Effect of Primary Letrozole Treatment on Tumor Expression of mTOR and HIF-1α and Relation to Clinical Response

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Introduction:</div>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.<div class="boxTitle">Patients and Methods:</div>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.<div class="boxTitle">Results:</div>LET-based therapy induced a downregulation of phospho-mTOR and HIF-1α expression (<span style="font-style:italic;">P</span> = .0001 and <span style="font-style:italic;">P</span> < .004, respectively). The reduction of HIF-1α expression observed was positively correlated with phospho-mTOR reduction (<span style="font-style:italic;">P</span> < .03); however, no treatment interaction between the two proteins was detected. HIF-1α expression was significantly modulated by the treatment (<span style="font-style:italic;">P</span> < .004) with a reduction both in the LET arm (45%, n = 36/80) (<span style="font-style:italic;">P</span> = .05) and LET-CYC arm (55%, n = 44/80) (<span style="font-style:italic;">P</span> = .04). HIF-1α reduction showed a relationship with clinical response confined in LET arm only (<span style="font-style:italic;">P</span> < .03).<div class="boxTitle">Conclusions:</div>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.</span>

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