BRCA1-Mutated Estrogen Receptor-Positive Breast Cancer Shows BRCAness, Suggesting Sensitivity to Drugs Targeting Homologous Recombination Deficiency.
Purpose:As estrogen receptor-positive (ER+) breast cancer inBRCA1mutation carriers arises at an older age with less aggressive tumor characteristics than ER-negative (ER-)BRCA1-mutated breast cancer, it has been suggested that these tumors are "sporadic" and notBRCA1driven. With the introduction of targeted treatments specific for tumors with a nonfunctioningBRCA1orBRCA2gene, the question whether theBRCAgenes are impaired in the tumor is highly relevant. Therefore, we performed genomic profiling ofBRCA1-mutated ER+tumors.Experimental Design:Genomic profiling,BRCA1promoter methylation assessment, and loss of heterozygosity analysis were done on 16BRCA1-mutated ER+tumors. Results were compared with 57BRCA1-mutated ER-tumors, 36BRCA2-mutated ER+-associated tumors, and 182 sporadic ER+tumors.Results:The genomic profile ofBRCA1-mutated ER+tumors was different fromBRCA1-mutated ER-breast tumors, but highly similar toBRCA2-mutated ER+tumors. In 83% of theBRCA1-mutated ER+tumors, loss of the wild-typeBRCA1allele was observed. In addition, clinicopathologic variables inBRCA1-mutated ER+cancer were also more similar toBRCA2-mutated ER+and sporadic ER+breast cancer than toBRCA1-mutated ER-cancers.Conclusions:AsBRCA1-mutated ER+tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis inBRCA1-mutated ER+tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting theBRCA1gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER+breast cancer.Clin Cancer Res; 23(5); 1236-41. ©2016 AACR.
Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. e.lips@nki.nl p.nederlof@nki.nl.|Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Esther H
EH
Lips
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Rashmie D
RD
Debipersad
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Caroline E
CE
Scheerman
Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Lennart
L
Mulder
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Gabe S
GS
Sonke
Department of Clinical Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Lizet E
LE
van der Kolk
Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.|Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Jelle
J
Wesseling
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Frans B L
FB
Hogervorst
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Petra M
PM
Nederlof
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011960:Receptors, Estrogen / Q000235:genetics*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen