title: Neoadjuvant chemotherapy with paclitaxel and everolimus in breast cancer patients with non-responsive tumours to epirubicin/cyclophosphamide (EC) ± bevacizumab - results of the randomised GeparQuinto study (GBG 44).
abstract: BACKGROUND
  We 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.
  
  
  METHODS
  Patients 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.
  
  
  RESULTS
  Of 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.
  
  
  CONCLUSIONS
  Neoadjuvant 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.
  
  
  BACKGROUND
  Novartis, Roche, and Sanofi-Aventis.
authors.affiliation: Universtitäts-Frauenklinik, Düsseldorf, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Claus
authors.initials: C
authors.lastname: Hanusch
authors.forename: Mahdi
authors.initials: M
authors.lastname: Rezai
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.forename: Kornelia
authors.initials: K
authors.lastname: Kittel
authors.forename: Jörn
authors.initials: J
authors.lastname: Hilfrich
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwedler
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Blohmer
authors.forename: Hans
authors.initials: H
authors.lastname: Tesch
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerber
authors.forename: Cornelia
authors.initials: C
authors.lastname: Höß
authors.forename: Sherko
authors.initials: S
authors.lastname: Kümmel
authors.forename: Christine
authors.initials: C
authors.lastname: Mau
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.forename: Fariba
authors.initials: F
authors.lastname: Khandan
authors.forename: Serban Dan
authors.initials: SD
authors.lastname: Costa
authors.forename: Petra
authors.initials: P
authors.lastname: Krabisch
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Valentina
authors.initials: V
authors.lastname: Nekljudova
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.forename: Gunter von
authors.initials: Gv
authors.lastname: Minckwitz
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D003520:Cyclophosphamide / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015251:Epirubicin / Q000009:adverse effects; D000068338:Everolimus; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D015412:Mastectomy, Segmental; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D020360:Neoadjuvant Therapy; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D015251:Epirubicin; D003520:Cyclophosphamide; D000068338:Everolimus; D017239:Paclitaxel; D020123:Sirolimus