title: Comparative genomic analysis of primary tumors and metastases in breast cancer.
abstract: Personalized medicine uses genomic information for selecting therapy in patients with metastatic cancer. An issue is the optimal tissue source (primary tumor or metastasis) for testing. We compared the DNA copy number and mutational profiles of primary breast cancers and paired metastases from 23 patients using whole-genome array-comparative genomic hybridization and next-generation sequencing of 365 "cancer-associated" genes. Primary tumors and metastases harbored copy number alterations (CNAs) and mutations common in breast cancer and showed concordant profiles. The global concordance regarding CNAs was shown by clustering and correlation matrix, which showed that each metastasis correlated more strongly with its paired tumor than with other samples. Genes with recurrent amplifications in breast cancer showed 100% (ERBB2, FGFR1), 96% (CCND1), and 88% (MYC) concordance for the amplified/non-amplified status. Among all samples, 499 mutations were identified, including 39 recurrent (AKT1, ERBB2, PIK3CA, TP53) and 460 non-recurrent variants. The tumors/metastases concordance of variants was 75%, higher for recurrent (92%) than for non-recurrent (73%) variants. Further mutational discordance came from very different variant allele frequencies for some variants. We showed that the chosen targeted therapy in two clinical trials of personalized medicine would be concordant in all but one patient (96%) when based on the molecular profiling of tumor and paired metastasis. Our results suggest that the genotyping of primary tumor may be acceptable to guide systemic treatment if the metastatic sample is not obtainable. However, given the rare but potentially relevant divergences for some actionable driver genes, the profiling of metastatic sample is recommended.
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.|Département d'Oncologie Médicale, CRCM, Institut Paoli-Calmettes, Marseille, France.|Faculté de Médecine, Aix-Marseille Université, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Guille
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: José
authors.initials: J
authors.lastname: Adélaïde
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Garnier
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Carbuccia
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.|Département d'Oncologie Médicale, CRCM, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Monneur
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.|Faculté de Médecine, Aix-Marseille Université, Marseille, France.|Département de Biopathologie, CRCM, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.affiliation: Département d'Oncologie Médicale, CRCM, Institut Paoli-Calmettes, Marseille, France.|Faculté de Médecine, Aix-Marseille Université, Marseille, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Goncalves
authors.affiliation: Département d'Oncologie Médicale, CRCM, Institut Paoli-Calmettes, Marseille, France.|Faculté de Médecine, Aix-Marseille Université, Marseille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Max
authors.initials: M
authors.lastname: Chaffanet
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization / Q000379:methods*; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics / Q000379:methods; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis
chemical_list: D000970:Antineoplastic Agents
keywords: array-CGH; breast cancer; genomics; metastasis; sequencing