title: EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases?
abstract: OBJECTIVE
  Both bone and brain are frequent sites of metastasis in non-small cell lung cancer (NSCLC). Conflicting data exist whether EGFR mutant (+) patients are more prone to develop brain metastases or have a better outcome with brain metastases compared to EGFR/KRAS wildtype (WT) or KRAS+ patients. For bone metastases this has not been studied.
  
  
  METHODS
  In this retrospective case-control study all EGFR+ (exons 19 and 21) patients diagnosed at two pathology departments were selected (2004/2008 to 2012). For every EGFR+ patient a consecutive KRAS+ and WT patient with metastatic NSCLC (mNSCLC) was identified. Patients with another malignancy within 2 years of mNSCLC diagnosis were excluded. Data regarding age, gender, performance score, histology, treatment, bone/brain metastases diagnosis, skeletal related events (SRE) and subsequent survival were collected.
  
  
  RESULTS
  189 patients were included: 62 EGFR+, 65 KRAS+, 62 WT. 32%, 35% and 40%, respectively, had brain metastases (p=0.645). Mean time to brain metastases was 20.8 [± 12.0], 10.8 [± 9.8], 16.4 [± 10.2] months (EGFR+-KRAS+, p = 0.020, EGFR+-WT, p = 0.321). Median post brain metastases survival was 12.1 [5.0-19.1], 7.6 [1.2-14.0], 10.7 [1.5-19.8] months (p = 0.674). 60%, 52% and 50% had metastatic bone disease (p=0.528). Mean time to development of metastatic bone disease was 13.4 [± 10.6], 23.3 [± 19.4], 16.4 [± 9.6] months (p = 0.201). Median post metastatic bone disease survival was 15.0 [10.6-20.3], 9.0 [5.2-12.9], 3.2 [0.0-6.9] months (p = 0.010). Time to 1st SRE was not significantly different.
  
  
  CONCLUSIONS
  Incidence of brain and bone metastases was not different between EGFR+, KRAS+ and WT patients. Post brain metastases survival, time from mNSCLC diagnosis to metastatic bone disease and 1st SRE did not differ either. Post metastatic bone disease survival was significantly longer in EGFR+ patients. Although prevention of SRE's is important for all patients, the latter finding calls for a separate study for SRE preventing agents in EGFR+ patients.
authors: Department of Pulmonary Diseases, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Electronic address: lizza.hendriks@mumc.nl.
authors: L E L
authors: LE
authors: Hendriks
authors: Department of Pulmonary Diseases, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
authors: E F
authors: EF
authors: Smit
authors: Department of Pulmonary Diseases, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors: B A H
authors: BA
authors: Vosse
authors: Department of Pulmonary Diseases, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
authors: W W
authors: WW
authors: Mellema
authors: Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
authors: D A M
authors: DA
authors: Heideman
authors: Department of Pulmonary Diseases, Atrium Medical Center, H. Dunantstraat 5, 6419 PC Heerlen, The Netherlands.
authors: G P
authors: GP
authors: Bootsma
authors: Department of Pulmonary Diseases, VieCuri, Tegelseweg 210, 5912 BL Venlo, The Netherlands.
authors: M
authors: M
authors: Westenend
authors: Department of Pulmonary Diseases, Laurentius Hospital, Mgr. Driessenstraat 6, 6043 CV Roermond, The Netherlands.
authors: C
authors: C
authors: Pitz
authors: Department of Pulmonary Diseases, Orbis Medical Center, PO Box 5500, 6130 MB Sittard, The Netherlands.
authors: G J
authors: GJ
authors: de Vries
authors: Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, PO Box 3035, 6202 NA Maastricht, The Netherlands.
authors: R
authors: R
authors: Houben
authors: Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
authors: K
authors: K
authors: Grünberg
authors: Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors: M
authors: M
authors: Bendek
authors: Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors: E-J M
authors: EJ
authors: Speel
authors: Department of Pulmonary Diseases, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors: A-M C
authors: AM
authors: Dingemans
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000175:diagnosis / Q000401:mortality / Q000556:secondary; D001932:Brain Neoplasms / Q000175:diagnosis / Q000401:mortality / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed
chemical_list: D066246:ErbB Receptors
keywords: Bone metastases; Brain metastases; EGFR; KRAS; NSCLC; Survival