Die Expression von SRC vor und nach neoadjuvanter Radiochemotherapie im lokal fortgeschrittenen Rektumkarzinom cUICC II/III.
Expression of SRC before and after neoadjuvant chemoradiotherapy in locally advanced rectal cancer cUICCII/III
by Felix Rühlmann
Date of Examination:2016-02-02
Date of issue:2016-01-12
Advisor:Prof. Dr. Torsten Liersch
Referee:Prof. Dr. Torsten Liersch
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Martin Oppermann
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EnglishPurpose: SRC, one of the oldest proto-oncogenes, is encoding for the tyrosine kinase of the same name. The protein, which is localized in the cytosol as well as in the cell membrane, is involved in cell proliferation and migration. In the actual analysis SRC expression was determined in cancer tissue of locally advanced rectal adenocarcinoma from pretreatment biopsies and resection specimen. The expression level was correlated with clinicopathological data to evaluate the predictive and prognostic capacity. Patients and Methods: For this monocentric analysis 186 consecutive patients with locally advanced rectal cancer (median: 63,7 years; 130 men (69,9%), 56 women (30,1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14,5%). The other patients received a standardized neoadjuvant radiochemotherapy with 50,4 Gy and 5-FU (n=103; 55,4%) or 5-FU+oxaliplatin (n=56; 30,1%) followed by adjuvant chemotherapy with 5-FU or 5-FU+oxaliplatin. All patients were treated within phase-II/III trials of the German Rectal Cancer Study Group or analogous to these protocols. SRC expression was determined with immunohistochemical staining as H-score from pretreatment biopsies and residual tumor tissue from the resection specimen. The results were correlated with clinicopathological parameters and long-term follow-up. Results: The expression of SRC was evaluated in two different tumor samples: pretherapeutic biopsies (mean H-Score: 229) and resection specimen (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Besides an increased protein expression was associated with fewer distant metastases in residual tumor tissue (p=0,04). Furthermore, the overexpression of SRC in pretreatment tumor biopsies showed a trend for a longer cancer-specific survival (p=0.05) and less local relapses (p=0,06) during long-term follow-up. In patients with a positive nodal status there was a positive correlation of SRC expression with disease-free survival (p=0.02). Patients who received a standardized neaodjuvant radiochemotherapy with 5-FU + Oxaliplatin benefited from high SRC expression in pretherapeutic biopsies with regard to the nodal status. Conclusions: Low SRC expression in rectal cancer seems to be associated with a worse long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted adjuvant treatment, as SRC could be used as potential target in future therapeutic strategies. This should be validated and further analyzed within multi-centric clinical trials.
Keywords: SRC; rectal cancer; chemoradiotherapy
Schlagwörter: SRC; Rektumkarzinom; Radiochemotherapie