title: Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer.
abstract: OBJECTIVE
  To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC).
  
  
  METHODS
  Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers.
  
  
  RESULTS
  Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).
  
  
  CONCLUSIONS
  The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bazzola
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Foroni
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Andreis
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Zanoni
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: R Cappelletti
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Allevi
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Aguggini
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Strina
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Milani
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Venturini
authors.affiliation: U.O. Diagnostica per Immagini-Figlie di San Camillo-Via F Filzi 56, Cremona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ferrozzi
authors.affiliation: U.O. di Anatomia Patologica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Giardini
authors.affiliation: U.O. di Anatomia Patologica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bertoni
authors.affiliation: CRUK Tumor Pathology Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: H
authors.initials: H
authors.lastname: Turley
authors.affiliation: CRUK Tumor Pathology Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: K
authors.initials: K
authors.lastname: Gatter
authors.affiliation: Dipartimento di Medicina Sperimentale, Via Volturno, 39, 43100 Parma, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Petronini
authors.affiliation: Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
authors.forename: S B
authors.initials: SB
authors.lastname: Fox
authors.affiliation: Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: U.O. Chirurgia Generale, Dipartimento di Chirurgia, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Martinotti
authors.affiliation: U.O. Chirurgia Generale, Dipartimento di Chirurgia, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Berruti
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bottini
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Reynolds
authors.affiliation: U.O.di Patologia Mammaria-Breast Cancer Unit, U.S. Terapia Molecolare e Farmacogenomica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Generali
mesh_terms: D059250:Administration, Metronomic; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016032:Randomized Controlled Trials as Topic; D000077157:Sorafenib; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009570:Nitriles; D010671:Phenylurea Compounds; D014230:Triazoles; D009536:Niacinamide; D000077289:Letrozole; D003520:Cyclophosphamide; D000077157:Sorafenib