Failure of downregulation of survivin following neoadjuvant radiochemotherapy in rectal cancer is associated with distant metastases and shortened survival.
OBJECTIVE
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.


METHODS
One hundred sixteen patients with stage II/III rectal cancer treated with 5-FU-based 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 = 0.026) and ypUICC (P = 0.05) stage as well as DFS (P = 0.038) after preoperative RCT. High posttreatment survivin levels were associated with advanced ypT stage (P = 0.03) and residual lymph node metastases (P = 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 = 0.0056) and cancer-related death (P = 0.026), and correlated significantly with DFS (P = 0.011*/0.02**) and CSS (P = 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 anti-survivin strategies in multimodal rectal cancer therapy within future randomized clinical trials.
Department of General and Visceral Surgery, University Medical Center, Gottingen, Germany. tsprenger@chirurgie-goettingen.de
Thilo
T
Sprenger
Franz
F
Rödel
Tim
T
Beissbarth
Lena-Christin
LC
Conradi
Hilka
H
Rothe
Kia
K
Homayounfar
Hendrik A
HA
Wolff
B Michael
BM
Ghadimi
Müjdat
M
Yildirim
Heinz
H
Becker
Claus
C
Rödel
Torsten
T
Liersch
D000368:Aged; D001706:Biopsy; D017024:Chemotherapy, Adjuvant / Q000379:methods; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009362:Neoplasm Metastasis; D011379:Prognosis; D018714:Radiotherapy, Adjuvant / Q000379:methods; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D012008:Recurrence; D000077022:Survivin; D016896:Treatment Outcome
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin