title: Gene signature-guided dasatinib therapy in metastatic breast cancer.
abstract: OBJECTIVE
  Dasatinib has limited single-agent activity in unselected patients with metastatic breast cancer. Several gene signatures predictive of dasatinib response in vitro have been reported. The purpose of this three-arm, phase II study was to prospectively assess the utility of three previously published gene signatures to select patients with clinical benefit from dasatinib.
  
  
  METHODS
  Patients with metastatic breast cancer underwent biopsy for gene expression profiling in an academic CLIA laboratory; those who were positive for any one of three predictive gene signatures (dasatinib sensitivity signature, SRC pathway activity signature, and dasatinib target index) received dasatinib 100 mg orally daily. The three marker-defined cohorts were analyzed separately, using early stopping rules for futility.
  
  
  RESULTS
  Ninety-seven patients were enrolled, 93 underwent biopsy, and 80% of the biopsies were sufficient for molecular testing. Thirty patients were positive for at least one signature and received treatment. Only 1 patient experienced clinical benefit and had stable disease over 300 days. All three arms were closed early for futility. There was one serious biopsy-related adverse event (hematoma and pain following a liver biopsy). There were no unexpected toxicities from dasatinib.
  
  
  CONCLUSIONS
  None of the three predictive gene signatures, although supported by preclinical evidence, defined tumors clinically sensitive to dasatinib as a single agent.
authors.affiliation: Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. lajos.pusztai@yale.edu.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Stacy
authors.initials: S
authors.lastname: Moulder
authors.affiliation: Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Altan
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Danielle
authors.initials: D
authors.lastname: Kwiatkowski
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.affiliation: New York University Langone Medical Center, New York University, New York, New York.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.affiliation: Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rony
authors.initials: R
authors.lastname: Avritscher
authors.affiliation: Department of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lewis
authors.initials: L
authors.lastname: Strauss
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Christos
authors.initials: C
authors.lastname: Hatzis
authors.affiliation: Bristol-Myers Squibb Inc., New York, New York.
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000069439:Dasatinib; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012307:Risk Factors; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D059467:Transcriptome; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019061:src-Family Kinases; D000069439:Dasatinib