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

Date Published: March 20, 2007

Publisher: Public Library of Science

Author(s): Philippe Bertheau, Elisabeth Turpin, David S Rickman, Marc Espié, Aurélien de Reyniès, Jean-Paul Feugeas, Louis-François Plassa, Hany Soliman, Mariana Varna, Anne de Roquancourt, Jacqueline Lehmann-Che, Yves Beuzard, Michel Marty, Jean-Louis Misset, Anne Janin, Hugues de Thé, Lajos Pusztai

Abstract: BackgroundIn 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 FindingsIn 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/m2 epirubicin and 1,200 mg/m2 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.ConclusionsThis 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.

Partial Text: Breast cancers are a heterogeneous group of tumors. While most breast cancer patients receive chemotherapy, less than 20% of those receiving neoadjuvant treatment will reach complete pathological response (disappearance of invasive tumor cells in pathological tissue samples), which strongly predicts long-term survival [1–5]. Predictive molecular determinants for conventionally dosed chemotherapy responses are only emerging [6–8], and very little is known regarding prediction of response to dose-dense treatments.

We show that in noninflammatory breast cancers, TP53 mutations are highly predictive of complete responses to a dose-intense neoadjuvant epirubicin–cyclophosphamide chemotherapy regimen. Why did previous studies fail to identify this relationship? We believe that the results reported here reflect the use of a very aggressive DNA-damaging regimen and of a highly efficient technique to determine TP53 status, which detects not only mutations and deletions, but also abnormal splicing events [18]. It is also possible that some previous studies were biased by the presence of inflammatory breast cancers in the study population.



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