This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Generali, D. Articles by Berruti, A. PubMed PubMed Citation Articles by Generali, D. Articles by Berruti, A.

Down-Regulation of Phosphatidylinositol 3'-Kinase/AKT/Molecular Target of Rapamycin Metabolic Pathway by Primary Letrozole-Based Therapy in Human Breast Cancer

Authors' Affiliations: ¹ Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; ² Unità di Patologia Mammaria-Breast Cancer Unit, ³ Centro di Medicina Molecolare ad Indirizzo Oncologico, ⁴ Anatomia Patologica Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; ⁵ Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia; and ⁶ Oncologia Medica, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino Azienda Ospedaliera San Luigi di Orbassano, Orbassano, Italy

Requests for reprints: Alfredo Berruti, Oncologia Medica, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Azienda Ospedaliera San Luigi di Orbassano, Regione Gonzole 10, Orbassano 10043, Italy. Phone: 39-0119026512; Fax: 39-0119026882; E-mail: alfredo.berruti{at}gmail.com.

Purpose: The phosphatidylinositol 3'-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown.

Experimental Design: PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide.

Results: Basal expression of the pathway was not significantly correlated with response or patient outcome. Both letrozole alone and letrozole with cyclophosphamide resulted in a significant reduction of PI3K expression (P = 0.02 and P < 0.005, respectively) and phospho-mTOR expression (P = 0.0001 and P = 0.0001, respectively). pAKT showed no change in the letrozole arm, whereas it was significantly decreased in the letrozole plus cyclophosphamide arm (P < 0.005). pAKT expression reduction was associated with a greater response rate (P = 0.05) and greater reduction in Ki67 expression (P = 0.05). Phospho-mTOR expression reduction was associated with a significantly longer disease-free survival in a multivariate analysis (P = 0.02).

Conclusions: Letrozole inhibits key molecules in the PI3K pathway that are important targets of new drugs being developed to overcome resistance. Changes in these molecules may have prognostic significance. These results should be taken into account when planning prospective trials testing up-front aromatase inhibitor with drugs targeting the PI3K/AKT/mTOR signaling pathway.