title: Bone turnover markers as predictive indicators of outcome in patients with breast cancer and bone metastases treated with bisphosphonates: results from a 2-year multicentre observational study (ZOMAR study).
abstract: BACKGROUND
  We evaluated the evolution and predictive value of bone turnover markers (BTMs) and circulating tumor cells (CTCs) with respect to mortality, disease progression (DP) and skeletal-related events (SREs), in patients with bone metastatic breast cancer (BmBCa). The correlation between BTMs and CTCs was also studied.
  
  
  METHODS
  In a 2-year observational, multicenter study, the levels of three BTMs (N- and C-terminal telopeptides of collagen I [NTX and αα-CTX], and bone-specific alkaline phosphatase [BSAP]) and CTCs were analyzed every three months. Patients received zoledronic acid (4mg every 28days) from the baseline visit.
  
  
  RESULTS
  234 patients were analyzed. The levels of the BTMs were increased at baseline and significantly decreased after 3months (P<0.05). In the Cox regression univariate analyses significant hazard ratios (HRs) for death were found for pathological BSAP values at baseline (5.03 [95% CI: 1.214-20.839; P=0.0259]) and at 3months (3.41 [95% CI: 1.367-8.498; P=0.0085]). HRs >2 were found for increased baseline and 3-month levels of NTX and CTC (P<0.05). Only increased baseline BSAP levels were associated with DP (HR=2.25 [95% CI: 1.391-3.626; P=0.0009]). No biomarker was associated with SREs. In the multivariate analysis, pathologic levels at 3months of NTX and BSAP were significantly associated with mortality (HRs=3.59 [95% CI: 1.375-9.382; P=0.0091] and 3.25 [95% CI: 1.293-8.189; P=0.0120], respectively). CTC and BSAP were correlated during all study timepoints (P<0.05).
  
