title: Comprehensive genomic profiling of malignant phyllodes tumors of the breast.
abstract: Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease.
  
  
  
  DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions.
  
  
  
  The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549-BRAF or FGFR3-TACC3 were identified in 2/24 (8.3%) tumors.
  
  
  
  This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.
authors.affiliation: Albany Medical College, Albany, NY, USA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Nozad
authors.affiliation: Albany Medical College, Albany, NY, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Sheehan
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Gay
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Vergilio
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Suh
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Shakti
authors.initials: S
authors.lastname: Ramkissoon
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hirshfield
authors.affiliation: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ali
authors.affiliation: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Albany Medical College, Albany, NY, USA. jross@foundationmedicine.com.|Foundation Medicine, Inc., Cambridge, MA, USA. jross@foundationmedicine.com.|Department of Pathology and Laboratory Medicine, Albany Medical College, 47 New Scotland Ave, Albany, NY, 12208, USA. jross@foundationmedicine.com.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Jon H
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D003557:Phyllodes Tumor / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
keywords: Comprehensive genomic profiling; MED12; Malignant phyllodes tumor; NF1; Targeted therapy