title: Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response.
abstract: BACKGROUND
  Preclinical results showing therapeutic effect and low toxicity of metronomic chemotherapy with cyclophosphamide (Cy) + celecoxib (Cel) for mammary tumors encouraged its translation to the clinic for treating advanced breast cancer patients (ABCP).
  
  
  METHODS
  A single-arm, mono-institutional, non-randomized, phase II, two-step clinical trial (approved by Bioethics Committee and Argentine Regulatory Authority) was designed. Patients received Cy (50 mg po.d) + Cel (200 mg p.o.bid). Patient eligibility criteria included: ABCP who progressed to anthracyclines, taxanes and capecitabine, ≤4 chemotherapy schemes, with good performance status. Several pro- and anti-angiogenic molecules and cells were determined as biomarkers. Informed consent was signed by all patients. Primary endpoint was clinical benefit (CB).
  
  
  RESULTS
  Twenty patients were enrolled. Main clinical outcomes were prolonged disease stabilization and partial remission in 10/20 and 1/20 patients, respectively. CB was 55 %, and time to progression (TTP) was 21.1 weeks. Median TTP in patients who achieved CB was 35.6 weeks, and mean overall survival was 44.20 weeks. There were no grade 3/4 toxicities associated with treatment. Circulating endothelial cells (CECs) increased at the time of progression in patients who showed CB (P = 0.014). Baseline CECs and circulating endothelial progenitor cells showed marginal associations with TTP. Serum VEGF decreased (P = 0.050), sVEGFR-2 increased (P = 0.005) and VEGF/sVEGFR-2 ratio decreased during treatment (P = 0.041); baseline VEGF and VEGF/sVEGFR-2 were associated with TTP (P = 0.035 and P = 0.030, respectively), while sVEGFR-2 did not.
  
  
  CONCLUSIONS
  Treatment was effective, showing low toxicity profile and excellent tolerability. The combination had anti-angiogenic effect. Increased levels of CEC could be useful for detecting progression. Baseline VEGF and VEGF/sVEGFR-2 values could be useful as early predictors of response.
  
  
  BACKGROUND
  ANMAT#4596/09.
authors.affiliation: Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, S2000KTR, Rosario, Argentina. haperroud@gmail.com.|National Scientific and Technical Research Council (CONICET), Rosario, Argentina. haperroud@gmail.com.
authors.forename: Herman Andres
authors.initials: HA
authors.lastname: Perroud
authors.affiliation: Institute of Oncology of Rosario, Rosario, Argentina.
authors.forename: Carlos Maria
authors.initials: CM
authors.lastname: Alasino
authors.affiliation: Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, S2000KTR, Rosario, Argentina.|National Scientific and Technical Research Council (CONICET), Rosario, Argentina.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Rico
authors.affiliation: Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, S2000KTR, Rosario, Argentina.
authors.forename: Leandro Ernesto
authors.initials: LE
authors.lastname: Mainetti
authors.affiliation: Institute of Oncology of Rosario, Rosario, Argentina.
authors.forename: Francisco
authors.initials: F
authors.lastname: Queralt
authors.affiliation: Institute of Immunology, School of Medical Sciences, National University of Rosario, Rosario, Argentina.|Research Council of the National University of Rosario (CIUNR), Rosario, Argentina.
authors.forename: Stella Maris
authors.initials: SM
authors.lastname: Pezzotto
authors.affiliation: Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, S2000KTR, Rosario, Argentina.
authors.forename: Viviana Rosa
authors.initials: VR
authors.lastname: Rozados
authors.affiliation: Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, S2000KTR, Rosario, Argentina. graciela.scharovsky@gmail.com.|Research Council of the National University of Rosario (CIUNR), Rosario, Argentina. graciela.scharovsky@gmail.com.
authors.forename: O Graciela
authors.initials: OG
authors.lastname: Scharovsky
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D000068579:Celecoxib / Q000008:administration & dosage / Q000009:adverse effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018450:Disease Progression; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy / Q000379:methods; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D000068579:Celecoxib
keywords: Angiogenesis; Biomarkers; Celecoxib; Cyclophosphamide; Metronomic chemotherapy