Abstract P3-06-14: Identification of Prognosis-Relevant Subgroups in Patients with Chemoresistant Triple Negative Breast Cancer

Abstract

Abstract Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. TNBC patients with pathologic complete response (pCR) have excellent survival, but those with residual disease after neoadjuvant chemotherapy have significantly worse outcome. However, some patients having extensive residual cancer burden after neoadjuvant chemotherapy do not relapse, and we hypothesize that there may be subgroups with diverse prognosis among these chemoresistant TNBC patients. Methods: Forty-nine cases with residual cancer from 111 TNBC patients treated with neoadjuvant chemotherapy (in M.D. Anderson Cancer Center, 2000–2006) constituted the discovery cohort. Twenty-five chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (in Baylor College of Medicine and Methodist Hospital, 2002–2006) were chosen for validation. Extended validation was performed in 269 operable TNBC predicted to be chemoresistant (using a JAMA-published genomic predictor) from public databases. Results: By comparing the gene expression data from cases in relapse with those from un-relapsed cases, we established a 7-gene prognostic signature (including AR, ESR2, GATA3, GBX2, KRT16, MMP28, and WNT11) using dChip and gene enrichment analyses. In the discovery cohort, the signature showed positive predictive value (PPV; i.e., cumulative relapse rate of patients predicted to relapse in 3 years) of 95.4% and negative predictive values (NPV; i.e., relapse-free survival of patients predicted not to relapse in 3 years) of 100%. In the validation cohort, the classifier predicted correctly with PPV of 75.0% and NPV of 76.9% at 3 years. Compared with patients predicted not to relapse, those predicted to relapse had a hazard ratio of 3.37 (95% CI, 1.15–9.85) for disease recurrence or death in 3 years. In an extended validation cohort of 269 patients, our signature discriminated chemoresistant TNBC in overall cohort (PPV, 52.4%; NPV, 77.7%; log rank P < 0.0001), or each subset (e.g., log rank p = 0.001 for Rotterdam set; p = 0.013 for Frankfurt set), with adjusted overall hazard ratio of 2.07 (95% CI, 1.26–3.39). This signature was the only marker that could effectively predict the relapse in patients with chemoresistant TNBC. Of note, the subgroup predicted not to relapse was characterized by high expression of luminal-like genes (AR, GATA3), while the subgroup predicted to have high possibility of relapse was characterized by high expression of cancer stem cell and epithelial-to-mesenchymal transition associated genes (WNT11, MMP28). The former corresponded to the luminal AR subtype and the latter to the mesenchymal stem-like subtype, according to Pietenpol's TNBC subtype classification. Conclusion: We developed a clinically useful prognostic signature for chemoresistant TNBC. For these chemoresistant TNBC patients, new therapeutic strategies targeting AR-activation or cancer stem cells need to be developed. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-14.