title: Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003.
abstract: OBJECTIVE
  S0003 was a phase III trial of carboplatin/paclitaxel with or without the hypoxic cytotoxin tirapazamine in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). We investigated the relationship between clinical outcomes and plasma levels of the hypoxia-associated protein osteopontin (OPN) in patients on this protocol.
  
  
  METHODS
  Baseline plasma was obtained from 172 patients. In 56 patients, sequential plasma was obtained after one or two cycles. Concentrations of OPN, as well as plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF), were measured using enzyme-linked immunosorbent assay. Tumor expression of OPN was assessed by immunohistochemistry in 61 matched archival specimens.
  
  
  RESULTS
  Patients with lower OPN levels (below the median) had a significantly superior overall survival compared with patients with higher levels, regardless of treatment arm (hazard ratio [HR] = 0.60, P = .002). A similar correlation was observed for progression-free survival (HR = 0.69, P = .02). When examined as a continuous variable, OPN maintained its significant association with both progression-free (HR = 1.05, P = .01) and overall survival (HR = 1.09, P < .0001). Patients with lower plasma OPN levels were significantly more likely to have tumor response (P = .03). No differences were observed between treatment arms. Tumor OPN levels did not correlate with patient outcomes or with plasma levels. No associations were observed between patient outcomes and VEGF or PAI-1 levels; however, plasma concentrations of these markers were significantly interrelated (P < .0001) and significantly decreased after treatment (P = .0002 and P = .03, respectively).
  