  
  CONCLUSIONS
  Baseline levels of NTX, BSAP and CTCs, and changes after treatment initiation with bisphosphonates, may be useful for the prognostic assessment of patients with BmBCa. BSAP showed the strongest prognostic value.
authors.affiliation: Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret, 167, 08025 Barcelona, Spain; Medicine Department, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: ABarnadasM@santpau.cat.
authors.forename: Agustí
authors.initials: A
authors.lastname: Barnadas
authors.affiliation: Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda. de Córdoba, s/n, 28041 Madrid, Spain. Electronic address: luis_manso@hotmail.com.
authors.forename: Luis
authors.initials: L
authors.lastname: Manso
authors.affiliation: Bioquímica Investigación, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040 Madrid, Spain. Electronic address: CPiedra@fjd.es.
authors.forename: Concepción
authors.initials: C
authors.lastname: de la Piedra
authors.affiliation: Medical Department, Novartis Farmacéutica S.A., Gran Via de les Corts Catalanes, 764, 08013 Barcelona, Spain. Electronic address: cristina.meseguer@novartis.com.
authors.forename: Cristina
authors.initials: C
authors.lastname: Meseguer
authors.affiliation: Medical Oncology Department, Hospital Ramón y Cajal, Ctra. de Colmenar Viejo, Km. 9100, 28034 Madrid, Spain. Electronic address: ccrespo.hurc@salud.madrid.org.
authors.forename: Carmen
authors.initials: C
authors.lastname: Crespo
authors.affiliation: Oncology Department, Hospital Vall d'Hebrón, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain. Electronic address: pagomez@vhebron.net.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gómez
authors.affiliation: Oncology Department, Complejo Hospitalario Universitario de A Coruña, As Xubias, 84, 15006 A Coruña, Spain. Electronic address: Lourdes.Calvo.Martinez@sergas.es.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Calvo
authors.affiliation: Oncology Department, Hospital Universitario Basurto, Avda. de Montevideo, 18, 48013 Bilbao, Spain. Electronic address: purificacion.martinezdelprado@osakidetza.net.
authors.forename: Purificación
authors.initials: P
authors.lastname: Martinez
authors.affiliation: Oncology Department, Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot, 0, 41013 Sevilla, Spain. Electronic address: manuel.ruiz.borrego.sspa@juntadeandalucia.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ruiz-Borrego
authors.affiliation: Medical Oncology Service, Hospital Universitari Son Dureta, Andrea Doria, 55, 07014 Palma de Mallorca, Spain. Electronic address: antonia.perellom@ssib.es.
authors.forename: Antonia
authors.initials: A
authors.lastname: Perelló
authors.affiliation: Medical Oncology Department, Hospital Universitario Miguel Servet, Paseo Isabel la Católica, 1-3, 50009 Zaragoza, Spain. Electronic address: aantont@gmail.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Antón
authors.affiliation: Medical Oncology Department, Hospital Virgen Macarena, Avda. Dr. Fedriani, 3, 41007 Sevilla, Spain. Electronic address: manuelcodesvillena@gmail.com.
authors.forename: Manuel
authors.initials: M
authors.lastname: Codes
authors.affiliation: Medical Oncology Department, Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Crta. Canyet, 08916 Badalona, Spain. Electronic address: mmargeli@iconcologia.net.
authors.forename: Mireia
authors.initials: M
authors.lastname: Margelí
authors.affiliation: Oncology Department, Hospital Insular de Gran Canaria, Plaza Doctor Pasteur, s/n, 35016 Las Palmas de Gran Canaria, Spain. Electronic address: amuriasrosales@gmail.com.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Murias
authors.affiliation: Medical Oncology Department, Hospital Universitario Nuestra Señora de Valme, Avda. de Bellavista, s/n, 41014 Sevilla, Spain. Electronic address: jsalvad2002@yahoo.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Salvador
authors.affiliation: Medical Oncology Department, Corporació Sanitària Parc Taulí, Parc Taulí, 1, 08208 Sabadell, Spain. Electronic address: msegui@tauli.cat.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Seguí
authors.affiliation: Oncology Department, Hospital Universitario Marqués de Valdecilla, Avda. Valdecilla, s/n, 39008 Santander, Spain. Electronic address: ajuan@humv.es.
authors.forename: Ana
authors.initials: A
authors.lastname: de Juan
authors.affiliation: Medical Oncology Department, Fundación Instituto Valenciano de Oncología, Profesor Beltrán Bàguena, 8, 46009 Valencia, Spain. Electronic address: jogagre@hotmail.com.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Gavilá
authors.affiliation: Medical Oncology Department, Hospital Universitario Central de Asturias, Celestino Villamil, s/n, 33006 Oviedo, Spain. Electronic address: malucab@hotmail.com.
authors.forename: María
authors.initials: M
authors.lastname: Luque
authors.affiliation: Oncology Department, Hospital Costa del Sol, Autovía A-7, Km. 187, 29603 Marbella, Málaga, Spain. Electronic address: dipema2026@gmail.com.
authors.forename: Diego
authors.initials: D
authors.lastname: Pérez
authors.affiliation: Medical Oncology Service, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain. Electronic address: zamorapilar@gmail.com.
authors.forename: Pilar
authors.initials: P
authors.lastname: Zamora
authors.affiliation: Oncology Department, Hospital General Río Carrión, Avda. Donantes de Sangre, s/n, 34005 Palencia, Spain. Electronic address: aarizcun@gmail.com.
authors.forename: Alberto
authors.initials: A
authors.lastname: Arizcuma
authors.affiliation: Medical Oncology Department, Hospital Virgen de la Salud, Avda. de Barber, 30, 45071 Toledo, Spain. Electronic address: jignaciochacon@gmail.com.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Chacón
authors.affiliation: Oncology Service, Hospital de la Creu Roja, Avinguda Josep Molins, 29-41, 08906 L'Hospitalet de Llobregat, Spain. Electronic address: lucia.heras@sanitatintegral.org.
authors.forename: Lucía
authors.initials: L
authors.lastname: Heras
authors.affiliation: Bioquímica Investigación, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040 Madrid, Spain. Electronic address: mmartinf@fjd.es.
authors.forename: Marta
authors.initials: M
authors.lastname: Martin-Fernández
authors.affiliation: Epidemiology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040 Madrid, Spain. Electronic address: IMahillo@fjd.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mahillo-Fernández
authors.affiliation: Medicine Department, Universitat Autònoma de Barcelona, Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Passeig Marítim de la Barceloneta, 25-29, 08003 Barcelona, Spain. Electronic address: ITusquets@parcdesalutmar.cat.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Tusquets
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D016723:Bone Remodeling / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Bisphosphonates; Bone metastases; Bone turnover markers; Breast cancer; Circulating tumor cells; Zoledronic acid