|Year : 2018 | Volume
| Issue : 10 | Page : 719-723
Survivin expression as an independent predictor of overall survival in pancreatic adenocarcinoma
John Contis1, Panagis M Lykoudis1, Kallirroi Goula2, Despoina Karandrea2, Agathi Kondi-Pafiti2
1 2nd Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, Athens, Greece
2 Department of Pathology, Aretaieio University Hospital, National and Kapodistrian University of Athens, Athens, Greece
|Date of Web Publication||24-Sep-2018|
Panagis M Lykoudis
2nd Department of Surgery, Aretaieio University Hospital, 75, Vas. Sofias Ave., Athens, 11528
Source of Support: None, Conflict of Interest: None
Context: Survivin is an antiapoptotic protein with a role in tumorigenesis and suggested prognostic value in several proliferative diseases.
Aims: This study aimed to examine the role of survivin as a prognostic marker in pancreatic adenocarcinoma (PDAC).
Settings and Design: Fifty-one specimens of PDAC were assessed for survivin expression by immunohistochemistry.
Subjects and Methods: Overall survival and 1-, 3-, and 5-year survival were retrieved retrospectively.
Statistical Analysis Used: Bivariate analysis was conducted using Chi-square and Mann–Whitney U tests, while survival analysis was conducted using Kaplan–Meier statistics.
Results: Of the 51 assessed cases, 49% were positive for survivin. Survivin expression was significantly correlated 1-year survival and overall survival, particularly in bcl-2 positive cases.
Conclusions: Survivin may be implicated in the bcl-2 and p53 pathways and therefore in the biology of PDAC. Its potential use as a survival predictor and therapeutic target represent a promising field.
Keywords: Apoptosis, pancreatic adenocarcinoma, survival, survivin
|How to cite this article:|
Contis J, Lykoudis PM, Goula K, Karandrea D, Kondi-Pafiti A. Survivin expression as an independent predictor of overall survival in pancreatic adenocarcinoma. J Can Res Ther 2018;14, Suppl S3:719-23
|How to cite this URL:|
Contis J, Lykoudis PM, Goula K, Karandrea D, Kondi-Pafiti A. Survivin expression as an independent predictor of overall survival in pancreatic adenocarcinoma. J Can Res Ther [serial online] 2018 [cited 2020 Oct 21];14:719-23. Available from: https://www.cancerjournal.net/text.asp?2018/14/10/719/187346
| > Introduction|| |
Pancreatic adenocarcinoma (PDAC) remains the fourth cause of death due to malignancies in the USA with an overall 5-year survival of <5%. Despite the progress in our understanding of PDAC biology, as well as advances in diagnosis and treatment, survival rates seem to decrease, unlike other malignancies. The diagnosis of PDAC in later stages and lack of precise stratification of patients for successful treatment tailoring are considered the main causes for these outcomes. A number of molecules have been proposed in literature as predictors for survival, appearing thus as candidates for inclusion in prognostic models and for molecular targeted therapies.
Survivin is a member of the inhibitors of the apoptosis family, involved in cell division regulation and inhibition of apoptosis. Overexpression of survivin has been found in many human malignancies including lymphoma, and nonsmall cell lung cancer, usually accompanying more aggressive forms followed by worse outcomes. Research on targeting survivin in an effort to inhibit its proliferative action in malignancies has yielded encouraging results concerning different types of cancer.,
This study aims to reassess the potential prognostic role of survivin expression in PDAC as well as to examine whether established prognostic markers are confounding factors in the correlation between survivin expression and overall survival.
| > Subjects and Methods|| |
The archives of the Pathology Department of a single tertiary center were searched for specimens regarding PDAC during a 5-year period (2003–2007). Fifty-one consecutive cases were identified, and relevant paraffin-embedded archived tissue and histopathology slides were retrieved. Sections from the archived paraffin-embedded tumor tissues were obtained and examined by Ventana automatic immunostain method, using antihuman bcl-2 protein (DAKO M0887, clone 124), p53 antibody (DAKO, M7001, DO-7), EGFR (Zymed Lab Inc., San Francisco, CA, USA), and survivin (A-Diagnostics Intern, San Antonio, TX, USA) according to manufacturers' instructions with appropriate positive and negative controls. The immunoreaction was evaluated semiquantitatively, depending on the percentage of positively stained cells to the total number of cells examined (at least 100 cells/case). The score was considered negative (-) where the percentage of positively stained cells was <10% of total cells examined, and positive (+) where >10% of cells were stained. Positive immunoreaction was observed at the nuclei (p53), the cytoplasm (bcl-2 and survivin), and at the cellular membrane and the cytoplasm (EGFR). Data regarding patient's gender and age, as well as tumor grading, were obtained from the relevant histopathology reports. The archives of the oncology department were accessed to document data regarding survival. None of the included patients was lost during follow-up, thus patients who were still alive at the time data were collected, had completed a 5-year follow-up. Overall survival was calculated from the time of surgical operation, and survival in 1, 3, and 5 years were calculated accordingly.
