title: Impact of gene expression profiling tests on breast cancer outcomes.
abstract: OBJECTIVE
  To assess the evidence that three marketed gene expression-based assays improve prognostic accuracy, treatment choice, and health outcomes in women diagnosed with early stage breast cancer.
  
  
  METHODS
  We evaluated the evidence for three gene expression assays on the market; Oncotype DX, MammaPrint and the Breast Cancer Profiling (BCP or H/I ratio) test, and for gene expression signatures underlying the assays. We sought evidence on: analytic performance of tests, clinical validity (i.e., prognostic accuracy and discrimination), clinical utility (i.e., prediction of treatment benefit), harms, impact on clinical decision making and health care costs.
  
  
  RESULTS
  Few papers were found on the analytic validity of the Oncotype DX and MammaPrint tests, but these showed reasonable within-laboratory replicability. Pre-analytic issues related to sample storage and preparation may play a larger role than within-laboratory variation. For clinical validity, studies differed according to whether they examined the actual test that is currently being offered to patients or the underlying gene signature. Almost all of the Oncotype DX evidence was for the marketed test, the strongest validation study being from one arm of a randomized controlled trial (NSABP-14) with a clinically homogeneous population. This study showed that the test, added in a clinically meaningful manner to standard prognostic indices. The MammaPrint signature and test itself was examined in studies with clinically heterogeneous populations (e.g., mix of ER positivity and tamoxifen treatment) and showed a clinically relevant separation of patients into risk categories, but it was not clear exactly how many predictions would be shifted across decision thresholds if this were used in combination with traditional indices. The BCP test itself was examined in one study, and the signature was tested in a variety of formulations in several studies. One randomized controlled trial provided high quality retrospective evidence of the clinical utility of Oncotype DX to predict chemotherapy treatment benefit, but evidence for clinical utility was not found for MammaPrint or the H/I ratio. Three decision analyses examined the cost-effectiveness of breast cancer gene expression assays, and overall were inconclusive.
  
  
  CONCLUSIONS
  Oncotype DX is furthest along the validation pathway, with strong retrospective evidence that it predicts distant spread and chemotherapy benefit to a clinically relevant extent over standard predictors, in a well-defined clinical subgroup with clear treatment implications. The evidence for clinical implications of using MammaPrint was not as clear as with Oncotype DX, and the ability to predict chemotherapy benefit does not yet exist. The H/I ratio test requires further validation. For all tests, the relationship of predicted to observed risk in different populations still needs further study, as does their incremental contribution, optimal implementation, and relevance to patients on current therapies.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Renee F
authors.initials: RF
authors.lastname: Wilson
authors.forename: Spyridon S
authors.initials: SS
authors.lastname: Marinopoulos
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Eric B
authors.initials: EB
authors.lastname: Bass
authors.forename: Steven N
authors.initials: SN
authors.lastname: Goodman
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome