title: Pharmacogenomic predictor discovery in phase II clinical trials for breast cancer.
abstract: OBJECTIVE
  We examined if supervised analysis of gene expression data from phase II studies could identify HER-2 overexpression as a predictor of response to trastuzumab.
  
  
  METHODS
  Gene expression data from 132 newly diagnosed breast cancers were used to simulate 50,000 single-agent phase II trastuzumab studies. True HER-2 amplification was assessed by fluorescence in situ hybridization.
  
  
  RESULTS
  Only 3.67% of the simulated studies yielded HER-2 as the top predictor, >96% of the individual "studies" picked a different gene as the most predictive of trastuzumab response. HER-2 was included in the top 10 gene list 9.73% of the time. When HER-2 was a priori defined as a potential predictor, 99.6% of the simulated studies confirmed overexpression among responders. Candidate marker testing may be more efficient than de novo predictor discovery in phase II trials. We describe a tandem, two-step phase II trial design for rapid marker assessment that combines two optimal two-stage phase II trials into a single study. In the first stage, unselected patients are treated, and if insufficient responses are seen, the trial remains open for marker-positive patients only and a second two-stage trial commences.
  
  
  CONCLUSIONS
  The probability of successful discovery of drug-specific pharmacogenomic response markers in a typical phase II study is small. The evaluation of predefined predictors using tandem two-step phase II design has the advantages of estimating response rates in both unselected and marker-selected patient populations and allows for simultaneous screening of multiple different predictors for the same drug and several distinct predictor-drug pairs in a single, parallel multiarm trial.
authors.affiliation: Department of Breast Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1439, USA. lpusztai@mdanderson.org
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: Keith
authors.initials: K
authors.lastname: Anderson
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017322:Clinical Trials, Phase II as Topic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010597:Pharmacogenetics / Q000379:methods*; D011336:Probability; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D000068878:Trastuzumab