RTOG 8610 is the first major, phase III randomized trial to test the hypothesis that short-term neoadjuvant androgen deprivation therapy (ADT) combined with radiotherapy (RT) would improve treatment outcomes compared with RT alone. Long-Term Results of this study suggests that the addition of 4 months of ADT to RT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events35
. Now It is clear that long-term ADT + RT should be used in “high-risk” patients (clinical stage T2c-3, Gleason score 7–10, PSA> 20 ng/mL) and “low-risk” patients (clinical stage T1c-2a, Gleason score 2–6, PSA< 20 ng/mL) may benefit from short-term ADT + RT. Whether “intermediate risk” patients (clinical stage T2b, Gleason score 7, PSA 10–20 ng/mL) benefit from a combination of ADT and RT is not clear. Although the risk stratification system described by D’Amico et al
is widely used and is relatively simple, it suffers from heterogeneity within the intermediate risk group36
. To address this heterogeneity, it is necessary to create additional subgroups using novel prognostic markers in order to correlate with survival end point. Based on our preclinical studies of Survivin in human prostate cancer cell models and the previous reports of Survivin as a molecular marker in other cancers, we hypothesized that Survivin expression may serve as a prognostic factor for prostate cancer patients and different subcellular localization of Survivin may alter its prognostic role. We tested these hypotheses using samples from men with locally advanced prostate cancer enrolled in RTOG 8610.
The prognostic value of Survivin expression in prostate cancer has remained unclear. Most of the studies which have analyzed the prognostic significance of Survivin expression were either performed without accounting for the subcellular location of the protein, or reported Survivin location to be restricted to the cytoplasm of tumor cells 16, 17, 26
. Our study for the first time separately describes the expression of Survivin protein in both the nuclear and cytoplasmic compartments of prostate cancer cells. In our analysis we identified that a different prognostic role is played by the nuclear and cytoplasmic Survivin expression. In particular, the nuclear expression of Survivin identified patients with improved overall and prostate cancer survival, while the cytoplasmic overexpression of Survivin was associated with increased rate of local progression. These findings have been confirmed by univariate and/or multivariate analysis of survival. In the multivariate analyses of nuclear and cytoplasmic Survivin, we used the independent variable “assigned treatment” to examine the risk of RT + hormone therapy as compared to RT alone. None of the analyses shown the significant difference between the two groups. However, among 50 patients who received salvage hormone therapy as “clinically indicated” for disease relapse, those with nuclear Survivin intensity score >191.2 showed a significant increase in five-year prostate cancer survival compared to patients with Survivin intensity score ≤191.2 (74.3% vs.
= 0.010), indicating that this subgroup of relapsed patients with higher nuclear Survivin expression may benefit from salvage hormone therapy.
Although growing evidence suggests that Survivin expression in cancer cells may represent an important prognostic marker to predict disease outcome, current reports are inconsistent and propose opposing conclusions. Cytoplasmic Survivin immunoreactivity has been observed in the vast majority of human tumors and it has been consistently associated with poor prognosis 19
. Nuclear staining has been linked with a favorable prognosis in patients with gastric carcinoma 37
, breast carcinoma 38
, osteosarcoma 39
, bladder mucosa and transitional cell carcinoma40
, and pancreatic cancer41
. In contrast, studies in hepatocellular carcinoma 42, 43
, esophageal malignancies 44
, and mantle cell lymphoma 45
have shown nuclear Survivin to be associated with poor survival. In addition, Survivin has been detected in the nuclei of non-small-cell lung cancer 46
and ovarian cancer 47
from clinical samples, without any significant relation with clinical outcome. The results of these studies have contributed to the confusion regarding the role of nuclear expression of Survivin. The prognostic difference for nuclear Survivin among these studies is likely tumor-specific.
It has been demonstrated that Survivin exists in two distinct subcellular pools: cytoplasmic and nuclear 18
. The two Survivin pools are immunochemically distinct and independently modulated during cell cycle progression. Survivin has been described both as a chromosomal passenger protein in the nucleus and as a microtubule-associated protein in cytoplasm. In the nucleus, Survivin interacts with aurora kinase B and INCENP to complete mitosis 48
, suggesting that strong nuclear staining of Survivin may represent increased mitotic events. Conversely, in the cytoplasm, Survivin blocks intrinsic and extrinsic apoptosis by directly inhibiting caspase-3 and -7, as well as interfering with caspase-9 49
. This may partly explain the different prognostic implications of cytoplasmic and nuclear Survivin. The distinct roles of Survivin may also be due in part to splice variations. Survivin has four splice variants with different subcellular localizations: Survivin-2α Survivin-2β, Survivin-3β, and Survivin-δEx3 20–25
. Survivin-δEx3 is localized preferentially in the nucleus, whereas the wild type Survivin and Survivin 2β isoforms are found in the cytoplasm. Survivin-2β and Survivin-δEx3 may antagonize wild type Survivin by forming heterodimers with reduced antiapoptotic potential, and acting as naturally occurring antagonists of Survivin 24, 50
. Different isoforms of Survivin may interact, and the subcellular location ratio of the protein may contribute to the complex regulation of apoptosis and cell division according to these studies. Because the antibody we used in the immunohistochemical staining recognizes all these variants, it is not surprising that the intracellular location of Survivin has different prognostic implications in prostate cancer.
In summary, the present study is the first report to establish the prognostic relevance of the Survivin expression in prostate cancer in relation to its cellular distribution. The nuclear expression of Survivin is associated with improved overall and prostate cancer survival, while the cytoplasmic overexpression of Survivin is associated with increased rate of local progression in patients with locally advanced prostate cancer treated on RTOG 8610. Our data may reflect the divergent functions of Survivin isoforms, which exhibit distinct subcellular localizations. This study represents a retrospective correlative analysis performed on a prospective phase III study. The majority of patients entered this trail prior to the PSA era, and the extent of disease at entry is much more advanced than in the patients we see now who are being diagnosed in the second decade of the PSA era. Our data should be viewed with some caution because of the small dataset, low statistical power and potential cutpoint bias. A larger independent cohort of men with earlier-stage prostate cancer treated with radiotherapy should be investigated to clarify the potential of Survivin in prostate cancer prognosis.