title: High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology.
abstract: BACKGROUND
  Bcl-2 promotes cell survival by inhibiting adapters needed for the activation and cleavage of caspases thus blocking the proteolytic cascade that ultimately dismantles the cell. Bcl-2 has been investigated as a prognostic factor in non small cell lung cancer (NSCLC) patients with conflicting results.
  
  
  METHODS
  Here, we quantitatively assessed Bcl-2 expression in two large and independent cohorts to investigate the impact of Bcl-2 on survival. AQUA(R), a fluorescent-based method for analysis of in situ protein expression, was used to measure Bcl-2 protein levels and classify tumors by Bcl-2 expression in a cohort of 180 NSCLC patients. An independent cohort of 354 NSCLC patients was used to validate Bcl-2 classification and evaluate outcome.
  
  
  RESULTS
  Fifty % and 52% of the cases were classified as high expressers in training and validation cohorts respectively. Squamous cell carcinomas were more likely to be high expressers compared to adenocarcinomas (63% vs. 45%, p = 0.002); Bcl-2 was not associated with other clinical or pathological characteristics. Survival analysis showed that patients with high BCL-2 expression had a longer median survival compared to low expressers (22 vs. 17.5 months, log rank p = 0.014) especially in the subset of non-squamous tumors (25 vs. 13.8 months, log rank p = 0.04). Multivariate analysis revealed an independent lower risk for all patients with Bcl-2 expressing tumors (HR = 0.53, 95% CI 0.37-0.75, p = 0.0003) and for patients with non-squamous tumors (HR = 0.5, 95% CI 0.31-0.81, p = 0.005).
  
