TY - JOUR
T1 - 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)
AU - Campone, Mario
AU - Bachelot, Thomas
AU - Treilleux, Isabelle
AU - Pistilli, Barbara
AU - Salleron, Julia
AU - Seegers, Valérie
AU - Arnedos, Monica
AU - Loussouarn, Delphine
AU - Wang, Qing
AU - Vanlemmens, Laurence
AU - Jimenez, Marta
AU - Rios, Maria
AU - Diéras, Véronique
AU - Leroux, Agnès
AU - Paintaud, Gilles
AU - Rezai, Keyvan
AU - André, Fabrice
AU - Lion, Maëva
AU - Merlin, Jean Louis
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - Biomarker
KW - Everolimus
KW - HER2+ breast cancer
KW - PI3K/AKT/mTOR
KW - Trastuzumab
UR - http://www.scopus.com/inward/record.url?scp=85117226602&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2021.09.017
DO - 10.1016/j.ejca.2021.09.017
M3 - Article
AN - SCOPUS:85117226602
SN - 0959-8049
VL - 158
SP - 169
EP - 180
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -