title: Concordance of genomic alterations between primary and recurrent breast cancer.
abstract: There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed.
authors.affiliation: Authors' Affiliations: Departments of Investigational Cancer Therapeutics, Surgical Oncology, Bioinformatics and Computational Biology, Pathology, Systems Biology, and Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Foundation Medicine, Cambridge, Massachusetts; Albany Medical College, Albany, New York; Fundacion para la Investigacion; Departments of Hematology-Oncology and Pathology, Hospital Clinico Universitario de Valencia; and INCLIVA Biomedical Research Institute, Valencia, Spain.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.forename: Jaime
authors.initials: J
authors.lastname: Ferrer-Lozano
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Jose A
authors.initials: JA
authors.lastname: Pérez-Fidalgo
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Gary A
authors.initials: GA
authors.lastname: Palmer
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.forename: Pilar
authors.initials: P
authors.lastname: Eroles
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Barrera
authors.forename: Octavio
authors.initials: O
authors.lastname: Burgues
authors.forename: Ana M
authors.initials: AM
authors.lastname: Lluch
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zheng
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Maureen T
authors.initials: MT
authors.lastname: Cronin
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gonzalez-Angulo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging