Abstract 3502: Clinical characteristics and combined somatic mutation using target sequencing among breast cancer patients with germline BRCA mutation
Authors: Park Sehhoon , Lee Eunjin , Park Seri , Lee Sohee , Hur Joon Young , Yoon Sang Eun , Lee Kangkook , Cho Jang Ho , Kim Ji-Yeon , Ahn Jin Seok , Im Young-Hyuck , Park Woong-Yang , Park Yeon Hee 
Published: August 2019

Abstract
Purpose: Although both gBRCA1/2 mutations are known to increases incidences of breast and ovarian cancer by abruption in homologous recombination pathway, gBRCA1 mutant mainly present with a molecular subtype of triple negative breast cancer (TNBC) and gBRCA2 with hormone receptor (HR) positive which we have little understanding regarding the underlying pathophysiology. In this study, we have comprehensively analyzed clinical characteristics and somatic mutation in gBRCA1/2 mutant patients.
Methods: Patients with gBRCA mutation tested (n=2720) in Samsung Medical Center between Jan 2007 to Oct 2018 were retrospectively reviewed. 386 patients were identified as gBRCA mutant and follow-up period less than 2 years (n=105), insufficient clinical data (n=22) and no surgical treatment (n=6) were excluded. Total of 259 patients, gBRCA1 (n=128), gBRCA2 (n=126) and both gBRCA1/2 mutation (n=5), were analyzed. Among the study population, 46 patients had deep target sequencing data with 40 patients also available for matched transcriptome outcome.
Results: Median age was 40 years old (range 23-68). Patients were mostly under pre-menopausal status (81.2%) with invasive ductal carcinoma pathology (86.2%). Initial stage at diagnosis were stage 0 (4.7%), 1 (30.3%), 2 (40.6%) and 3 (24.4%). A novel mutation was observed in 16.9% of the study population and frameshift (44.9%) and nonsense (31.5%) mutations were predominant. Molecular subtypes were as follows: HR-positive (n=125, 49.2%), HR/HER2 positive (n=10, 3.9%), HER2 positive (n=3, 1.2%) and TNBC (n=116, 46.7%). TNBC was observed mostly in gBRCA1 mutant patients (71.9% vs. 19.1%) and HR-positive in gBRCA2 mutant patients (76.2% vs. 22.7%). Sixty-seven patients (26.4%) experienced disease recurrence and median time to recurrence were 145.0 months (95% confidential interval 107.3-170.2). Looking into co-altered somatic mutation using target sequencing (n=45), notably, alteration in other DNA-damage response pathway-related genes, such as TP53 (60%), ATR (27%), CHEK2 (20%), MSH6 (20%), were identified. Evaluated for mutual exclusivity, only gBRCA2 was significantly (P&lt;0.05) exclusive with CDH2, KDM5A, GNA, TGFBR2, MAP3K1, MLL3, TP53. Mean tumor mutation burden was 13.05 per mega bases with no difference between gBRCA1 and gBRCA2mutant.
Conclusions: From our dataset, we have witnessed similar clinical characteristics but the difference in molecular subtype between gBRCA1/2 mutant. Despite the fact that both gBRCA1/2 mutations disrupt the homologous recombination pathways, this study provides early evidence regarding the hypothesis that difference in co-occurred somatic alteration between gBRCA1/2 lead to different carcinogenesis mechanism which consequences different molecular subtype. Detail analyses using paired transcriptome result will be presented in the poster.
Citation Format: Sehhoon Park, Eunjin Lee, Seri Park, Sohee Lee, Joon Young Hur, Sang Eun Yoon, Kangkook Lee, Jang Ho Cho, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Woong-Yang Park, Yeon Hee Park. Clinical characteristics and combined somatic mutation using target sequencing among breast cancer patients with germline BRCA mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3502.