title: Genomic hallmarks of homologous recombination deficiency in invasive breast carcinomas.
abstract: Therapeutic strategies targeting Homologous Recombination Deficiency (HRD) in breast cancer requires patient stratification. The LST (Large-scale State Transitions) genomic signature previously validated for triple-negative breast carcinomas (TNBC) was evaluated as biomarker of HRD in luminal (hormone receptor positive) and HER2-overexpressing (HER2+) tumors. The LST genomic signature related to the number of large-scale chromosomal breakpoints in SNP-array tumor profile was applied to identify HRD in in-house and TCGA sets of breast tumors, in which the status of BRCA1/2 and other genes was also investigated. In the in-house dataset, HRD was predicted in 5% (20/385) of sporadic tumors luminal or HER2+ by the LST genomic signature and the inactivation of BRCA1, BRCA2 or RAD51C confirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring in BRCA1/2 mutant carriers, the corresponding wild-type allele was retained emphasizing the importance of determining the tumor status. In the TCGA luminal and HER2+ subtypes HRD incidence was estimated at 5% (18/329, 95%CI: 5-8%) and 2% (1/59, 95%CI: 2-9%), respectively. In TNBC cisplatin-based neo-adjuvant clinical trials, HRD is shown to be a necessary condition for cisplatin sensitivity. This analysis demonstrates the high performance of the LST genomic signature for HRD detection in breast cancers, which suggests its potential as a biomarker for genetic testing and patient stratification for clinical trials evaluating platinum salts and PARP inhibitors.
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.
authors: Elodie
authors: E
authors: Manié
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.
authors: Tatiana
authors: T
authors: Popova
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.
authors: Aude
authors: A
authors: Battistella
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.
authors: Julien
authors: J
authors: Tarabeux
authors: Département De Biologie Des Tumeurs, Institut Curie, Paris, F-75248, France.
authors: Virginie
authors: V
authors: Caux-Moncoutier
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.|Département De Biologie Des Tumeurs, Institut Curie, Paris, F-75248, France.
authors: Lisa
authors: L
authors: Golmard
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.
authors: Nicholas K
authors: NK
authors: Smith
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.|Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, K7L 3N6, Canada.
authors: Christopher R
authors: CR
authors: Mueller
authors: Département De Biologie Des Tumeurs, Institut Curie, Paris, F-75248, France.|Centre De Ressources Biologiques, Institut Curie, Paris, F-75248, France.
authors: Odette
authors: O
authors: Mariani
authors: Département De Biologie Des Tumeurs, Institut Curie, Paris, F-75248, France.
authors: Brigitte
authors: B
authors: Sigal-Zafrani
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|Département De Recherche Translationnelle, Institut Curie, Paris, F-75248, France.
authors: Thierry
authors: T
authors: Dubois
authors: Département De Biologie Des Tumeurs, Institut Curie, Paris, F-75248, France.
authors: Anne
authors: A
authors: Vincent-Salomon
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.|Département De Biologie Des Tumeurs, Institut Curie, Paris, F-75248, France.
authors: Claude
authors: C
authors: Houdayer
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.|Département De Biologie Des Tumeurs, Institut Curie, Paris, F-75248, France.|Sorbonne Paris Cité, University Paris-Descartes, Paris, F-75270, France.
authors: Dominique
authors: D
authors: Stoppa-Lyonnet
authors: Centre De Recherche, Institut Curie, Paris, F-75248, France.|INSERM U830, Paris, F-75248, France.
authors: Marc-Henri
authors: MH
authors: Stern
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D019457:Chromosome Breakage; D005260:Female; D024522:Genes, BRCA2; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D059767:Recombinational DNA Repair / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: BRCA1; BRCA2; breast carcinoma; homologous recombination deficiency