Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer.

Yu KD, Zhu R, Zhan M, Rodriguez AA, Yang W, Wong S, Makris A, Lehmann BD, Chen X, Mayer I, Pietenpol JA, Shao ZM, Symmans WF, Chang JC
Clin Cancer Res. 2013 19 (10): 2723-33

PMID: 23549873 · PMCID: PMC3655097 · DOI:10.1158/1078-0432.CCR-12-2986

PURPOSE - Patients with triple-negative breast cancer (TNBC) and residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. We hypothesize that there are subgroups of patients with chemoresistant TNBC with different prognosis.

EXPERIMENTAL DESIGN - Forty-nine chemoresistant cases from 111 patients with TNBC treated with neoadjuvant chemotherapy (M.D. Anderson Cancer Center, Houston, TX) constituted the discovery cohort, and 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital, Houston, TX) were chosen for validation. Extended validation was carried out in 269 operable TNBC predicted to be chemoresistant by expression pattern from published datasets.

RESULTS - We established a seven-gene prognostic signature using dChip and gene set enrichment analyses. In the independent validation cohort, the classifier predicted correctly with positive predictive value of 75.0% and negative predictive value (i.e., relapse-free survival; RFS) of 76.9% at 3 years. Those predicted to relapse had a HR of 4.67 [95% confidence interval (CI): 1.27-17.15] for relapse in 3 years. In extended validation, patients predicted not to relapse exhibited 3-year RFS of 78.9%, whereas the 3-year RFS was 48.5% for patients predicted to relapse, with HR of 2.61 (95% CI: 1.52-4.49). The TNBC subgroup that predicted to have relatively favorable prognosis was characterized by high expression of "luminal-like" genes [androgen-receptor (AR) and GATA3], whereas the subgroup with worse prognosis was characterized by expression of cancer stem-cell markers.

CONCLUSION - We developed a clinically relevant signature for patients with chemoresistant TNBC. For these women, new therapeutic strategies like targeting AR activation or cancer stem cells may need to be developed.

©2013 AACR

MeSH Terms (21)

Adult Cohort Studies Drug Resistance, Neoplasm Estrogen Receptor beta Female GATA3 Transcription Factor Gene Expression Profiling Gene Expression Regulation, Neoplastic Homeodomain Proteins Humans Kaplan-Meier Estimate Keratin-16 Matrix Metalloproteinases, Secreted Middle Aged Neoadjuvant Therapy Neoplasm, Residual Oligonucleotide Array Sequence Analysis Prognosis Receptors, Androgen Triple Negative Breast Neoplasms Wnt Proteins

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