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

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.

The association between the T309G polymorphism of the MDM2 gene and sensitivity to anticancer drug is dependent on the p53 mutational status in cellular models

“…In the clinics, the question has not yet received definitive answers; it appears, however, that a loss of p53 function is frequently associated with resistance to treatment in several malignancies . However, in a recent study on basal-like breast cancers treated by neo-adjuvant chemotherapy using an alkylating agent (cyclophosphamide), all tumours harbouring a mutated p53 presented a complete pathological response to treatment (Bertheau et al, 2007).…”

Changes in allelic imbalances in locally advanced breast cancers after chemotherapy

“…In previous studies (Bertheau et al, 2002(Bertheau et al, , 2007, we have shown in non-inflammatory locally advanced breast cancers that TP53 mutations are highly predictive of complete pathological response to high-dose epirubicin/cyclophosphamide chemotherapy. TP53 is known to control genomic integrity (Vogelstein et al, 2000), and is induced by cytotoxic drugs (Lowe et al, 1993;Bunz et al, 1999), whereas its potential role as a prognostic and a predictive marker in cancer patients remains controversial (Vousden and Prives, 2005;Berns, 2006).…”

“…Whereas obviously, we cannot explore the genome of tumours that underwent complete response, those that were not eradicated can be analysed. Note that we have previously shown that TP53 mutant tumours that did not undergo complete remissions have a worse prognosis than the other groups (Bertheau et al, 2007). This might be caused by chemotherapy-induced additional genetic changes that favour progression.…”

“…Among 80 non-inflammatory locally advanced breast cancers treated in a single institution from 1997 to 2001 with first-line chemotherapy and already studied for their TP53 status and response to treatment (Bertheau et al, 2007), we included 29 patients who fulfilled all the following criteria: patient informed of the study according to our Institutional Review Board recommendations; identical treatment (6 cycles of a dose -dense regimen associating 75 mg m À2 epirubicin and 1200 mg m À2 cyclophosphamide, given every 14 days with G-CSF support in case of febrile neutropenia; Cottu et al, 1999); and incomplete pathological response to treatment. The patients were women aged 23 to 87 (median age 43).…”

Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

“…Owing to the differing drug regimens and tumour subtypes tested, the analysis of TP53 mutations (and p53 protein expression) and anthracycline response has given conflicting results (Bidard et al, 2008). Although some reports suggest that TP53 mutations confer resistance to anthracyclines (Aas et al, 1996;Rahko et al, 2003), others have shown mutations to increase sensitivity (Bertheau et al, 2002(Bertheau et al, , 2009. Similarly, BRCA1 has multiple roles in breast cancer including DNA damage repair, transcriptional regulation, and regulation of cell cycle checkpoints.…”