Failure of Downregulation of Survivin Following Neoadjuvant Radiochemotherapy in Rectal Cancer Is Associated with Distant Metastases and Shortened Survival

Abstract

Purpose: Valid molecular markers need to be implemented in clinical trials to fulfill the demand of a risk-adapted and more individualized multimodal therapy of locally advanced primary rectal cancer. In this study, the expression of the inhibitor-of-apoptosis (IAP) protein survivin was evaluated in pretreatment biopsies and corresponding posttreatment resection specimens, and was correlated to histo-pathological tumor characteristics and clinical follow-up.Patients and Methods: One hundred sixteen patients with stage II/III rectal cancer treated with 5-FUbased neoadjuvant radiochemotherapy (RCT) at a single university medical centre within the German Rectal Cancer Trials were investigated. Survivin expression in pretreatment biopsies and surgical resection specimens were determined by immunohistochemistry by two independent institutions and correlated with histopathologic parameters, tumor recurrences, disease-free (DFS), and overall cancer-specific survival (CSS).Results: In pretreatment biopsies, a higher survivin expression correlated with advanced ypT (P ¼ 0.026) and ypUICC (P ¼ 0.05) stage as well as DFS (P ¼ 0.038) after preoperative RCT. High posttreatment survivin levels were associated with advanced ypT stage (P ¼ 0.03) and residual lymph node metastases (P ¼ 0.04). Moreover, neoadjuvant RCT resulted in a significant downregulation of survivin expression (P < 0.0001). A failure of RCT-induced downregulation was associated with development of distant metastases (P ¼ 0.0056) and cancer-related death (P ¼ 0.026), and correlated significantly with DFS (P ¼ 0.011*/0.02**) and CSS (P ¼ 0.0017*/0.01**) in uni-* and multivariate** analyses.Conclusions: Survivin expression displays a marker with prognostic utility in rectal cancers. These results underline the potential of survivin to monitor individual response to RCT and encourage antisurvivin strategies in multimodal rectal cancer therapy within future randomized clinical trials.

Survivin is highly expressed in CD34+38− leukemic stem/progenitor cells and predicts poor clinical outcomes in AML

“…39 Among the 47 cases with paired diagnosis and relapse samples in the current study, we did not observe a consistent pattern of change in survivin levels (P ϭ .64) and saw both increases and decreases in survivin levels in the relapsed samples. However, we did observe that survivin levels were more likely to be increased (n ϭ 28) than decreased (n ϭ 19) at relapse.…”

Upregulation of stromal cell-derived factor 1α expression is associated with the resistance to neoadjuvant chemoradiotherapy of locally advanced rectal cancer: Angiogenic markers of neoadjuvant chemoradiation

“…Recently, studies have attempted to identify predictive biomarkers, yet various studies only compared pre-treatment and post-treatment changes in biomarker expression (5). In this study, we investigated the predictive relevance of AM expression both in pre-treatment biopsies and in corresponding surgical specimens of 55 patients with LARC treated with standadised 5-FU-based NCRT.…”

“…Recent studies have attempted to identify predictive biomarkers such as Ki-67, p53, p21, p27, bax, BCL-2, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), survivin and thymidylate synthase (5,6). However, clinical use of these biomarkers requires further evaluation in prospective clinical trials (7).…”

Gastrointestinale Tumore – interdisziplinäre Diskussion neuer Daten

“…18). Zudem konnte kürzlich gezeigt werden, dass, wenn es mithilfe der präoperativen RCT nicht gelingt, eine Herabregulierung von Survivin, eines Apoptose-Inhibitors, zu induzieren, bei den betroffenen Patienten mit einer erhöhten Fernmetastasierungsrate und einem signifikant verkürzten OS gerechnet werden muss [118].…”