  
  CONCLUSIONS
  Bcl-2 expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of NSCLC patients.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. valsamo.anagnostou@yale.edu
authors.forename: Valsamo K
authors.initials: VK
authors.lastname: Anagnostou
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lowery
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Zolota
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Tzelepi
authors.forename: Arun
authors.initials: A
authors.lastname: Gopinath
authors.forename: Camil
authors.initials: C
authors.lastname: Liceaga
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Panagopoulos
authors.forename: Konstantina
authors.initials: K
authors.lastname: Frangia
authors.forename: Lynn
authors.initials: L
authors.lastname: Tanoue
authors.forename: Daniel
authors.initials: D
authors.lastname: Boffa
authors.forename: Scott
authors.initials: S
authors.lastname: Gettinger
authors.forename: Frank
authors.initials: F
authors.lastname: Detterbeck
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Dougenis
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Syrigos
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D018287:Carcinoma, Large Cell / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation; D015331:Cohort Studies; D003237:Connecticut; D005260:Female; D006115:Greece; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2
references.citation: Cancer. 2003 Jul 1;98(1):135-43
references.pmid: 12833466
references.citation: Tumori. 2008 May-Jun;94(3):398-405
references.pmid: 18705409
references.citation: Lung Cancer. 2006 May;52(2):241-7
references.pmid: 16529843
references.citation: Hum Pathol. 1995 Nov;26(11):1227-32
references.pmid: 7590697
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9545-52
references.pmid: 8790367
references.citation: Chest. 2007 Sep;132(3 Suppl):277S-289S
references.pmid: 17873174
references.citation: Virchows Arch. 1998 May;432(5):441-4
references.pmid: 9645443
references.citation: Chest. 2003 Jun;123(6):1858-67
references.pmid: 12796161
references.citation: Histopathology. 2004 Jan;44(1):54-63
references.pmid: 14717670
references.citation: Nat Med. 2002 Nov;8(11):1323-7
references.pmid: 12389040
references.citation: Oncogene. 2006 Aug 7;25(34):4697-705
references.pmid: 16892083
references.citation: Cancer Res. 2007 Feb 1;67(3):1176-83
references.pmid: 17283153
references.citation: Appl Immunohistochem Mol Morphol. 2007 Mar;15(1):31-7
references.pmid: 17536304
references.citation: Lung Cancer. 2009 Sep;65(3):377-82
references.pmid: 19150580
references.citation: Nature. 2005 Jun 2;435(7042):677-81
references.pmid: 15902208
references.citation: Annu Rev Immunol. 1995;13:513-43
references.pmid: 7612233
references.citation: Anticancer Res. 2004 May-Jun;24(3b):1925-8
references.pmid: 15274378
references.citation: Science. 1998 Aug 28;281(5381):1322-6
references.pmid: 9735050
references.citation: Cancer Res. 2005 Jul 1;65(13):5554-60
references.pmid: 15994927
references.citation: Cancer Res. 1994 Jan 1;54(1):256-60
references.pmid: 8261449
references.citation: Lung Cancer. 1998 Dec;22(3):181-90
references.pmid: 10048471
references.citation: Int J Clin Pract. 2006 Jun;60(6):675-82
references.pmid: 16805752
references.citation: Cancer Cell. 2006 Nov;10(5):389-99
references.pmid: 17097561
references.citation: N Engl J Med. 2006 Dec 14;355(24):2542-50
references.pmid: 17167137
references.citation: Hum Pathol. 2002 Jan;33(1):105-10
references.pmid: 11823980
references.citation: J Thorac Oncol. 2009 Apr;4(4):486-91
references.pmid: 19240654
references.citation: Br J Cancer. 2003 Jul 7;89(1):55-64
references.pmid: 12838300
references.citation: Lancet. 2003 Aug 9;362(9382):433-9
references.pmid: 12927430
references.citation: Int J Radiat Oncol Biol Phys. 2001 May 1;50(1):13-8
references.pmid: 11316541
references.citation: Science. 1997 Dec 12;278(5345):1966-8
references.pmid: 9395403
references.citation: IUBMB Life. 2008 Jun;60(6):390-7
references.pmid: 18425793
references.citation: Clin Cancer Res. 2004 Nov 15;10(22):7662-70
references.pmid: 15569999
references.citation: Br J Cancer. 1999 Feb;79(5-6):952-8
references.pmid: 10070896
references.citation: J Clin Oncol. 2008 Sep 1;26(25):4180-8
references.pmid: 18757333
references.citation: Eur J Surg Oncol. 2003 Oct;29(8):654-7
references.pmid: 14511612
references.citation: Breast Cancer Res. 2008;10(2):R35
references.pmid: 18430249
references.citation: Oncogene. 2007 Feb 1;26(5):652-61
references.pmid: 16909121
references.citation: Philos Trans R Soc Lond B Biol Sci. 1994 Aug 30;345(1313):289-95
references.pmid: 7846127
references.citation: Cell. 1993 Aug 27;74(4):609-19
references.pmid: 8358790
references.citation: Cell Death Differ. 1997 Aug;4(6):443-56
references.pmid: 16465265
references.citation: Lung Cancer. 2003 Dec;42(3):275-81
references.pmid: 14644514
references.citation: J Natl Cancer Inst. 2005 Dec 21;97(24):1808-15
references.pmid: 16368942
references.citation: J Clin Oncol. 2008 Feb 20;26(6):870-6
references.pmid: 18281659
references.citation: Clin Cancer Res. 2004 Nov 1;10(21):7252-9
references.pmid: 15534099
references.citation: Trends Cell Biol. 1998 Aug;8(8):324-30
references.pmid: 9704409
references.citation: J Clin Oncol. 2002 Nov 1;20(21):4285-91
references.pmid: 12409326
references.citation: Science. 1998 Aug 28;281(5381):1305-8
references.pmid: 9721089
references.citation: Leuk Res. 2006 Mar;30(3):322-31
references.pmid: 16213584
references.citation: Am J Respir Cell Mol Biol. 2009 Feb;40(2):135-46
references.pmid: 18676776
references.citation: Nature. 1990 Nov 22;348(6299):334-6
references.pmid: 2250705