Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers - PubMed (original) (raw)

Clinical Trial

doi: 10.1634/theoncologist.2009-0243. Epub 2010 Mar 12.

Fabrice André, Christine Desmedt, Chafika Mazouni, Sylvie Giacchetti, Elisabeth Turpin, Marc Espié, Louis-François Plassa, Michel Marty, Philippe Bertheau, Christos Sotiriou, Martine Piccart, W Fraser Symmans, Lajos Pusztai, Hugues de Thé

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Clinical Trial

Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers

Jacqueline Lehmann-Che et al. Oncologist. 2010.

Abstract

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.

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Conflict of interest statement

Disclosures

Jacqueline Lehmann-Che: None; Fabrice André: None; Christine Desmedt: None; Chafika Mazouni: None; Sylvie Giacchetti: None; Elisabeth Turpin: None; Marc Espié: None; Louis-François Plassa: None; Michel Marty: None; Philippe Bertheau: None; Christos Sotiriou: None; Martine Piccart: None; W. Fraser Symmans: None; Lajos Pusztai: None; Hugues de Thé: None.

Section editor Kathleen Pritchard has disclosed no financial relationships relevant to the content of this article. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.

Figures

Figure 1.

Figure 1.

Pathologic complete response (pCR) rate according to alkylating agent dose. (A): Patients with _p53_-mutated tumors. (B): Patients with wild-type p53 tumors. Abbreviations: ddEC, dose-dense epirubicin and cyclophosphamide; E, single-agent epirubicin; FAC, 5-fluorouracil, doxorubicin, and cyclophosphamide.

Figure 2.

Figure 2.

Efficacy of high-dose alkylating agents in patients with estrogen receptor–negative _p53_-mutated tumors. Abbreviations: ddEC, dose-dense epirubicin and cyclophosphamide; E, single-agent epirubicin; FAC, 5-fluorouracil, doxorubicin, and cyclophosphamide; pCR, pathologic complete response.

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