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Effect of primary letrozole treatment on tumor expression of mTOR and HIF-1α and relation to clinical response

Authors :
Giulia Brugnoli
Mara Ardine
Laura Zanotti
Maria Rosa Cappelletti
Maria Elena Vailati
Daniele Generali
Ramona Bertoni
Sergio Aguggini
Adrian L Harris
G Allevi
Giuseppina Ferrero
Alfredo Berruti
Alberto Bottini
Carla Strina
Francesca Bedussi
Manuela Milani
Michela Forti
Stephen B. Fox
Generali, Daniele
Berruti, Alfredo
Cappelletti, Maria Rosa
Zanotti, Laura
Brugnoli, Giulia
Forti, Michela
Bedussi, Francesca
Vailati, Maria Elena
Milani, Manuela
Strina, Carla
Ardine, Mara
Aguggini, Sergio
Allevi, Giovanni
Ferrero, Giuseppina
Bertoni, Ramona
Bottini, Alberto
Harris, Adrian L.
Fox, Stephen B.
Publication Year :
2015

Abstract

INTRODUCTION: Recently the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the aromatase inhibitor exemestane has been shown to double the progression-free survival rate in advanced breast cancer. However, the effect of the interrelated pathways of hypoxia-inducible factor-1α (HIF-1α) and mTOR signaling, both of which are associated with a more aggressive breast cancer phenotype and endocrine resistance, on response in the neoadjuvant setting is unknown. We, therefore, have investigated the influence of these pathways with the aim of better defining those patients most likely to benefit from an endocrine-based therapy associated with/without mTOR inhibitors. PATIENTS AND METHODS: A total of 107 women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to 6 months of primary letrozole (2.5 mg/daily) (LET) or LET plus oral "metronomic" cyclophosphamide (50mg/daily) (LET-CYC). Phospo-mTOR and HIF-1α were evaluated in tumor specimens collected before and after treatment using a tissue microarray format. RESULTS: LET-based therapy induced a downregulation of phospho-mTOR and HIF-1α expression (P = .0001 and P < .004, respectively). The reduction of HIF-1α expression observed was positively correlated with phospho-mTOR reduction (P < .03); however, no treatment interaction between the two proteins was detected. HIF-1α expression was significantly modulated by the treatment (P < .004) with a reduction both in the LET arm (45%, n = 36/80) (P = .05) and LET-CYC arm (55%, n = 44/80) (P = .04). HIF-1α reduction showed a relationship with clinical response confined in LET arm only (P < .03). CONCLUSIONS: In this neoadjuvant population, LET was able to modulate the phospho-mTOR and HIF-1α pathways and may define a subpopulation of nonresponders who may be most likely to benefit from mTOR inhibitors

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....62a98c535b03c23c891737deeb457fc9