1. A phase II randomised study of preoperative trastuzumab alone or combined with everolimus in patients with early HER2-positive breast cancer and predictive biomarkers (RADHER trial)
- Author
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Barbara Pistilli, Marta Jimenez, Thomas Bachelot, Fabrice Andre, Keyvan Rezai, Julia Salleron, Laurence Vanlemmens, Jean-Louis Merlin, Mario Campone, Valérie Seegers, Qing Wang, Maëva Lion, Agnès Leroux, Gilles Paintaud, Isabelle Treilleux, Delphine Loussouarn, Véronique Diéras, Monica Arnedos, Maria Rios, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Département cancer environnement (Centre Léon Bérard - Lyon), Centre Léon Bérard [Lyon], Institut Gustave Roussy (IGR), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Institut Curie [Paris], Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Hôpital René HUGUENIN (Saint-Cloud), Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lille-UNICANCER, Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), and Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Combination therapy ,[SPI.AUTO]Engineering Sciences [physics]/Automatic ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Trastuzumab ,Internal medicine ,Mucositis ,Medicine ,PI3K/AKT/mTOR ,Everolimus ,skin and connective tissue diseases ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,0303 health sciences ,business.industry ,Biomarker ,HER2+ breast cancer ,medicine.disease ,Rash ,3. Good health ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,medicine.symptom ,business ,medicine.drug - Abstract
Introduction Resistance to trastuzumab in breast cancer is an ongoing challenge. Clinical and biological effects of co-targeting HER2 and mammalian target of rapamycin (mTOR) in patients with HER2-positive early operable breast cancer via the addition of everolimus to preoperative trastuzumab were evaluated in a phase II randomised study. Methods Patients were randomised 1:1 to receive trastuzumab (4 mg/kg initial dose then 2 mg/kg weekly for 5 weeks) alone or combined with everolimus (10 mg/day for 6 weeks) and then underwent surgery. Tumours were assessed by clinical examination and echography at the baseline and on treatment. The primary end-point was the clinical response rate at 6 weeks. Pathological response and safety were also evaluated. Baseline and surgery tumour samples were assessed by immunohistochemistry and multiplex immunoanalysis for predictive downstream effectors of the PI3K/AKT/mTOR and MAP kinase (MAPK) pathways. Results Eighty-two patients were enrolled, 41 per arm. The clinical response rates were 34.1% and 43.9% with trastuzumab alone and combined with everolimus, respectively. Pathological response rates were 43.6% and 47.5%, respectively. Addition of everolimus increased toxicity, notably mucositis (82.5% versus 5.0%) and rash (57.5% versus 10.0%), but grade III/IV events were rare. No correlation between response to treatments and baseline candidate biomarkers was identified, except for PIK3CA mutations which were found to predict trastuzumab resistance. Significant changes were seen in several MAPK pathway effectors after combination therapy. Conclusions The addition of everolimus did not improve the efficacy, but induced MAPK signalling. Combination therapy to overcome pathway cross-talk should be considered to maximise the effectiveness of trastuzumab in this setting. ClinicalTrial.gov Identifier NCT00674414.
- Published
- 2021