Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

• Authors: Adel Tabchy, Vicente Valero, Tatiana Vidaurre, Ana Lluch, Henry Gomez, Miguel Martin, Yuan Qi, Luis Javier Barajas-Figueroa, Eduardo Souchon, Charles Coutant, Franco D Doimi, Nuhad K Ibrahim, Yun Gong, Gabriel N Hortobagyi, Kenneth R Hess, W Fraser Symmans, Lajos Pusztai
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 21 Pg. 5351-61 (Nov 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20829329 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Biomarkers, Pharmacological
• Biomarkers, Tumor
• Doxorubicin
• Cyclophosphamide
• Paclitaxel
• Fluorouracil

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Pharmacological (analysis, metabolism)
• Biomarkers, Tumor (analysis, genetics, metabolism)
• Breast Neoplasms (diagnosis, drug therapy, genetics)
• Carcinoma, Ductal, Breast (diagnosis, drug therapy, genetics)
• Cyclophosphamide (administration & dosage)
• Doxorubicin (administration & dosage)
• Female
• Fluorouracil (administration & dosage)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Middle Aged
• Paclitaxel (administration & dosage)
• Predictive Value of Tests
• Prognosis
• Treatment Outcome