Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.
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.
Lehmann-Che
Jacqueline
J
INSERM/CNRS/University Paris 7, UMR 944/7212, Hôpital Saint Louis, 1, av Claude Vellefaux, 75 475 Paris Cedex 10, France.
André
Fabrice
F
Desmedt
Christine
C
Mazouni
Chafika
C
Giacchetti
Sylvie
S
Turpin
Elisabeth
E
Espié
Marc
M
Plassa
Louis-François
LF
Marty
Michel
M
Bertheau
Philippe
P
Sotiriou
Christos
C
Piccart
Martine
M
Symmans
W Fraser
WF
Pusztai
Lajos
L
de Thé
Hugues
H
D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D016158:Genes, p53; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D055815:Young Adult
D018943:Anthracyclines; D003520:Cyclophosphamide; D004317:Doxorubicin; D015251:Epirubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases