Prediction of the outcome of preoperative chemotherapy in breast cancer using DNA probes that provide information on both complete and incomplete responses.
BACKGROUND
DNA microarray technology has emerged as a major tool for exploring cancer biology and solving clinical issues. Predicting a patient's response to chemotherapy is one such issue; successful prediction would make it possible to give patients the most appropriate chemotherapy regimen. Patient response can be classified as either a pathologic complete response (PCR) or residual disease (NoPCR), and these strongly correlate with patient outcome. Microarrays can be used as multigenic predictors of patient response, but probe selection remains problematic. In this study, each probe set was considered as an elementary predictor of the response and was ranked on its ability to predict a high number of PCR and NoPCR cases in a ratio similar to that seen in the learning set. We defined a valuation function that assigned high values to probe sets according to how different the expression of the genes was and to how closely the relative proportions of PCR and NoPCR predictions to the proportions observed in the learning set was. Multigenic predictors were designed by selecting probe sets highly ranked in their predictions and tested using several validation sets.


RESULTS
Our method defined three types of probe sets: 71% were mono-informative probe sets (59% predicted only NoPCR, and 12% predicted only PCR), 25% were bi-informative, and 4% were non-informative. Using a valuation function to rank the probe sets allowed us to select those that correctly predicted the response of a high number of patient cases in the training set and that predicted a PCR/NoPCR ratio for validation sets that was similar to that of the whole learning set. Based on DLDA and the nearest centroid method, bi-informative probes proved more successful predictors than probes selected using a t test.


CONCLUSIONS
Prediction of the response to breast cancer preoperative chemotherapy was significantly improved by selecting DNA probe sets that were successful in predicting outcomes for the entire learning set, both in terms of accurately predicting a high number of cases and in correctly predicting the ratio of PCR to NoPCR cases.
Natowicz
René
R
AP-HP, Hôpital Tenon, Department of Gynecology, 4 rue de la Chine, F-75020 Paris, France. natowicr@esiee.fr
Incitti
Roberto
R
Horta
Euler Guimarães
EG
Charles
Benoît
B
Guinot
Philippe
P
Yan
Kai
K
Coutant
Charles
C
Andre
Fabrice
F
Pusztai
Lajos
L
Rouzier
Roman
R
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D015342:DNA Probes / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D017063:Outcome Assessment, Health Care / Q000379:methods*; D011300:Preoperative Care / Q000379:methods; D011379:Prognosis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015342:DNA Probes; D009363:Neoplasm Proteins