Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer.
OBJECTIVE
We developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases.


METHODS
One hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases.


RESULTS
Overall pCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant.


CONCLUSIONS
A 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients).
Hess
Kenneth R
KR
Department of Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1439, USA.
Anderson
Keith
K
Symmans
W Fraser
WF
Valero
Vicente
V
Ibrahim
Nuhad
N
Mejia
Jaime A
JA
Booser
Daniel
D
Theriault
Richard L
RL
Buzdar
Aman U
AU
Dempsey
Peter J
PJ
Rouzier
Roman
R
Sneige
Nour
N
Ross
Jeffrey S
JS
Vidaurre
Tatiana
T
Gómez
Henry L
HL
Hortobagyi
Gabriel N
GN
Pusztai
Lajos
L
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D009841:Oligonucleotides; D017239:Paclitaxel / Q000008:administration & dosage; D011237:Predictive Value of Tests; D012372:ROC Curve; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D009841:Oligonucleotides; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil