title: Genomic characteristics of trastuzumab-resistant Her2-positive metastatic breast cancer.
abstract: OBJECTIVE
  Resistance to trastuzumab therapy is linked to phosphoinositol 3-kinase (PI3K) pathway activation. One key downstream effector and regulator of this pathway is the mechanistic target of rapamycin (mTOR). In 2011, a phase I/II study evaluated the combination of trastuzumab and everolimus (a mTOR inhibitor) for treatment of Her2-positive metastatic breast cancer (MBC) for patients who had progressed on trastuzumab-based therapy.
  
  
  METHODS
  We retrospectively analyzed GeneChip microarray data from 22 of 47 patients included in the study.
  
  
  RESULTS
  Using an unbiased approach, we found that mutations in BRAF, EGFR and KIT are significantly more common in this heavily treated population when compared with the cohort of invasive breast carcinoma patients in The Cancer Genome Atlas (TCGA). Furthermore, 10 out of 22 patients had PIK3CA mutations (45.4%) but PI3KCA status was not predictive of PFS in our cohort. Finally, the use of OncoScantmhas allowed us to detected mutations in five genes that have not been shown to be mutated in TCGA subset of Her-2 overexpressing breast cancer: CTNNB1, HRAS, KRAS, NF2 and SMARCB1.
  
  
  CONCLUSIONS
  Mutational burden in heavily treated trastuzumab-resistant Her2-positive metastatic breast cancer is highly variable and not directly correlated with outcome. Activation of the MAPK/ERK pathway through mutations in EGFR, BRAF or KIT may mediate resistance to trastuzumab.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Mateus
authors.initials: M
authors.lastname: de Oliveira Taveira
authors.affiliation: Harvard Medical School, Boston, MA, USA.|University of Connecticut, Storrs, CT, USA.
authors.forename: Sheida
authors.initials: S
authors.lastname: Nabavi
authors.affiliation: Affymetrix, San Francisco, CA, USA.|Vitruvian Networks, San Francisco, CA, USA.
authors.forename: Yuker
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Harvard Medical School, Boston, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tonellato
authors.affiliation: MD Anderson, Houston, TX, USA.|Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.affiliation: Weill Cornell Medical College, New York, NY, USA.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. gwulf@bidmc.harvard.edu.
authors.forename: Gerburg M
authors.identifier: http://orcid.org/0000-0001-7868-6231
authors.initials: GM
authors.lastname: Wulf
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D012189:Retrospective Studies; D000068878:Trastuzumab / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Everolimus; Her2; Metastatic breast cancer; Phosphoinositol 3-kinase; Trastuzumab; mTOR