title: BRCA1 alterations with additional defects in DNA damage response genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy.
abstract: The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in BRCA1 or BRCA2 mutation carriers. As tumors with the phenotype have defects in the DNA damage response pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. The methylation and/or loss or uniparental disomy (UPD) of BRCA1 (BRCA1 alterations) and the loss or UPD of BRCA2 (BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, of the 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P < 0.001 and P < 0.001) and higher percentage of TP53 alterations (P < 0.001 and P < 0.001) than those without. Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4, or ERCC1/2 in tumors, patients with additional defects in DNA damage response genes had worse OS (P = 0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer.
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.|Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Takada
authors.affiliation: Divisions of Breast Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Nagai
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haruta
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Ryuichi P
authors.initials: RP
authors.lastname: Sugino
authors.affiliation: Divisions of Breast Surgery, Saitama Cancer Center, Ina, Saitama, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tozuka
authors.affiliation: Divisions of Breast Surgery, Saitama Cancer Center, Ina, Saitama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takei
authors.affiliation: Divisions of Breast Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Ohkubo
authors.affiliation: Divisions of Breast Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Pathology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kurosumi
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Division of Tumor Biology, Department of Pathology, Kyoto University School of Medicine, Kyoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Division of Tumor Biology, Department of Pathology, Kyoto University School of Medicine, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Division of Tumor Biology, Department of Pathology, Kyoto University School of Medicine, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Yasuhiko
authors.identifier: 0000-0001-7361-9582
authors.initials: Y
authors.lastname: Kaneko
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D004249:DNA Damage / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015996:Survival Rate
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor