François Bertucci1, Mahmoud Fekih2, Aurélie Autret3, Thierry Petit4, Florence Dalenc5, Christelle Levy6, Gilles Romieu7, Jacques Bonneterre8, Jean-Marc Ferrero9, Pierre Kerbrat10, Patrick Soulie11, Marie-Ange Mouret-Reynier12, Thomas Bachelot13, Florence Lerebours14, Jean-Christophe Eymard15, Mathilde Deblock16, Alain Lortholary17, Anne-Claire Hardy-Bessard18, Philippe Barthelemy19, Hervé Bonnefoi20, Emmanuelle Charafe-Jauffret21, François-Clément Bidard22, Patrice Viens21, Jérôme Lemonnier23, Jean-Yves Pierga24. 1. 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. 2. Institut Gustave Roussy, Villejuif, France. 3. Département d'Oncologie Médicale, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, France. 4. Centre Paul Strauss, Strasbourg, France. 5. Institut Claudius Regaud, IUCT, Toulouse, France. 6. Centre François Baclesse, Caen, France. 7. Institut Régional du Cancer de Montpellier, Montpellier, France. 8. Centre Oscar Lambret, Lille, France. 9. Centre Antoine Lacassagne, Nice, France. 10. Centre Eugène Marquis, Rennes, France. 11. Institut de Cancérologie de l'Ouest, Angers, France. 12. Centre Jean Perrin, Clermont Ferrand, France. 13. Centre Léon Bérard, Lyon, France. 14. Institut Curie, Saint Cloud, France. 15. Institut Jean Godinot, Reims, France. 16. Institut de Cancérologie de Lorraine, Centre Alexis Vautrin, Nancy, France. 17. Centre Catherine de Sienne, Nantes, France. 18. Centre Armoricain de Radiothérapie, d'Imagerie et d'Oncologie, Plérin, France. 19. Centre Hospitalier Régional Universitaire, Strasbourg, France. 20. Institut Bergonié, Bordeaux, France. 21. Département d'Oncologie Médicale, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, France; Aix-Marseille Université, Marseille, France. 22. Institut Curie, Paris, France. 23. R&D UNICANCER, UCBG, Paris, France. 24. Institut Curie, Paris, France; Université Paris Descartes, Paris, France.
Abstract
BACKGROUND: 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. METHODS: 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. FINDINGS: 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%]). INTERPRETATION: 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. FUNDING: Roche, La Ligue Nationale contre le Cancer, UNICANCER, and Chugai Pharma.
BACKGROUND: 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. METHODS: 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. FINDINGS: 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%]). INTERPRETATION: 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. FUNDING: Roche, La Ligue Nationale contre le Cancer, UNICANCER, and Chugai Pharma.
Authors: Wendy A Woodward; Massimo Cristofanilli; Sofia D Merajver; Steven Van Laere; Lajos Pusztai; Francois Bertucci; Fedor Berditchevski; Kornelia Polyak; Beth Overmoyer; Gayathri R Devi; Esta Sterneck; Robert Schneider; Bisrat G Debeb; Xiaoping Wang; Kenneth L van Golen; Randa El-Zein; Omar M Rahal; Angela Alexander; James M Reuben; Savitri Krishnamurthy; Anthony Lucci; Naoto T Ueno Journal: J Cancer Date: 2017-10-09 Impact factor: 4.207
Authors: Ricardo Costa; Cesar A Santa-Maria; Giovanna Rossi; Benedito A Carneiro; Young Kwang Chae; William J Gradishar; Francis J Giles; Massimo Cristofanilli Journal: Oncotarget Date: 2017-02-14