High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology.
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.
Anagnostou
Valsamo K
VK
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. valsamo.anagnostou@yale.edu
Lowery
Frank J
FJ
Zolota
Vassiliki
V
Tzelepi
Vassiliki
V
Gopinath
Arun
A
Liceaga
Camil
C
Panagopoulos
Nikolaos
N
Frangia
Konstantina
K
Tanoue
Lynn
L
Boffa
Daniel
D
Gettinger
Scott
S
Detterbeck
Frank
F
Homer
Robert J
RJ
Dougenis
Dimitrios
D
Rimm
David L
DL
Syrigos
Konstantinos N
KN
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
D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2
Cancer. 2003 Jul 1;98(1):135-43
12833466
Tumori. 2008 May-Jun;94(3):398-405
18705409
Lung Cancer. 2006 May;52(2):241-7
16529843
Hum Pathol. 1995 Nov;26(11):1227-32
7590697
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9545-52
8790367
Chest. 2007 Sep;132(3 Suppl):277S-289S
17873174
Virchows Arch. 1998 May;432(5):441-4
9645443
Chest. 2003 Jun;123(6):1858-67
12796161
Histopathology. 2004 Jan;44(1):54-63
14717670
Nat Med. 2002 Nov;8(11):1323-7
12389040
Oncogene. 2006 Aug 7;25(34):4697-705
16892083
Cancer Res. 2007 Feb 1;67(3):1176-83
17283153
Appl Immunohistochem Mol Morphol. 2007 Mar;15(1):31-7
17536304
Lung Cancer. 2009 Sep;65(3):377-82
19150580
Nature. 2005 Jun 2;435(7042):677-81
15902208
Annu Rev Immunol. 1995;13:513-43
7612233
Anticancer Res. 2004 May-Jun;24(3b):1925-8
15274378
Science. 1998 Aug 28;281(5381):1322-6
9735050
Cancer Res. 2005 Jul 1;65(13):5554-60
15994927
Cancer Res. 1994 Jan 1;54(1):256-60
8261449
Lung Cancer. 1998 Dec;22(3):181-90
10048471
Int J Clin Pract. 2006 Jun;60(6):675-82
16805752
Cancer Cell. 2006 Nov;10(5):389-99
17097561
N Engl J Med. 2006 Dec 14;355(24):2542-50
17167137
Hum Pathol. 2002 Jan;33(1):105-10
11823980
J Thorac Oncol. 2009 Apr;4(4):486-91
19240654
Br J Cancer. 2003 Jul 7;89(1):55-64
12838300
Lancet. 2003 Aug 9;362(9382):433-9
12927430
Int J Radiat Oncol Biol Phys. 2001 May 1;50(1):13-8
11316541
Science. 1997 Dec 12;278(5345):1966-8
9395403
IUBMB Life. 2008 Jun;60(6):390-7
18425793
Clin Cancer Res. 2004 Nov 15;10(22):7662-70
15569999
Br J Cancer. 1999 Feb;79(5-6):952-8
10070896
J Clin Oncol. 2008 Sep 1;26(25):4180-8
18757333
Eur J Surg Oncol. 2003 Oct;29(8):654-7
14511612
Breast Cancer Res. 2008;10(2):R35
18430249
Oncogene. 2007 Feb 1;26(5):652-61
16909121
Philos Trans R Soc Lond B Biol Sci. 1994 Aug 30;345(1313):289-95
7846127
Cell. 1993 Aug 27;74(4):609-19
8358790
Cell Death Differ. 1997 Aug;4(6):443-56
16465265
Lung Cancer. 2003 Dec;42(3):275-81
14644514
J Natl Cancer Inst. 2005 Dec 21;97(24):1808-15
16368942
J Clin Oncol. 2008 Feb 20;26(6):870-6
18281659
Clin Cancer Res. 2004 Nov 1;10(21):7252-9
15534099
Trends Cell Biol. 1998 Aug;8(8):324-30
9704409
J Clin Oncol. 2002 Nov 1;20(21):4285-91
12409326
Science. 1998 Aug 28;281(5381):1305-8
9721089
Leuk Res. 2006 Mar;30(3):322-31
16213584
Am J Respir Cell Mol Biol. 2009 Feb;40(2):135-46
18676776
Nature. 1990 Nov 22;348(6299):334-6
2250705