Letrozole in the Neoadjuvant Setting: The P024 Trial

Breast Cancer Res Treat. 2007;105 Suppl 1(Suppl 1):33-43. doi: 10.1007/s10549-007-9701-x. Epub 2007 Oct 3.

Abstract

Neoadjuvant chemotherapy trials have consistently reported lower response rates in hormone receptor-positive (HR+) breast cancer when compared with HR- cases. Preoperative endocrine therapy has therefore become a logical alternative and has gained considerable momentum from the finding that aromatase inhibitors (AIs) are more effective than tamoxifen for HR+ breast cancer in both the neoadjuvant and adjuvant settings. The most convincing neoadjuvant trial to demonstrate the superiority of an AI versus tamoxifen was the P024 study, a large multinational double-blind trial in postmenopausal women with HR+ breast cancer ineligible for breast-conserving surgery. The overall response rate (ORR) was 55% for letrozole and 36% for tamoxifen (P<0.001). Significantly more letrozole-treated patients underwent breast-conserving surgery (45 vs. 35%, respectively; P=0.022). In addition, ORR was significantly higher with letrozole than tamoxifen in the human epidermal growth factor receptor HER1/HER2+ subgroup (P=0.0004). The clinical efficacy of letrozole in HER2+ breast cancer was confirmed by fluorescent in situ hybridization analysis and was found to be comparable to that of HER2- cases (ORR 71% in both subsets). Biomarker studies confirmed the superiority of letrozole in centrally assessed estrogen receptor-positive (ER+) tumors and found a strong relationship with the degree of ER positivity for both agents. Interestingly, letrozole was effective even in marginally ER+ tumors and, unlike tamoxifen, consistently reduced the expression from estrogen-regulated genes (progesterone receptor and trefoil factor 1). Furthermore, when analyzed by Ki67 immunohistochemistry, letrozole was significantly more effective than tamoxifen in reducing tumor proliferation (P=0.0009). Thus, neoadjuvant letrozole is safe and superior to tamoxifen in the treatment of postmenopausal women with HR+ locally advanced breast cancer.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Hormonal / administration & dosage*
  • Aromatase Inhibitors / administration & dosage*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / surgery
  • Double-Blind Method
  • Female
  • Humans
  • Immunohistochemistry
  • Letrozole
  • Mastectomy, Segmental / methods
  • Middle Aged
  • Neoadjuvant Therapy
  • Neoplasms, Hormone-Dependent / drug therapy*
  • Neoplasms, Hormone-Dependent / mortality
  • Neoplasms, Hormone-Dependent / surgery
  • Nitriles / administration & dosage*
  • Postmenopause
  • Prognosis
  • Receptor, ErbB-2 / drug effects
  • Receptors, Estrogen / drug effects
  • Survival Analysis
  • Tamoxifen / administration & dosage*
  • Triazoles / administration & dosage*

Substances

  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • Nitriles
  • Receptors, Estrogen
  • Triazoles
  • Tamoxifen
  • Letrozole
  • Receptor, ErbB-2