaridis Georgios , Manoussou Kyriaki , Zagouri Flora Zagouri , Pectasides Dimitrios , Vlachos Ioannis , Tikas Ioannis , Lakis Sotiris , Konstantopoulou Irene , Pentheroudakis George , Gogas Helen , Papakostas Pavlos , Christodoulou Christos , Yannoukakos Drakoulis , Fountzilas George 
Published: July 2017

Abstract
Background - aim: Germline mutation carriers in BRCA1 and related genes frequently develop triple-negative breast carcinomas (TNBC) that presumably preserve the inherited mutation. Herein, we examined the clinicopathologic features and prognostic impact of paired germline and tumor genotypes in this disease.
Methods: We compared baseline germline and paraffin tumor genotype data (next generation [NGS] and Sanger sequencing) from 194 patients with operable TNBC who were treated with anthracyclines-taxanes based chemotherapy within adjuvant trials by our Group. Because tissue NGS did not target BRCA-related genes, we additionally interrogated the presence of germline mutations in tumor and non-cancerous breast tissues, in carriers with available tissue material (n=33). We validated all NGS germline mutations with Sanger sequencing and ensured matched germline/tumor identity with microsatellite testing.
Results: We identified 50 (26%) germline mutation carriers, 39 in BRCA1, 4 in BRCA2 and the rest in RAD51C, BARD1, RAD50, NBN, MRE11A and BRIP1. BRCA1 carriers were younger as compared to non-BRCA1 carriers (median 42y.o. vs. 56y.o, respectively; p=0.020), premenopausal (p=0.014), and had lower nodal status (p&lt;0.001). Somatic mutations were found in 136 tumors, TP53 in 113 (81%). The germline mutant allele was lost in 14/33 (42%) tumor and matched normal tissues (mut-LOH). Loss affected 12 BRCA1 mutations, among them the common pathogenic p.Q1756fsX74 (c.5266dupC) and p.G1738R (c.5212G&gt;A), and 2 BRCA2 mutations. In one such tumor, the germline mutation was replaced by a somatic BRCA1 (p.Q1811X [c.5431C&gt;T]). Tumors with mut-LOH were more often TP53 mutant as compared to those with preserved germline mutations, which had mutations in other genes as well (p=0.034). Overall though, TP53 mutations were not associated with germline status. Germline mutations and tumor TP53 mutations were not individually associated with patient disease-free survival (DFS) but interacted with each other: in non-carriers, TP53 status did not affect outcome; in carriers, those with mutant TP53 had unfavorable DFS compared to those with wild-type TP53 tumors (interaction p, multivariate analysis: 0.053).
Conclusions: Germline BRCA-related TNBC may be distinguished into two groups with potentially different biological characteristics, those with preserved and lost inherited mutation. The interaction between germline status and tumor TP53 mutations may have treatment implications and seems worthy pursuing in larger studies. Combined germline/tumor genotype testing may be needed for TNBC patient classification, especially in the context of clinical trials.
Citation Format: Vassiliki Kotoula, Florentia Fostira Fostira, Kyriaki Papadopoulou, Paraskevi Apostolou, Eleftheria Tsolaki, Georgios Lazaridis, Kyriaki Manoussou, Flora Zagouri Zagouri, Dimitrios Pectasides, Ioannis Vlachos, Ioannis Tikas, Sotiris Lakis, Irene Konstantopoulou, George Pentheroudakis, Helen Gogas, Pavlos Papakostas, Christos Christodoulou, Drakoulis Yannoukakos, George Fountzilas. The fate of germline BRCA related mutations in breast tumor tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1755. doi:10.1158/1538-7445.AM2017-1755