Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer.
OBJECTIVE
We examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FACx6 preoperative chemotherapy. We also did an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms.


METHODS
Two hundred and seventy-three patients were randomly assigned to receive either weekly paclitaxel × 12 followed by FAC × 4 (T/FAC, n = 138), or FAC × 6 (n = 135) neoadjuvant chemotherapy. All patients underwent a pretreatment fine-needle aspiration biopsy of the tumor for gene expression profiling and treatment response prediction.


RESULTS
The pCR rates were 19% and 9% in the T/FAC and FAC arms, respectively (P < 0.05). In the T/FAC arm, the positive predictive value (PPV) of the genomic predictor was 38% [95% confidence interval (95% CI), 21-56%], the negative predictive value was 88% (95% CI, 77-95%), and the area under the receiver operating characteristic curve (AUC) was 0.711. In the FAC arm, the PPV was 9% (95% CI, 1-29%) and the AUC was 0.584. This suggests that the genomic predictor may have regimen specificity. Its performance was similar to a clinical variable-based predictor nomogram.


CONCLUSIONS
Gene expression profiling for prospective response prediction was feasible in this international trial. The 30-gene predictor can identify patients with greater than average sensitivity to T/FAC chemotherapy. However, it captured molecular equivalents of clinical phenotype. Next-generation predictive markers will need to be developed separately for different molecular subsets of breast cancers.
Tabchy
Adel
A
Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1439, USA.
Valero
Vicente
V
Vidaurre
Tatiana
T
Lluch
Ana
A
Gomez
Henry
H
Martin
Miguel
M
Qi
Yuan
Y
Barajas-Figueroa
Luis Javier
LJ
Souchon
Eduardo
E
Coutant
Charles
C
Doimi
Franco D
FD
Ibrahim
Nuhad K
NK
Gong
Yun
Y
Hortobagyi
Gabriel N
GN
Hess
Kenneth R
KR
Symmans
W Fraser
WF
Pusztai
Lajos
L
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D011237:Predictive Value of Tests; D011379:Prognosis; D016896:Treatment Outcome
D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil