Journal
EUROPEAN JOURNAL OF CANCER
Volume 158, Issue -, Pages 169-180Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2021.09.017
Keywords
Biomarker; Everolimus; HER2+breast cancer; PI3K; AKT; mTOR; Trastuzumab
Categories
Funding
- French Health Ministry [PHRC 2008/17-2]
- Novartis
- Roche
Ask authors/readers for more resources
Adding everolimus to preoperative trastuzumab did not improve efficacy but induced MAPK signaling in HER2-positive early operable breast cancer patients. Combination therapy should be considered to maximize the effectiveness of trastuzumab in this setting.
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. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available