The Prognostic Significance of Survivin Expression in Breast Cancer

Jae-Won Oh; Woo-Ick Yang; Mi Jeong Lee; Seho Park; Byeong-Woo Park; Kyong-Sik Lee

doi:10.4048/jbc.2009.12.4.285

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Oh, Yang, Lee, Park, Park, and Lee: The Prognostic Significance of Survivin Expression in Breast Cancer

Original Article

J Breast Cancer 2009;12(4):285-294.

Published online: 31 December 2009

DOI: https://doi.org/10.4048/jbc.2009.12.4.285

The Prognostic Significance of Survivin Expression in Breast Cancer

Jae-Won Oh¹, Woo-Ick Yang², Mi Jeong Lee³, Seho Park¹, Byeong-Woo Park^1,^3,, Kyong-Sik Lee⁴

¹Department of Surgery, Yonsei University College of Medicine, Seoul, Korea

²Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

³Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea

⁴Department of Surgery, Pochon CHA University College of Medicine, Seongnam, Korea

E-mail: bwpark@yumc.yonsei.ac.kr

Received 3 April 2009 Accepted 2 June 2009

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

Survivin is a member of the inhibitors of apoptosis family. It has recently comes into the limelight as a promising tumor marker, but many previous reports have shown controversial results regarding the significance and prognostic value of a survivin expression. In this study we determined the correlation between the survivin expression and the conventional prognostic markers and we also investigated the outcomes according to the localization of the survivin expression.

Methods

Tissue microarray (TMA) blocks were made with formalin-fixed paraffin-embedded tissues from 185 breast cancer patients and the immunohistochemical staining was done using an anti-survivin antibody. Among these, 157 patients were available for a survivin expression. The conventional clinicopathologic features and overall survival were correlated with the localization of the survivin expression.

Results

Survivin was expressed in 101 breast cancers (64.3%). A higher cytoplasmic survivin expression were noted in the older group (p=0.003), in the node-negative cancers (p= 0.012), in the earlier tumor stages (p=0.012) and in the cancers that had not been treated with adjuvant chemotherapy (p=0.014). On the contrary, a higher nuclear survivin expression was inversely correlated with an estrogen expression (p=0.006) and a progesterone receptor (p=0.043) expression. In terms of survival, a cytoplasmic expression was associated with improved overall survival (p=0.01) but a nuclear survivin expression was correlated with unfavorable overall survival (p=0.002). A high cytoplasmic to nuclear ratio of survivin was associated with improved overall survival (p=0.001) conversely, increased nuclear to cytoplasmic survivin ratio was correlated with unfavorable overall survival (p<0.0001). Multivariate analysis revealed that nuclear survivin expression (p= 0.001) and high nuclear to cytoplasmic survivin ratio (p=0.012) were independent predictor of overall survival.

Conclusion

Survivin is frequently expressed in primary breast cancer. A cytoplasmic survivin expression is a good prognostic predictor for patients with axillary node negative early breast cancers and a nuclear survivin expression is a worse independent predictor of overall survival for patients with axillary node positive breast cancers.

Keywords: Breast neoplasms, Prognostic factor, Survivin

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Fig 1.

Immunohistochemical staining results for survivin (DAB with hematoxylin counterstaining). (A) Nuclear staining of survivin (×200), (B) Cytoplasmic and nuclear staining of survivin (×200), (C) Cytoplasmic staining of survivin (×200) in invasive ductal carcinoma.

Fig 2.

Kaplan-Meier survival estimates for positive and negative cases of breast cancer regarding (A) cytoplasmic survivin expression and (B) nuclear survivin expression.

Fig 3.

Kaplan-Meier survival estimates for using a ratio of 2 as a cutoff. (A) cytoplasmic to nuclear survivin expression ratio and (B) nuclear to cytoplasmic survivin expression ratio.

Fig 4.

Kaplan-Meier survival curve according to lymph node negative group (A) and lymph node positive group (B) categorized by cytoplasmic survivin expression.

Fig 5.

Kaplan-Meier survival curve according to lymph node negative group (A) and lymph node positive group (B) categorized by nuclear survivin expression.

Fig 6.

Kaplan-Meier survival curve according to TNM stage categorized by cytoplasmic survivin expression.

Fig 7.

Kaplan-Meier survival curve according to TNM stage categorized by nuclear survivin expression.

Table 1.

Patients characteristics

	No. of patients	%
Age (yr)
<35	30	19.1
≥35	127	80.9
Size
<2 cm	52	33.1
2-5 cm	95	60.5
>5 cm	10	6.4
Lymph node status
Negative	59	37.6
Positive	98	62.4
TNM stage
1	23	14.6
2	84	53.5
3	50	31.8
Histologic grade
I	38	30.6
II+III	86	69.4
ER
Negative	81	51.6
Positive	76	48.4
PR
Negative	100	63.7
Positive	57	36.3
HER2
Negative	46	52.3
Positive	42	47.7
Hormonal therapy
No	84	55.3
Yes	68	44.7
Radiation therapy
No	99	66.9
Yes	49	33.1
Chemotherapy
No	48	31.2
Yes	106	68.8

ER=estrogen receptor; PR=progesterone receptor.

Table 2.

