Here, we used the TCGA database of 981 patients with BC to evaluate screening methods that better reflect BRCA germline mutations or characteristics of BRCAness and to identify genetic alterations within BRCA-associated cancer.
However, 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 subtype 11. Furthermore, based on a previous finding that the BRCA-deficient BC subtype is highly associated with TNBC, medications such as PARP inhibitors targeting BRCA-associated cancers have been used in limited cases, such as BRCA variations and the TNBC subtype 11. However, the genetic features resulting from BRCA1 or BRCA2 deficiency in BC have not been compared, and a single BRCA1/2-deficient BC subtype is typically considered. BRCA1 variations cause greater genomic instability than BRCA2 variations in ovarian cancer 8, and ovarian cancer patients with BRCA2 germline mutations show better clinical outcomes than BRCA1-mutated patients 9, 10. Although mutational signatures can predict BRCAness, factors that induce BRCAness remain unclear, and no markers have been suggested for > 30% of cases of BRCAness.Ī genome study of ovarian cancer recently revealed that BRCA1 and BRCA2 deficiency, either of which is considered the most important risk factor for hereditary BC and ovarian cancer, lead to different structural changes and mutation patterns in tumor genomes. The Sanger Institute group suggested that mutational signatures 3 and 8, identified based on analysis of deletion or substitution patterns through microhomology, can best predict HRD indicating BRCAness 6, 7. In fact, tumors lacking BRCA mutation but with HRD, similar responses to DNA damaging agents, and similar clinicopathologic features are referred to as having “BRCAness,” and the use of PARP inhibitors has been expanded to these tumors. 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. Based on this, olaparib was additionally approved by the FDA for maintenance treatment in platinum-sensitive patients, regardless of BRCA status.
#SIGA HRD TRIAL#
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 PFS 4, 5. In a global phase III trial involving patients with metastatic BC with germline BRCA1 or BRCA2 mutation, olaparib increased progression-free survival (PFS) by 2.8 months 3. Poly (ADP-ribose) polymerase (PARP) inhibitors are clinically beneficial in patients with BRCA-deficient ovarian, breast, and prostate cancer. The Cancer Genome Project (TCGA) serves as an important basis for understanding the genomics of tumor heterogeneity 2. One approach is examining the mutations of each tumor and defining distinct molecular signatures for categorization. To improve treatment, understanding tumor heterogeneity within and across subtypes and proper treatment strategies for each tumor is crucial. However, there is high heterogeneity, even within subtypes, making treatment difficult 1, 2. It reveals genetic differences between BRCA1 and BRCA2 and provides a basis for the identification of HRD and other BRCA-associated tumors.ĭepending on hormone receptor and human epidermal growth factor type II receptor (HER2) oncoprotein expression, breast cancer (BC) is traditionally classified into luminal A or B (i.e., estrogen and/or progesterone receptor-positive), HER2-enriched, or triple-negative BC (TNBC). A comparison of HRD features in BC revealed that BRCA1 exerts a stronger influence inducing HRD features than BRCA2 does.
Besides, BRCA1/2 mutations were dominantly observed in basal and luminal subtypes, respectively. HRD tumors were associated with high expression levels of BARD1 and BRIP1. This population showed a high level of mutations in DDR genes, including BRCA1/BRCA2. The BRCA signature was strongly associated with the HRD score top 10% (score ≥ 57) population.
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. To define the characteristics of these tumors and also to identify tumors without BRCA mutation but with homologous recombination deficiency (HRD) is clinically relevant. 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.
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