title: Relapsed classic E-cadherin (CDH1)-mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations.
abstract: OBJECTIVE
  We queried whether comprehensive genomic profiling using a next-generation sequencing-based assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC).
  
  
  METHODS
  DNA sequencing (Illumina HiSeq 2000) was conducted for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor-ligated, hybridization-captured libraries using DNA isolated from formalin-fixed paraffin-embedded sections from 22 histologically verified ILC.
  
  
  RESULTS
  A total of 75 genomic alterations were identified with an average of 3.4 alterations per tumor (range, 1-6), of which 35 were actionable for an average of 1.59 actionable alterations per patient (range, 0-3). Nineteen of 22 (86%) of the ILC samples harbored at least one actionable alteration. Six (27%) cases featured alterations in ERRB2 including 4 (18%) with ERBB2 mutation, 1 (5%) with an ERBB2 gene fusion, and 1 (5%) with an ERBB2 copy number gain (amplification). The enrichment of ERBB2 mutations/fusion in CDH1-mutated ILC (5 of 22, 23%) compared with the 5 ERBB2 mutations in a series of 286 non-CDH1-mutated breast cancers from which the ILC cases were obtained (5 of 286, 2%) was significant (P = 0.0006).
  
  
  CONCLUSIONS
  Comprehensive genomic profiling of relapsed CDH1-mutated ILC revealed actionable genomic alterations in 86% of cases, featured a high incidence of ERBB2 alterations, and can reveal actionable alterations that can inform treatment decisions for patients with ILC.
authors.affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208, USA. rossj@mail.amc.edu
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Christine E
authors.initials: CE
authors.lastname: Sheehan
authors.forename: Ann B
authors.initials: AB
authors.lastname: Boguniewicz
authors.forename: Geoff
authors.initials: G
authors.lastname: Otto
authors.forename: Sean R
authors.initials: SR
authors.lastname: Downing
authors.forename: James
authors.initials: J
authors.lastname: Sun
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.forename: John A
authors.initials: JA
authors.lastname: Curran
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.forename: Gary
authors.initials: G
authors.lastname: Palmer
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006651:Histocytochemistry; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D016612:Paraffin Embedding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D016707:Tissue Fixation
chemical_list: D015820:Cadherins; D018719:Erb-b2 Receptor Tyrosine Kinases