Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer

Ana M. Gonzalez-Angulo, A. Akcakanat, S. Liu, M. C. Green, J. L. Murray, H. Chen, S. L. Palla, K. B. Koenig, A. M. Brewster, V. Valero, N. K. Ibrahim, S. Moulder-Thompson, J. K. Litton, E. Tarco, J. Moore, P. Flores, D. Crawford, M. J. Dryden, W. F. Symmans, A. SahinS. H. Giordano, L. Pusztai, K. A. Do, G. B. Mills, G. N. Hortobagyi, F. Meric-Bernstam

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Background: Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Patients and methods: Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m2 i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m2 i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity. Results: Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelveweek RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. Conclusion: The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group.

Original languageEnglish (US)
Pages (from-to)1122-1127
Number of pages6
JournalAnnals of Oncology
Volume25
Issue number6
DOIs
StatePublished - Jun 2014
Externally publishedYes

Keywords

  • Neoadjuvant systemic therapy
  • PI3K pathway inhibition
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Hematology
  • Oncology

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