title: Bevacizumab plus neoadjuvant chemotherapy in patients with HER2-negative inflammatory breast cancer (BEVERLY-1): a multicentre, single-arm, phase 2 study.
abstract: Addition of bevacizumab to standard chemotherapy in the neoadjuvant setting in patients with HER2-negative metastatic breast cancer improves progression-free survival and the proportion of patients achieving pathological complete response. In the BEVERLY-1 (UCBG-0802) trial we aimed to assess the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy in the treatment of patients with HER2-negative inflammatory breast cancer.
  
  
  
  We did this phase 2, single-arm trial at 20 hospitals in France. We enrolled women aged 18 years or older who had non-metastatic HER2-negative inflammatory breast cancer. Patients underwent 3-week treatment cycles, receiving neoadjuvant intravenous fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), cyclophosphamide (500 mg/m(2)), and bevacizumab (15 mg/kg) during cycles 1-4, then docetaxel (100 mg/m(2)) and bevacizumab during cycles 5-8. 2-4 weeks after surgery, patients received adjuvant radiotherapy, hormone therapy (if they had a hormone receptor-positive tumour), and adjuvant intravenous bevacizumab. The primary endpoint was pathological complete response in breast and axillary lymph nodes after neoadjuvant treatment, determined after centralised review in accordance with Sataloff classification and assessed in the intention-to-treat population. Our analysis of toxic effects included all patients who received at least one dose of bevacizumab. The trial is complete and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00820547.
  
  
  
  Between Jan 16, 2009, and Sept 8, 2010, we enrolled 101 patients, one of whom withdrew consent before treatment, leaving 100 patients in the primary endpoint analysis. After neoadjuvant therapy, 19 (19% [95% CI 12-28]; p=0·16) of 100 patients achieved a pathological complete response according to centralised review. The most frequent grade 3-4 events during the neoadjuvant phase were neutropenia (89 [89%] of 100 patients), febrile neutropenia (37 [37%]), and mucositis (23 [23%]) and during the adjuvant phase the most frequent grade 3-4 adverse event was proteinuria (5 [7%] of 75 patients). One (1%) patient died of thrombotic microangiopathy after cycle 1, which was thought to be related to bevacizumab. Two patients (3%) developed transitory heart failure. 48 (48%) patients had serious adverse events, the most frequent of which was febrile neutropenia (28 [28%]).
  
  
  
  Our results suggest that the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy does not provide clinical benefit to patients with non-metastatic HER2-negative inflammatory breast cancer. Longer follow-up and correlative studies to identify patients who might benefit from bevacizumab are needed.
  
  
  
  Roche, La Ligue Nationale contre le Cancer, UNICANCER, and Chugai Pharma.
authors.affiliation: Département d'Oncologie Médicale, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, France; Aix-Marseille Université, Marseille, France. Electronic address: bertuccif@ipc.unicancer.fr.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Fekih
authors.affiliation: Département d'Oncologie Médicale, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Autret
authors.affiliation: Centre Paul Strauss, Strasbourg, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Petit
authors.affiliation: Institut Claudius Regaud, IUCT, Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.affiliation: Centre François Baclesse, Caen, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Levy
authors.affiliation: Institut Régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Romieu
authors.affiliation: Centre Oscar Lambret, Lille, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bonneterre
authors.affiliation: Centre Antoine Lacassagne, Nice, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: Centre Eugène Marquis, Rennes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Kerbrat
authors.affiliation: Institut de Cancérologie de l'Ouest, Angers, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Soulie
authors.affiliation: Centre Jean Perrin, Clermont Ferrand, France.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Mouret-Reynier
authors.affiliation: Centre Léon Bérard, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Institut Curie, Saint Cloud, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Lerebours
authors.affiliation: Institut Jean Godinot, Reims, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Eymard
authors.affiliation: Institut de Cancérologie de Lorraine, Centre Alexis Vautrin, Nancy, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Deblock
authors.affiliation: Centre Catherine de Sienne, Nantes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lortholary
authors.affiliation: Centre Armoricain de Radiothérapie, d'Imagerie et d'Oncologie, Plérin, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Hardy-Bessard
authors.affiliation: Centre Hospitalier Régional Universitaire, Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Barthelemy
authors.affiliation: Institut Bergonié, Bordeaux, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Bonnefoi
authors.affiliation: Département d'Oncologie Médicale, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, France; Aix-Marseille Université, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.affiliation: Institut Curie, Paris, France.
authors.forename: François-Clément
authors.initials: FC
authors.lastname: Bidard
authors.affiliation: Département d'Oncologie Médicale, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, France; Aix-Marseille Université, Marseille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.affiliation: R&D UNICANCER, UCBG, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lemonnier
authors.affiliation: Institut Curie, Paris, France; Université Paris Descartes, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D000068258:Bevacizumab; D003520:Cyclophosphamide; D000077143:Docetaxel; D015251:Epirubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids