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Background  In breast cancers, only a minority of patients fully benefit from the different chemotherapy regimens currently in use. Identification of markers that could predict the response to a particular regimen would thus be critically important for patient care. In cell lines or animal models,  tumor protein p53 (TP53)  plays a critical role in modulating the response to genotoxic drugs.  TP53  is activated in response to DNA damage and triggers either apoptosis or cell-cycle arrest, which have opposite effects on cell fate. Yet, studies linking  TP53  status and chemotherapy response have so far failed to unambiguously establish this paradigm in patients. Breast cancers with a  TP53  mutation were repeatedly shown to have a poor outcome, but whether this reflects poor response to treatment or greater intrinsic aggressiveness of the tumor is unknown.    Methods and Findings  In this study we analyzed 80 noninflammatory breast cancers treated by frontline (neoadjuvant) chemotherapy. Tumor diagnoses were performed on pretreatment biopsies, and the patients then received six cycles of a dose-dense regimen of 75 mg/m 2  epirubicin and 1,200 mg/m 2  cyclophosphamide, given every 14 days. After completion of chemotherapy, all patients underwent mastectomies, thus allowing for a reliable assessment of chemotherapy response. The pretreatment biopsy samples were used to determine the  TP53  status through a highly efficient yeast functional assay and to perform RNA profiling. All 15 complete responses occurred among the 28  TP53 -mutant tumors. Furthermore, among the  TP53 -mutant tumors, nine out of ten of the highly aggressive basal subtypes (defined by basal cytokeratin [KRT] immunohistochemical staining) experienced complete pathological responses, and only  TP53  status and basal subtype were independent predictors of a complete response. Expression analysis identified many mutant  TP53 -associated genes, including  CDC20, TTK, CDKN2A,  and the stem cell gene  PROM1,  but failed to identify a transcriptional profile associated with complete responses among  TP53  mutant tumors. In patients with unresponsive tumors, mutant  TP53  status predicted significantly shorter overall survival. The 15 patients with responsive  TP53 -mutant tumors, however, had a favorable outcome, suggesting that this chemotherapy regimen can overcome the poor prognosis generally associated with mutant  TP53  status.    Conclusions  This study demonstrates that, in noninflammatory breast cancers,  TP53  status is a key predictive factor for response to this dose-dense epirubicin–cyclophosphamide regimen and further suggests that the basal subtype is exquisitely sensitive to this association. Given the well-established predictive value of complete responses for long-term survival and the poor prognosis of basal and  TP53 -mutant tumors treated with other regimens, this chemotherapy could be particularly suited for breast cancer patients with a mutant  TP53,  particularly those with basal features.

Exquisite Sensitivity of TP53 Mutant and Basal Breast Cancers to a Dose-Dense Epirubicin−Cyclophosphamide Regimen