Enter Note Done


Keywords: Clinical testing; Cancer

T. Watanabe 1,2; T. Honda 1,3; H. Totsuka 4; E. Arai 5; Y. Kanai 5; K. Shiraishi 1; T. Kohno 1

1) Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; 2) Department of NCC Cancer Science, Tokyo Medical and Dental University, Tokyo, Japan; 3) Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan; 4) StaGen Cooperation, Ltd., Tokyo, Japan; 5) Department of Pathology, Keio University School of Medicine, Tokyo, Japan

Breast cancer diagnosed at ages of adolescent and young adults (AYA; 15 to 39 years old) consists approximately 5% of all breast, waiting for developing therapeutic options. Homologous recombination deficiency (HRD) phenotype often observed in tumors with BRCA1/2 deficiency is considered to be associated with efficacy of PARP inhibitor and platinum agent-based therapies. In this study, HRD score was calculated for 47 Japanese AYA breast cancers using their whole exome sequencing data. The HRD-high phenotype was defined as HRD scores ≥ 42. Genetic and pathological factors in HRD-high cases were determined by analyzing the sequencing data and DNA methylation chip analysis data as well as clinicopathological information of the cohort. The HRD-high phenotype was observed in 13/47 (27.7%) cases and was preferentially observed in cases with germline BRCA1/2 and somatic TP53 mutations, triple negative subtype and higher nuclear grades. Two “pathogenic” BRCA1/2 germline mutations were observed in the 13 HRD-high cases, while a case with a “likely pathogenic” BRCA1 germline mutation was judges as HRD-low. Three BRCA1 hypermethylated and a RAD51C hypermethylated cases were also included in the 13 HRD-high cases. A predictive model for the HRD-high phenotype was developed using a TCGA data set of all breast cancers (n = 744; Area under the curve [AUC] = 0.86) based on BRCA1/2 and TP53 mutations, hypermethylation status, triple negative subtype and higher nuclear grades. This prediction model was generated from coefficients of a logistic regression analysis and these five factors were statistically significant in a TCGA data set (P < 0.01). Its prediction power was validated in Japanese (n = 46; AUC = 0.90) and European (n = 58; AUC = 0.95) AYA cohorts. After excluding a factor of methylation status, the prediction model derived from four factors still showed high AUC (AUC = 0.85). Its prediction power was validated in Japanese (n = 46; AUC = 0.90) and European (n = 58; AUC = 0.96) AYA cohorts. These four factors can be assessed by gene panel tests and daily pathological analyses. Thus, this study clarified genomic and pathological factors associated with HRD phenotype of AYA breast cancers. The present predictive model would be a tool to identify AYA breast cancer patients who would benefit from PARP and/or platinum therapies in the clinical setting.