title: Evaluation of clinical parameters influencing the development of bone metastasis in breast cancer.
abstract: The development of metastases is a negative prognostic parameter for the clinical outcome of breast cancer. Bone constitutes the first site of distant metastases for many affected women. The purpose of this retrospective multicentre study was to evaluate if and how different variables such as primary tumour stage, biological and histological subtype, age at primary diagnosis, tumour size, the number of affected lymph nodes as well as grading influence the development of bone-only metastases.
  
  
  
  This retrospective German multicentre study is based on the BRENDA collective and included 9625 patients with primary breast cancer recruited from 1992 to 2008. In this analysis, we investigated a subgroup of 226 patients with bone-only metastases. Association between bone-only relapse and clinico-pathological risk factors was assessed in multivariate models using the tree-building algorithms "exhausted CHAID (Chi-square Automatic Interaction Detectors)" and CART(Classification and Regression Tree), as well as radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression.
  
  
  
  Multivariate analysis demonstrated that breast cancer subtypes have the strongest influence on the development of bone-only metastases (χ2 = 28). 29.9 % of patients with luminal A or luminal B (ABC-patients) and 11.4 % with triple negative BC (TNBC) or HER2-overexpressing tumours had bone-only metastases (p < 0.001). Five different mathematical models confirmed this correlation. The second important risk factor is the age at primary diagnosis. Moreover, BC subcategories influence the overall survival from date of metastatic disease of patients with bone-only metastases. Patients with bone-only metastases and TNBC (p < 0.001; HR = 7.47 (95 % CI: 3.52-15.87) or HER2 overexpressing BC (p = 0.007; HR = 3.04 (95 % CI: 1.36-6.80) have the worst outcome compared to patients with luminal A or luminal B tumours and bone-only metastases.
  
  
  
  The bottom line of different mathematical models is the prior importance of subcategories of breast cancer and the age at primary diagnosis for the appearance of osseous metastases. The primary tumour stage, histological subtype, tumour size, the number of affected lymph nodes, grading and NPI seem to have only a minor influence on the development of bone-only metastases.
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080, Würzburg, Germany. diessner-bw@t-online.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Diessner
authors.affiliation: Faculty of Mathematics and Computer Science, University of Bremen, Universitätsallee GW1, 28359, Bremen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wischnewsky
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080, Würzburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Stüber
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080, Würzburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080, Würzburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Krockenberger
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080, Würzburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Häusler
authors.affiliation: Department for Obstetrics and Gynecology, University of Ulm Medical School, Prittwitzstr. 43, 89075, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Janni
authors.affiliation: Department for Obstetrics and Gynecology, University of Ulm Medical School, Prittwitzstr. 43, 89075, Ulm, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kreienberg
authors.affiliation: Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), University of Mainz, Obere Zahlbacher Str. 69, 55131, Mainz, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Blettner
authors.affiliation: Department for Obstetrics and Gynecology, University of Ulm Medical School, Prittwitzstr. 43, 89075, Ulm, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Schwentner
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080, Würzburg, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Wöckel
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080, Würzburg, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Bartmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: BRENDA; Bone metastases; Breast cancer; Breast cancer subtypes; Skeleton