Localization of survivin expression by immunochemical methods

	No. of patients	%
Cytoplasm and/or nucleus
Negative	56	35.7
Positive	101	64.3
Cytoplasm
Negative	93	59.2
Positive	64	40.8
Nucleus
Negative	83	52.9
Positive	75	47.1
Both cytoplasm and nucleus
Negative	35	22.3
Positive	19	12.1
Cytoplasmic to nuclear ratio
<2	105	66.9
≥2	52	33.1
Nuclear to cytoplasmic ratio
<2	116	73.9
≥2	41	26.1

Table 3.

Association between survivin expression and tumor characteristics

	C-expression			N-expression
	Negative (93)	Positive (64)	p-value	Negative (83)	Positive (74)	p-value
Age (yr)			0.003			0.688
<35	25 (26.9)	5 (7.8)		17 (20.5)	13 (17.6)
≥35	68 (73.1)	59 (92.2)		66 (79.5)	61 (82.4)
Tumor size			0.385			0.274
<2 cm	30 (32.3)	22 (34.4)		30 (36.2)	22 (29.7)
2-5 cm	55 (59.1)	40 (62.5)		50 (60.2)	45 (60.8)
>5 cm	8 (8.6)	2 (3.1)		3 (3.6)	7 (9.5)
LN status			0.012			0.189
Negative	27 (29.0)	32 (50.0)		27 (32.5)	32 (43.2)
Positive	66 (71.0)	32 (50.0)		56 (67.5)	42 (56.8)
TNM stage			0.012			0.547
1	13 (14.0)	10 (15.6)		13 (15.7)	10 (13.5)
2	42 (45.2)	42 (65.6)		41 (49.4)	43 (58.1)
3	38 (40.8)	12 (18.8)		29 (34.9)	21 (28.4)
Histologic grade			0.297			0.051
I	21 (27.3)	17 (36.2)		25 (39.1)	13 (21.7)
II+III	56 (72.7)	30 (63.8)		39 (60.9)	47 (78.3)
HER2 status			0.194			0.099
Negative	23 (48.9)	23 (56.1)		22 (55.0)	24 (50.0)
Positive	24 (51.1)	18 (43.9)		18 (45.0)	24 (50.0)
ER			0.108			0.006
Negative	53 (57.0)	28 (43.7)		34 (41.0)	47 (63.5)
Positive	40 (43.0)	36 (56.3)		49 (59.0)	27 (36.5)
PR			0.129			0.030
Negative	64 (68.8)	36 (56.3)		46 (55.4)	54 (73.0)
Positive	29 (31.2)	28 (43.7)		37 (44.6)	20 (27.0)
HTx			0.124			0.441
No	51 (58.0)	33 (51.6)		48 (60.0)	36 (50.0)
Yes	37 (42.0)	31 (48.4)		32 (40.0)	36 (50.0)
RTx			0.339			0.738
No	55 (64.0)	44 (71.0)		50 (64.1)	49 (70.0)
Yes	31 (46.0)	18 (29.0)		28 (35.9)	21 (30.0)
CTx			0.014			0.602
No	21 (23.3)	27 (42.2)		23 (28.8)	25 (33.8)
Yes	69 (76.7)	37 (57.8)		57 (71.2)	49 (66.2)

C-expression=cytoplasmic expression; N-expression=nuclear expression; LN=lymph node; ER=estrogen receptor; PR=progesterone receptor; HTx=hormone therapy; RTx=radiation therapy; CTx=chemotherapy.

Table 4.

Prognostic significance of clinicopathologic variables

Variables	Risk rate	95% CI	p-value
Age (<35 vs ≥35)	0.532	0.320-0.887	0.013
Tumor size (<2 cm vs ≥2 cm)	0.926	0.584-1.468	0.743
LN metastasis (negative vs positive)	1.889	1.147-3.114	0.013
Histologic grade (I vs II, III)	1.786	1.040-3.067	0.035
Cytoplasmic survivin (negative vs positive)	0.540	0.336-0.868	0.011
Nuclear survivin (negative vs positive)	2.132	1.363-3.335	0.001
Cytoplasmic to nuclear ratio (<2 vs ≥2)	0.402	0.234-0.688	0.001
Nuclear to cytoplsmic ratio (<2 vs ≥2)	2.642	1.658-4.210	<0.001
ER status (negative vs positive)	0.654	0.419-1.022	0.059
PR status (negative vs positive)	0.514	0.313-0.843	0.008

LN=lymph node; ER=estrogen receptor; PR=progesterone receptor.

Table 5.

Multivariate Cox proportional hazard model for overall survival

Variables	Risk rate	95% CI	p-value
Age (<35 vs ≥35)	0.566	0.330-0.972	0.039
LN metastasis (negative vs positive)	2.046	1.141-3.668	0.016
Histologic grade (I vs II, III)	1.551	0.889-2.706	0.122
Cytoplasmic survivin (negative vs positive)	0.571	0.324-1.008	0.053
Nuclear survivin (negative vs positive)	2.258	1.370-3.721	0.001
Cytoplasmic to nuclear ratio^* (<2 vs 2≥)	0.524	0.274-1.001	0.051
Nuclear to cytoplsmic ratio^* (<2 vs 2≥)	2.010	1.116-3.466	0.012
PR status (negative vs positive)	0.678	0.392-1.170	0.163

CI=confidence interval; LN=lymph node; PR=progesterone receptor.

^* Adjusted for age, lymph node metastasis, histologic grade and PR status.

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