Background BRCAness is a characteristic feature of homologous recombination deficiency (HRD) mimicking BRCA gene mutation in breast cancer. We hypothesized that a measure to quantify BRCAness that causes synthetic lethality in BRCA mutated tumors will identify responders to PARP inhibitors. Methods A total of 6753 breast cancer patients from 3 large independent cohorts were analyzed. A score was generated by transcriptomic profiling using gene set variation analysis algorithm on 34 BRCA1-mutation related genes selected by high AUC levels in ROC curve between BRCA1 mutation and wildtype breast cancer. Results The score was significantly associated with BRCA1 mutation, high mutation load and intratumoral heterogeneity as expected, as well as with high HRD, DNA repair and MKi67 expression regardless of BRCA mutations. High BRCAness tumors enriched not only DNA repair, but also all five Hallmark cell proliferation-related gene sets. High BRCAness tumors were significantly associated with higher cytolytic activity and with higher anti-cancerous immune cell infiltration. Not only did the breast cancer cell lines with BRCA-mutation show high score, but even the other cells in human breast cancer tumor microenvironment were contributing to the score. The BRCAness score was the highest in triple-negative breast cancer consistently in all 3 cohorts. BRCAness was associated with response to chemotherapy and correlated strongly with response to PARP inhibitor in both triple-negative and ER-positive/HER2-negative breast cancer. Conclusions We established a novel BRCAness score using BRCA-mutation-related gene expressions and found that it associates with DNA repair and predicts response to PARP inhibitors regardless of BRCA mutation.

Granulomatous mastitis (GM) is a rare disease, particularly among men. Herein, we present a case of GM diagnosed in a 63-year-old male patient who showed reduction in the tumor size during 3 months of observation.

A 34-year-old woman with breast cancer and the BRCA2: p.Gln3047Ter was treated with olaparib. After tumor progression, cancer genomic profiling testing revealed the BRCA2 p.Gln3047Ter and p.Gln3047Tyr, with 48.9% and 0.37% allele frequency, respectively. These findings shed light on reversion mutation as a resistance mechanism to olaparib in breast cancer.

A rare missense mutation was identified as a reversion mutation using cancer genomic profiling and a suspected mechanism underlying resistance to olaparib in breast cancer.

549 Background: BRCAness is a generic term used to describe characteristic features of homologous recombination deficiency (HRD) mimicking mutations in BRCA genes. Although clinical genetic testing has increased the detection of mutations in BRCA1 and BRCA2, we hypothesized that a measure to quantify BRCAness will identify the responders to PARP inhibitors that cause synthetic lethality in BRCA mutation tumors. Methods: The BRCAness score was established by using gene set variation analysis (GSVA) algorithm on 34 BRCA-mutation related genes. We investigated the clinical relevance of the score by performing silico analyses of 6245 breast cancer patients using multiple independent large cohorts in this study. Results: A score to quantify BRCAness was generated using gene set variation analysis algorithm on 34 BRCA1-mutation related genes selected by high AUC levels in ROC curve between BRCA1 mutation and wildtype breast cancer. The score was significantly associated with BRCA1 mutation, high overall mutation load and intratumoral heterogeneity as well as high HRD, DNA repair and MKI67 expression regardless of mutation in BRCA gene. High score tumor enriched not only DNA repair, but also five cell proliferation-related gene sets (E2F targets, G2M checkpoint, MYC targets v1 and v2, and MITOTIC signaling) in Hallmark collection (all false discovery rate < 0.10). Breast cancers with high score were significantly associated with higher infiltration of anti-cancerous immune cells and higher cytolytic activity. Not all breast cancer cell lines with BRCA-mutation showed high score and the other cells in human breast cancer tumor microenvironment were contributing to the score. We found that the BRCAness score was the highest in triple-negative among subtypes consistently in all cohorts (all p < 0.001). Finally, BRCAness was associated with response to chemotherapy and correlated strongly with response to PARP inhibitor in both triple-negative (AUC = 0.815) and ER-positive/HER2-negative breast cancer (AUC = 0.715). Conclusions: We established a novel BRCAness score using mRNA expression of BRCA-mutation-related genes and found that it associates with DNA repair and response to PARP inhibitor regardless of BRCA mutation.