title: 18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial.
abstract: Purpose:We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with18F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-of-opportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial.Experimental Design:Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/changes.Results:One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB = 3 (P= 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold;P= 0.09). In Arm B, 18F-FMISO-PET lacked predictive/prognostic value.Conclusions:Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib.Clin Cancer Res; 23(6); 1432-41. ©2016 AACR.
authors: Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Madrid, Spain. mquintela@cnio.es.
authors: Miguel
authors: M
authors: Quintela-Fandino
authors: Medical Oncology Department, Hospital Clinico Universitario, Valencia, Spain.
authors: Ana
authors: A
authors: Lluch
authors: Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
authors: Luis
authors: L
authors: Manso
authors: Medical Oncology Department, Hospital de Montepríncipe, Madrid, Spain.
authors: Isabel
authors: I
authors: Calvo
authors: Medical Oncology Department, Hospital Vall d'Hebron, Barcelona, Spain.|Medical Oncology Department, Hospital Ramón y Cajal, Madrid, Spain.
authors: Javier
authors: J
authors: Cortes
authors: Medical Oncology Department, Hospital Clinico San Carlos, Madrid, Spain.
authors: José Angel
authors: JA
authors: García-Saenz
authors: Medical Oncology Department, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Spain.
authors: Miguel
authors: M
authors: Gil-Gil
authors: Medical Oncology Department, Hospital Ramón y Cajal, Madrid, Spain.
authors: Noelia
authors: N
authors: Martinez-Jánez
authors: Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain.
authors: Antonio
authors: A
authors: Gonzalez-Martin
authors: Medical Oncology Department, Hospital General de Albacete, Albacete, Spain.
authors: Encarna
authors: E
authors: Adrover
authors: Medical Oncology Department, Hospital Lozano Blesa, Zaragoza, Spain.
authors: Raquel
authors: R
authors: de Andres
authors: Medical Oncology Department, Institut Catala d'Oncologia-Josep Trueta, Girona, Spain.
authors: Gemma
authors: G
authors: Viñas
authors: Medical Oncology Department, Hospital Arnau de Vilanova, Valencia, Spain.
authors: Antonio
authors: A
authors: Llombart-Cussac
authors: Medical Oncology Department, Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain.
authors: Emilio
authors: E
authors: Alba
authors: Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain.
authors: Juan
authors: J
authors: Guerra
authors: Medical Oncology Department, Hospital Clinico Universitario, Valencia, Spain.
authors: Begoña
authors: B
authors: Bermejo
authors: Medical Oncology Department, Hospital Vall d'Hebron, Barcelona, Spain.
authors: Esther
authors: E
authors: Zamora
authors: Medical Oncology Department, Hospital Clinico San Carlos, Madrid, Spain.
authors: Fernando
authors: F
authors: Moreno-Anton
authors: Medical Oncology Department, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Spain.
authors: Sonia
authors: S
authors: Pernas Simon
authors: Medical Oncology Department, Hospital Ramón y Cajal, Madrid, Spain.
authors: Alfredo
authors: A
authors: Carrato
authors: Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Madrid, Spain.
authors: Antonio
authors: A
authors: Lopez-Alonso
authors: GEICAM, Madrid, Spain.
authors: María José
authors: MJ
authors: Escudero
authors: GEICAM, Madrid, Spain.
authors: Ruth
authors: R
authors: Campo
authors: GEICAM, Madrid, Spain.
authors: Eva
authors: E
authors: Carrasco
authors: Pathology Department, Hospital Ramon y Cajal, Madrid, Spain.
authors: José
authors: J
authors: Palacios
authors: Molecular Imaging Unit, CNIO - Spanish National Cancer Research Center, Madrid, Spain.
authors: Francisca
authors: F
authors: Mulero
authors: Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain.
authors: Ramon
authors: R
authors: Colomer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D008920:Misonidazole / Q000008:administration & dosage / Q000031:analogs & derivatives; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000072258:Tumor Hypoxia / Q000187:drug effects
chemical_list: D007211:Indoles; D008920:Misonidazole; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C031843:fluoromisonidazole; C508053:ERBB2 protein, human; C530716:nintedanib