Homologous repair deficiency score for identifying breast cancers with defective DNA damage response

Ahrum Min,Ahrum Min,Seock-Ah Im,Seongmin Choi,Kwangsoo Kim,Seock-Ah Im,Kyung-Hun Lee,Seock-Ah Im,Kyeonghun Jeong,Sun Kim,Kyung-Hun Lee,Seock-Ah Im,Seongyeong Kim,Koung Jin Suh,Koung Jin Suh

doi:10.1038/s41598-020-68176-y

Abstract

Breast cancer (BC) in patients with germline mutations of BRCA1/BRCA2 are associated with benefit from drugs targeting DNA damage response (DDR), but they account for only 5–7% of overall breast cancer. To define the characteristics of these tumors and also to identify tumors without BRCA mutation but with homologous recombination deficiency (HRD) is clinically relevant. To define characteristic features of HRD tumors and analyze the correlations between BRCA1/BRCA2 and BC subtypes, we analyzed 981 breast tumors from the TCGA database using the signature analyzer. The BRCA signature was strongly associated with the HRD score top 10% (score ≥ 57) population. This population showed a high level of mutations in DDR genes, including BRCA1/BRCA2. HRD tumors were associated with high expression levels of BARD1 and BRIP1. Besides, BRCA1/2 mutations were dominantly observed in basal and luminal subtypes, respectively. A comparison of HRD features in BC revealed that BRCA1 exerts a stronger influence inducing HRD features than BRCA2 does. It reveals genetic differences between BRCA1 and BRCA2 and provides a basis for the identification of HRD and other BRCA-associated tumors.

Highlights

Breast cancer (BC) in patients with germline mutations of BRCA1/BRCA2 are associated with benefit from drugs targeting DNA damage response (DDR), but they account for only 5–7% of overall breast cancer
These results suggest that BRCA and other homologous repair deficiency (HRD) markers determine response to Poly (ADP-ribose) polymerase (PARP) inhibitors and that these should be applied to patients with other homologous recombination deficiency (HRD) markers as well
Along with the observations that cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death ligand-1 (PD-L1), and indolamine 2,3-dioxygenase 1 (IDO1) expression levels were upregulated in signature 3 tumors and that BRCAmutated BCs showed increased tumor infiltrating lymphocytes (TILs) compared with BRCA wild-type, these data suggest the potential of using immune checkpoint inhibitors in BRCA-signature tumors[16,17]

Summary

Introduction

Breast cancer (BC) in patients with germline mutations of BRCA1/BRCA2 are associated with benefit from drugs targeting DNA damage response (DDR), but they account for only 5–7% of overall breast cancer. To define characteristic features of HRD tumors and analyze the correlations between BRCA1/BRCA2 and BC subtypes, we analyzed 981 breast tumors from the TCGA database using the signature analyzer. In an olaparib maintenance clinical phase II trial of patients with relapsed platinum-sensitive ovarian cancer in addition to BRCA-deficient tumors, one-third of patients with wild-type BRCA showed improvements in P FS4,5. Olaparib was approved by the FDA for maintenance treatment in platinum-sensitive patients, regardless of BRCA status. These results suggest that BRCA and other homologous repair deficiency (HRD) markers determine response to PARP inhibitors and that these should be applied to patients with other HRD markers as well. While BRCA1 deficiency is highly correlated with estrogen receptor-negative BC, no correlation has been reported between BRCA2 deficiency and the incidence of any specific BC s ubtype[11]

Methods

Results

Conclusion