title: Effect of Primary Letrozole Treatment on Tumor Expression of mTOR and HIF-1α and Relation to Clinical Response.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF). daniele.generali@gmail.com.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Cappelletti
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Laura
authors.initials: L
authors.lastname: Zanotti
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Giulia
authors.initials: G
authors.lastname: Brugnoli
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Michela
authors.initials: M
authors.lastname: Forti
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Francesca
authors.initials: F
authors.lastname: Bedussi
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Vailati
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Manuela
authors.initials: M
authors.lastname: Milani
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Carla
authors.initials: C
authors.lastname: Strina
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Mara
authors.initials: M
authors.lastname: Ardine
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Sergio
authors.initials: S
authors.lastname: Aguggini
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Allevi
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Ferrero
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Ramona
authors.initials: R
authors.lastname: Bertoni
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria/ US Terapia Molecolare (DG, MRC, LZ, GB, MF, FB, MEV, MM, CS, MA, SA, GA, ABo), and Anatomia Patologica (GF, RB), Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Oncologia Medica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy (ABe, GB); Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK (ALH); Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia (SBF).
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077289:Letrozole; D003520:Cyclophosphamide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases