title: Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer.
abstract: BACKGROUND
  HER3 activating mutations have been shown in preclinical models to be oncogenic and ligand-independent, but to depend on kinase-active HER2.
  
  
  METHODS
  Whole-exome sequencing of the primary HER2-negative breast cancer and its HER2-negative synchronous liver metastasis from a 46-year-old female revealed the presence of an activating and clonal HER3 G284R mutation.
  
  
  RESULTS
  HER2 dual blockade with trastuzumab and lapatinib as third-line therapy led to complete metabolic response in 2 weeks and confirmed radiological partial response after 8 weeks. Following the resection of the liver metastasis, the patient remains disease-free 40 weeks after initiation of the HER2 dual blockade therapy. Immunohistochemical analysis demonstrated a substantial reduction of phospho-rpS6 and phospho-AKT in the post-therapy biopsy of the liver metastasis.
  
  
  CONCLUSIONS
  This is the first-in-man evidence that anti-HER2 therapies are likely effective in breast cancers harboring HER3 activating mutations.
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA fcbidard@curie.fr.
authors.forename: F-C
authors.initials: FC
authors.lastname: Bidard
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: C K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Cottu
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: S
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pharmacy, Institut Curie, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Escalup
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Sakr
authors.affiliation: Department of Surgery, Institut Curie, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Reyal
authors.affiliation: Department of Surgery, Institut Curie, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Mariani
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lim
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: L
authors.initials: L
authors.lastname: Norton
authors.affiliation: Department of Radiology, Institut Curie, Paris.
authors.forename: V
authors.initials: V
authors.lastname: Servois
authors.affiliation: Department of Pathology, Institut Curie, Paris.
authors.forename: B
authors.initials: B
authors.lastname: Sigal
authors.affiliation: Department of Pathology, Institut Curie, Paris.
authors.forename: A
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: B
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France Paris Descartes University, Paris, France.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Pierga
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics*; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: HER3 mutations; breast cancer; dual HER2 blockade; massively parallel sequencing; precision medicine