title: Limits of predictive models using microarray data for breast cancer clinical treatment outcome.
abstract: Data from microarray studies have been used to develop predictive models for treatment outcome in breast cancer, such as a recently proposed predictive model for antiestrogen response after tamoxifen treatment that was based on the expression ratio of two genes. We attempted to validate this model on an independent cohort of 58 patients with resectable estrogen receptor-positive breast cancer. We measured expression of the genes HOXB13 and IL17BR with real time-quantitative polymerase chain reaction and assessed the association between their expression and outcome by use of univariate logistic regression, area under the receiver-operating-characteristic curve (AUC), a two-sample t test, and a Mann-Whitney test. We also applied standard supervised methods to the original microarray dataset and to another independent dataset from similar patients to estimate the classification accuracy obtainable by using more than two genes in a microarray-based predictive model. We could not validate the performance of the two-gene predictor on our cohort of samples (relation between outcome and the following genes estimated by logistic regression: for HOXB13, odds ratio [OR] = 1.04, 95% confidence interval [CI] = 0.92 to 1.16, P = .54; for IL17BR, OR = 0.69, 95% CI = 0.40 to 1.20, P = .18; and for HOXB13/IL17BR, OR = 1.30, 95% CI = 0.88 to 1.93, P = .18). Similar results were obtained with the AUC, a two-sample two-sided t test, and a Mann-Whitney test. In addition, estimates of classification accuracies applied to two independent microarray datasets highlighted the poor performance of treatment-response predictive models that can be achieved with the sample sizes of patients and informative genes to date.
authors.affiliation: Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. james.reid@ifom-ieo-campus.it
authors.forename: James F
authors.initials: JF
authors.lastname: Reid
authors.forename: Lara
authors.initials: L
authors.lastname: Lusa
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.forename: Danila
authors.initials: D
authors.lastname: Coradini
authors.forename: Silvia
authors.initials: S
authors.lastname: Veneroni
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.forename: Manuela
authors.initials: M
authors.lastname: Gariboldi
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy*; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D015233:Models, Statistical; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D012372:ROC Curve; D018123:Receptors, Interleukin / Q000235:genetics; D053722:Receptors, Interleukin-17; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; C408922:IL17RB protein, human; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17