  
  CONCLUSIONS
  Pretreatment plasma levels of OPN are significantly associated with patient response, progression-free survival, and overall survival in chemotherapy-treated patients with advanced NSCLC.
authors.affiliation: Division of Hematology and Oncology, University of California, Davis Cancer Center, 4501 X St, Ste 3016, Sacramento, CA 95817, USA. pcmack@ucdavis.edu
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.forename: Mary W
authors.initials: MW
authors.lastname: Redman
authors.forename: Kari
authors.initials: K
authors.lastname: Chansky
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Williamson
authors.forename: Nichole C
authors.initials: NC
authors.lastname: Farneth
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Quynh-Thu
authors.initials: QT
authors.lastname: Le
authors.forename: John J
authors.initials: JJ
authors.lastname: Crowley
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D016190:Carboplatin / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D053495:Osteopontin / Q000097:blood*; D016019:Survival Analysis; D000077704:Tirapazamine; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D014227:Triazines; D053495:Osteopontin; D000077704:Tirapazamine; D016190:Carboplatin
references.citation: J Immunol. 2005 Nov 15;175(10):6257-63
references.pmid: 16272275
references.citation: Oncogene. 1996 Jul 4;13(1):97-104
references.pmid: 8700559
references.citation: Cancer Lett. 2001 Oct 10;171(2):215-22
references.pmid: 11520606
references.citation: Curr Mol Med. 2006 Dec;6(8):819-30
references.pmid: 17168734
references.citation: J Clin Invest. 1995 Feb;95(2):713-24
references.pmid: 7532190
references.citation: Microsc Res Tech. 2003 Feb 1;60(2):186-98
references.pmid: 12539173
references.citation: J Clin Oncol. 2000 Mar;18(6):1351-9
references.pmid: 10715308
references.citation: Clin Cancer Res. 2004 Mar 1;10(5):1588-96
references.pmid: 15014008
references.citation: Clin Cancer Res. 2006 Mar 1;12(5):1507-14
references.pmid: 16533775
references.citation: Adv Exp Med Biol. 2003;510:69-75
references.pmid: 12580407
references.citation: J Biol Chem. 1995 Nov 3;270(44):26232-8
references.pmid: 7592829
references.citation: Cancer Chemother Pharmacol. 1997;39(4):361-6
references.pmid: 9025778
references.citation: Prostate. 2007 Feb 15;67(3):330-40
references.pmid: 17192877
references.citation: Eur J Nucl Med Mol Imaging. 2003 Jun;30(6):844-50
references.pmid: 12692685
references.citation: Cancer Res. 1999 Jan 1;59(1):219-26
references.pmid: 9892210
references.citation: Br J Cancer. 2005 Aug 22;93(4):453-7
references.pmid: 16091764
references.citation: Int J Radiat Oncol Biol Phys. 2000 Nov 1;48(4):919-22
references.pmid: 11072146
references.citation: Nature. 2001 May 17;411(6835):375-9
references.pmid: 11357145
references.citation: Semin Oncol. 2002 Feb;29(1 Suppl 4):102-9
references.pmid: 11894020
references.citation: Semin Radiat Oncol. 1996 Jan;6(1):22-36
references.pmid: 10717159
references.citation: CA Cancer J Clin. 2001 Jan-Feb;51(1):15-36
references.pmid: 11577478
references.citation: N Engl J Med. 2005 Oct 13;353(15):1564-73
references.pmid: 16221779
references.citation: Int J Radiat Oncol Biol Phys. 1997 May 1;38(2):285-9
references.pmid: 9226314
references.citation: Anticancer Res. 1989 Sep-Oct;9(5):1291-9
references.pmid: 2686530
references.citation: Lung Cancer. 1996 Nov;15(3):311-23
references.pmid: 8959677
references.citation: Oncogene. 1999 Jul 22;18(29):4237-46
references.pmid: 10435636
references.citation: Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3337-43
references.pmid: 16740755
references.citation: Clin Cancer Res. 2003 Jan;9(1):59-67
references.pmid: 12538452
references.citation: Gut. 2007 Jun;56(6):782-9
references.pmid: 17148500
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1087-97
references.pmid: 17548669
references.citation: J Clin Oncol. 2005 Dec 20;23(36):9097-104
references.pmid: 16361616
references.citation: Cancer Res. 2000 Feb 15;60(4):883-7
references.pmid: 10706099
references.citation: Oncology. 2005;68(2-3):285-92
references.pmid: 16015046
references.citation: J Cancer Res Clin Oncol. 2007 Sep;133(9):643-52
references.pmid: 17479289
references.citation: Nature. 1996 Jan 4;379(6560):88-91
references.pmid: 8538748
references.citation: Cancer Res. 2007 Jun 1;67(11):5141-7
references.pmid: 17545592
references.citation: Lung Cancer. 2001 Dec;34 Suppl 3:S75-80
references.pmid: 11740998
references.citation: J Clin Oncol. 1997 Aug;15(8):2996-3018
references.pmid: 9256144
references.citation: Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1239-42
references.pmid: 3744945
references.citation: J Biochem Mol Biol. 2003 Jan 31;36(1):120-7
references.pmid: 12542982
references.citation: J Leukoc Biol. 2006 Dec;80(6):1183-96
references.pmid: 16997855
references.citation: Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):167-75
references.pmid: 17707270
references.citation: Radiother Oncol. 1988 Dec;13(4):301-9
references.pmid: 2464183
references.citation: Blood. 2004 Oct 15;104(8):2224-34
references.pmid: 15231578
references.citation: Anticancer Res. 1992 Jan-Feb;12(1):43-7
references.pmid: 1567180
references.citation: Am J Respir Crit Care Med. 1999 Oct;160(4):1269-73
references.pmid: 10508818
references.citation: Intern Med. 2002 Feb;41(2):79-83
references.pmid: 11868612
references.citation: Lung Cancer. 2007 Sep;57(3):373-80
references.pmid: 17513004
references.citation: Semin Oncol. 1998 Jun;25(3 Suppl 8):10-4
references.pmid: 9704670
references.citation: J Clin Oncol. 2006 Nov 20;24(33):5291-7
references.pmid: 17114663
references.citation: J Natl Cancer Inst. 2005 May 4;97(9):643-55
references.pmid: 15870435
references.citation: Clin Cancer Res. 2005 Jul 1;11(13):4646-52
references.pmid: 16000556
references.citation: Br J Cancer Suppl. 1996 Jul;27:S209-12
references.pmid: 8763882