Evaluation of a 30-Gene Paclitaxel, Fluorouracil, Doxorubicin, and Cyclophosphamide Chemotherapy Response Predictor in a Multicenter Randomized Trial in Breast Cancer

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...

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Published in:Clinical cancer research 2010-11, Vol.16 (21), p.5351-5361
Main Authors: TABCHY, Adel, VALERO, Vicente, DOIMI, Franco D, IBRAHIM, Nuhad K, YUN GONG, HORTOBAGYI, Gabriel N, HESS, Kenneth R, SYMMANS, W. Fraser, PUSZTAI, Lajos, VIDAURRE, Tatiana, LLUCH, Ana, GOMEZ, Henry, MARTIN, Miguel, YUAN QI, BARAJAS-FIGUEROA, Luis Javier, SOUCHON, Eduardo, COUTANT, Charles
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Biomarkers, Pharmacological - analysis
Biomarkers, Pharmacological - metabolism
Biomarkers, Tumor - analysis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Breast Neoplasms - diagnosis
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Carcinoma, Ductal, Breast - diagnosis
Carcinoma, Ductal, Breast - drug therapy
Carcinoma, Ductal, Breast - genetics
Cyclophosphamide - administration & dosage
Doxorubicin - administration & dosage
Female
Fluorouracil - administration & dosage
Gene Expression Regulation, Neoplastic - drug effects
Gynecology. Andrology. Obstetrics
Humans
Mammary gland diseases
Medical sciences
Middle Aged
Paclitaxel - administration & dosage
Pharmacology. Drug treatments
Predictive Value of Tests
Prognosis
Treatment Outcome
Tumors
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Summary: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. 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. 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. 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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-10-1265