Chi-square and Mann–Whitney U tests were used for univariate analyses, and Kaplan–Meier analysis was additionally applied for correlation of survival with various independent variables. For the latter analysis, Breslow test was used to test for statistical significance because most deaths are expected early in the postoperative course, given the short survival of pancreatic cancer patients, and thus proportional hazards assumption is expected to be not true.,
All patients had consented for tissue preservation and research investigations; the study confirmed with The Code of Ethics of the World Medical Association and the approval of hospital's Ethical Committee.
| > Results|| |
Of a total of 51 patients, 62.7% were male (n = 32) and 37.3% were female (n = 19). Median age was 67 years (ranging between 35 and 78 years, 95% confidence interval [CI]: 63–69 years) and median overall survival was 12 months (ranging between 5 and 106 months, 95% CI: 7–17). Twelve patients had a Grade I tumor (23.5%), 23 patients had a Grade II tumor (45.1%), and 16 patients had a Grade III tumor (31.4%). The expression ratio for each protein is presented in [Table 1]. Eleven specimens were negative for all proteins (19%), seven specimens demonstrated expression of only one marker (12.1%), two markers were expressed in 16 specimens (27.6%), 15 specimens were positive for 3 factors (25.9%), and finally all four proteins were expressed in nine specimens (15.5%). One-year, 3-year, and 5-year survivals were 51%, 11.8%, and 5.9%, respectively.
Survivin expression was found to have statistically significant correlation with tumor grade (P = 0.025) and with p53 expression (P = 0.016), as well as with 1-year survival (P = 0.008) and overall survival (Breslow [generalized Wilcoxon] P = 0.035). Correlations of survivin expression with age, gender, EGFR expression, and bcl-2 expression were not statistically significant nor were those with 3- and 5-year survival. As far as correlations between survival outcomes and the rest of the independent variables (age, gender, grade, p53, bcl-2, and EGFR) are concerned, the only detected statistically significant correlation was the one between bcl-2 and five-year survival.
A Kaplan–Meier curve was created to demonstrate the correlation between survivin expression and overall survival (Breslow P = 0.035) [Figure 1]. According to the same method and using each of the other independent variables as a stratification variable, bcl-2 expression appeared as a confounding factor to the correlation between overall survival and survivin expression. The latter correlation remained statistically significant only in bcl-2 positive cases [Figure 2] but was insignificant in bcl-2 negative cases [Figure 3].
|Figure 1: Kaplan–Meier analysis of overall survival according to survivin expression|
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|Figure 2: Kaplan–Meier analysis of overall survival according to survivin expression on bcl-2 positive specimens demonstrating nonsignificant correlation|
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|Figure 3: Kaplan–Meier analysis of overall survival according to survivin expression on bcl-2 negative specimens demonstrating nonsignificant correlation|
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| > Discussion|| |
Since 1997, when Ambrosini et al. first reported the involvement of survivin in PDAC development and biological behavior, numerous research groups studied the role of this molecule in pancreatic cancer biology. Initially, it was demonstrated that survivin plays a significant role in apoptosis of PDAC cells. Several proliferative mechanisms, including Protein Kinases C and the MEK-ERK pathway, have been shown to mediate survivin's antiapoptotic action. Bhanot et al. also demonstrated that survivin expression increases as precancerous lesions evolve into phenotypically unambiguous infiltrative carcinoma. Survivin was also tested as a biomarker to help differentiate between malignant and benign disease in fine needle aspiration specimens, unfortunately without success though. Moreover, a number of studies have suggested that survivin may potentiate resistance of PDAC cells to certain chemotherapeutic agents, and consequently suppression of survivin's expression may restore/augment response to these agents.,,,,,,,,,,, Based on these findings, several groups have tried to downregulate survivin's function through immunological approaches, or genomic approaches such as antisense nucleotides, gene silencing, and translation inhibition.,,,
Survivin has been studied as a prognostic factor in PDAC, but although some groups have reported results which support such a role for survivin,,,,, other groups did not detect the aforementioned correlation.,, The only meta-analysis that has addressed this inconsistency detects a prognostic role for survivin; however, the authors of this paper admit certain weaknesses, involving mainly heterogeneity of outcome assessment among included studies that must be considered before adopting its conclusions. Besides, given that survivin expression has been correlated with the expression of other established prognostic factors such as bcl-2, EGFR,, and p53,, the reported relation between survivin expression and clinical outcomes may be secondary to the aforementioned correlations and it is thus unclear whether survivin is an independent prognostic factor.
In the present study, 54.9% of tumors were survivin positive while the reported ratio of survivin-positive PDACs varies between 44.8 and 93.9% in literature., This study reports a statistically significant correlation between survivin expression and overall survival, reproducing thus the findings of previous research groups.,,, In the studied sample, only bcl-2 expression qualified as a potential confounding factor and was investigated accordingly. On stratification of studied subjects according to bcl-2 expression, survivin maintained its prognostic role only in bcl-2 positive specimens. It can be argued thus that survivin is an independent prognostic factor in bcl-2 positive PDACs, with survivin-negative tumors associated with a prolonged overall survival, while in bcl-2 negative PDACs, this correlation is lost. It is characteristically reported in literature that simultaneous silencing of bcl-2 and survivin may augment cancer cell apoptosis. It can also be suggested that since survivin and p53 expressions show a statistically significant correlation, they may share partially common or at least linked molecular pathways. The latter correlation has also been reported previously in literature.
The above findings suggest a potential significant functional role of survivin in the biology of PDAC, linked with p53 and bcl-2 functions, and they also define a subgroup of patients, those with bcl-2 positive tumors, in which survivin expression is associated with worse survival and thus could be a used as a treatment target. However, this is a small cohort study, and relevant findings and conclusions should be investigated in larger series in order to establish solid deductions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]