title: Use of [(18)F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [(18)F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial.
abstract: BACKGROUND
  An effective and well tolerated treatment is needed for patients with early HER2-positive breast cancer who do not achieve a pathological complete response after neoadjuvant therapy. The AVATAXHER trial aimed to predict pathological complete response early with the use of PET and to investigate whether the addition of bevacizumab could improve the proportion of patients achieving a pathological complete response in patients unlikely to respond to treatment.
  
  
  METHODS
  AVATAXHER was a randomised, open-label, non-comparative, multicentre phase 2 study that enrolled women (≥18 years of age) with early-stage HER2-positive breast cancer from 26 oncology centres in France. Patients initially received two cycles of neoadjuvant docetaxel (100 mg/m(2) intravenously every 3 weeks) plus trastuzumab (8 mg/kg intravenously every 3 weeks then 6 mg/kg intravenously every 3 weeks for the second course). Before the first and second cycles, [(18)F]-fluorodeoxyglucose (FDG) PET was done and the change in standardised uptake value was used to predict pathological complete response in each patient. Patients who were predicted to be responders on PET continued to receive standard therapy. Predicted non-responders were randomly assigned (2:1) to receive four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) and trastuzumab (6 mg/kg intravenously every 3 weeks) plus bevacizumab (15 mg/kg intravenously every 3 weeks; group A) or continue on docetaxel plus trastuzumab alone (group B). Randomisation was open label and was done by an adaptive minimisation method. Although investigators and patients were aware of group assignment, the anatomo-pathologist in charge of centralised review of surgical samples and lymph nodes was masked to treatment assignment. The primary endpoint was centrally assessed pathological complete response according to the Chevallier classification. Efficacy analyses were done in the intention-to-treat population. Safety analyses in this Article were done on all patients who received at least one dose of treatment starting from cycle 3. Survival outcomes are not yet mature. This study is registered with ClinicalTrials.gov (NCT01142778) and EUDRACT (2009-013410-26).
  
  
  RESULTS
  Between May 19, 2010, and Oct 1, 2012, 152 patients were recruited for the study. Ten patients were subsequently excluded, leaving 142 patients in the intention-to-treat population. Of these 142 patients, 69 were predicted by [(18)F]-FDG PET to be treatment responders after two cycles of treatment. The 73 predicted non-responders were randomly assigned to group A (n=48) and group B (n=25). Pathological complete responses were noted in 37 (53·6%, 95% CI 41·2-65·7) of the PET responders, 21 (43·8%, 29·5-58·8) of those in group A, and six (24·0%, 9·4-45·1) of those in group B. Incidences of grade 3-4 adverse events were similar in all three groups. The most common grade 3-4 adverse events were neutropenia (four in PET responders, five in group A, and three in group B), febrile neutropenia (one, three, and one, respectively), and myalgia (four, none, and one, respectively). Overall, 24 serious adverse events were reported in 15 patients (PET responders: nine events in four [6%] of 67 patients; group A: 14 events in ten [21%] of 47 patients; group B: one event in one [4%] of 25 patients). No deaths occurred during the study.
  
  
  CONCLUSIONS
  In patients with HER2-positive breast cancer, early PET assessment can help to identify non-responders to neoadjuvant docetaxel plus trastuzumab therapy. In these patients, the addition of bevacizumab can increase the proportion of patients achieving a pathological complete response. This potential new role for PET and the activity of bevacizumab in this setting need to be confirmed in larger phase 3 trials.
  
  
  BACKGROUND
  Roche France.
authors.affiliation: Department of Medical Oncology, Centre Georges-Francois Leclerc, Dijon, France. Electronic address: bcoudert@cgfl.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Coudert
authors.affiliation: Department of Medical Oncology, Institut Curie, Université Paris Descartes, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.affiliation: Department of Medical Oncology, Centre Jean Perrin, Clermont Ferrand, France.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Mouret-Reynier
authors.affiliation: Department of Nuclear Medicine, Hopital Tenon, Paris, France.
authors.forename: Kaldoun
authors.initials: K
authors.lastname: Kerrou
authors.affiliation: Department of Medical Oncology, Centre Antoine-Lacassagne, Nice, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: Department of Medical Oncology, Centre Paul Strauss, Strasbourg, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Petit
authors.affiliation: Department of Medical Oncology, Centre Eugène Marquis, Rennes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Kerbrat
authors.affiliation: Department of Medical Oncology, Centre Hospitalier Universitaire Augustin-Morvan, Brest, France.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Dupré
authors.affiliation: Department of Medical Oncology et Unité INSERM U590, Centre Léon Berard, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Department of Surgery, Institut Daniel Hollard, Grenoble, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gabelle
authors.affiliation: Department of Surgery, Centre Oscar Lambret, Lille, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Giard
authors.affiliation: Department of Medical Oncology, Clinique Hartmann, Neuilly sur Seine, France.
authors.forename: David
authors.initials: D
authors.lastname: Coeffic
authors.affiliation: Department of Medical Oncology, CHU Bretonneau, Tours, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bougnoux
authors.affiliation: Department of Medical Oncology, Centre Pierre Curie, Beuvry, France.
authors.forename: Jean-Briac
authors.initials: JB
authors.lastname: Prevost
authors.affiliation: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, Laboratory of Pharmacology-Toxicology, Tours, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.affiliation: Immunology Department, CHU Bretonneau, Tours, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Thibault
authors.affiliation: Roche Laboratory, Boulogne Billancourt, France.
authors.forename: Juana
authors.initials: J
authors.lastname: Hernandez
authors.affiliation: Experis IT, Nanterre, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coudert
authors.affiliation: Department of Pathology, Centre Georges-Francois Leclerc, Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.affiliation: Department of Nuclear Medicine, Centre Georges-Francois Leclerc, Dijon, France.
authors.forename: Alina
authors.initials: A
authors.lastname: Berriolo-Riedinger
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D000077143:Docetaxel; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D011379:Prognosis; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000077143:Docetaxel; D019788:Fluorodeoxyglucose F18; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human