• Jens Huober, Peter A Fasching, Claus Hanusch, Mahdi Rezai, Holger Eidtmann, Kornelia Kittel, Jörn Hilfrich, Kathrin Schwedler, Jens-Uwe Blohmer, Hans Tesch, Bernd Gerber, Cornelia Höß, Sherko Kümmel, Christine Mau, Christian Jackisch, Fariba Khandan, Costa Serban Dan SD, Petra Krabisch, Sibylle Loibl, Valentina Nekljudova, Michael Untch, and Minckwitz Gunter von Gv.
• Universtitäts-Frauenklinik, Düsseldorf, Germany.
• Eur. J. Cancer. 2013 Jul 1; 49 (10): 2284-93.

BackgroundWe tested the oral mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to paclitaxel in patients with HER2-negative tumours not responding to initial neoadjuvant cytotoxic and anti-angiogenic treatment.MethodsPatients with primary HER2-negative tumours received four neoadjuvant cycles of epirubicin/cyclophosphamide (EC) with or without bevacizumab. Patients without clinical response were randomised to receive weekly paclitaxel (80 mg/m(2)) with or without everolimus (5mg p.o. daily, after a step-wise dose-escalation starting from 2.5mg bid) for 12 weeks before surgery. To detect an increase in pathological complete response (pCR; ypT0 ypN0) from 5% to 12.1% (odds ratio 2.62) 566 patients had to be recruited. The trial was stopped prematurely due to completion of accrual in the main study.FindingsOf 1948 patients initially starting neoadjuvant treatment 403 were randomised. A total of 18 (4.6%) patients, 7 (3.6%) treated with paclitaxel and everolimus and 11 (5.6%) treated with paclitaxel alone had a pCR (odds ratio 0.36 (OR) (95% confidence interval (CI), 0.24-1.6) p=0.34). Overall response rate in breast and lymph nodes at surgery was 52.2% after paclitaxel plus everolimus and 61.7% after paclitaxel alone (p=0.063). Breast conserving treatment was performed in 54.4% of patients with the combination treatment and 61.9% with paclitaxel alone (p=0.20). Mucosal inflammation, thrombocytopenia, neutropenia, infection, and skin rash were more frequent when everolimus was added to paclitaxel.InterpretationNeoadjuvant therapy with everolimus and paclitaxel for patients with HER2-negative disease unresponsive to EC with or without bevacizumab did not improve the pCR rate. Long-term outcome is awaited.FundingNovartis, Roche, and Sanofi-Aventis.Copyright © 2013 Elsevier Ltd. All rights reserved.

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