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, Gordon Mills, G. N. Hortobagyi, F. Meric-Bernstam

Research output: Contribution to journalArticle

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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 - Jan 1 2014
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Paclitaxel
Randomized Controlled Trials
Drug Therapy
Down-Regulation
Protein Array Analysis
Epirubicin
Stomatitis
Exanthema
Neutropenia
Phosphatidylinositol 3-Kinases
Fluorouracil
Cyclophosphamide
Vomiting
Anemia
Pneumonia
Everolimus
Breast Neoplasms
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

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

In: Annals of Oncology, Vol. 25, No. 6, 01.01.2014, p. 1122-1127.

Research output: Contribution to journalArticle

Gonzalez-Angulo, AM, Akcakanat, A, Liu, S, Green, MC, Murray, JL, Chen, H, Palla, SL, Koenig, KB, Brewster, AM, Valero, V, Ibrahim, NK, Moulder-Thompson, S, Litton, JK, Tarco, E, Moore, J, Flores, P, Crawford, D, Dryden, MJ, Symmans, WF, Sahin, A, Giordano, SH, Pusztai, L, Do, KA, Mills, G, Hortobagyi, GN & Meric-Bernstam, F 2014, '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', Annals of Oncology, vol. 25, no. 6, pp. 1122-1127. https://doi.org/10.1093/annonc/mdu124
Gonzalez-Angulo, Ana M. ; Akcakanat, A. ; Liu, S. ; Green, M. C. ; Murray, J. L. ; Chen, H. ; Palla, S. L. ; Koenig, K. B. ; Brewster, A. M. ; Valero, V. ; Ibrahim, N. K. ; Moulder-Thompson, S. ; Litton, J. K. ; Tarco, E. ; Moore, J. ; Flores, P. ; Crawford, D. ; Dryden, M. J. ; Symmans, W. F. ; Sahin, A. ; Giordano, S. H. ; Pusztai, L. ; Do, K. A. ; Mills, Gordon ; Hortobagyi, G. N. ; Meric-Bernstam, F. / 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. In: Annals of Oncology. 2014 ; Vol. 25, No. 6. pp. 1122-1127.
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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.",
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author = "Gonzalez-Angulo, {Ana M.} and A. Akcakanat and S. Liu and Green, {M. C.} and Murray, {J. L.} and H. Chen and Palla, {S. L.} and Koenig, {K. B.} and Brewster, {A. M.} and V. Valero and Ibrahim, {N. K.} and S. Moulder-Thompson and Litton, {J. K.} and E. Tarco and J. Moore and P. Flores and D. Crawford and Dryden, {M. J.} and Symmans, {W. F.} and A. Sahin and Giordano, {S. H.} and L. Pusztai and Do, {K. A.} and Gordon Mills and Hortobagyi, {G. N.} and F. Meric-Bernstam",
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TY - JOUR

T1 - 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

AU - Gonzalez-Angulo, Ana M.

AU - Akcakanat, A.

AU - Liu, S.

AU - Green, M. C.

AU - Murray, J. L.

AU - Chen, H.

AU - Palla, S. L.

AU - Koenig, K. B.

AU - Brewster, A. M.

AU - Valero, V.

AU - Ibrahim, N. K.

AU - Moulder-Thompson, S.

AU - Litton, J. K.

AU - Tarco, E.

AU - Moore, J.

AU - Flores, P.

AU - Crawford, D.

AU - Dryden, M. J.

AU - Symmans, W. F.

AU - Sahin, A.

AU - Giordano, S. H.

AU - Pusztai, L.

AU - Do, K. A.

AU - Mills, Gordon

AU - Hortobagyi, G. N.

AU - Meric-Bernstam, F.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Neoadjuvant systemic therapy

KW - PI3K pathway inhibition

KW - Triple negative breast cancer

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