Back to Search
Start Over
Effect of Primary Letrozole Treatment on Tumor Expression of mTOR and HIF-1α and Relation to Clinical Response.
- Source :
-
Journal of the National Cancer Institute. Monographs [J Natl Cancer Inst Monogr] 2015 May; Vol. 2015 (51), pp. 64-6. - 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.<br />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.<br />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).<br />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.<br /> (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Aged
Aged, 80 and over
Breast Neoplasms metabolism
Breast Neoplasms pathology
Cyclophosphamide administration & dosage
Drug Administration Schedule
Female
Humans
Immunohistochemistry
Letrozole
Middle Aged
Nitriles administration & dosage
Phosphorylation drug effects
Receptors, Estrogen metabolism
Signal Transduction drug effects
Treatment Outcome
Triazoles administration & dosage
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Breast Neoplasms drug therapy
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1745-6614
- Volume :
- 2015
- Issue :
- 51
- Database :
- MEDLINE
- Journal :
- Journal of the National Cancer Institute. Monographs
- Publication Type :
- Academic Journal
- Accession number :
- 26063890
- Full Text :
- https://doi.org/10.1093/jncimonographs/lgv018