The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer

Abstract

The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity. For this monocentric analysis 186 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%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up. The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up. High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.

Keywords: SRC; biomarker; preoperative chemoradiotherapy; rectal cancer; targeted therapy.; tyrosine kinase.

Figure 1

Study design. This figure shows the treatment of patients and time points of tissue collection for analysis of SRC expression. CEA, carcinoembryonic antigen; CT, contrast-enhanced computer tomography; EUS indicates endorectal ultrasound; MRI, magnetic resonance imaging; CSS, Cancer specific survival; DFS, Disease free survival; ox, oxaliplatin.

Figure 2

Images of immunhistochemical staining in resection specimens of rectal cancer: A SRC cytosolic staining intensity 0 in 40x magnification, B SRC cytosolic staining intensity in 40x magnification, C SRC cytosolic staining intensity in 40x magnification, D SRC cytosolic staining intensity III in 40x magnificationon.

Figure 2

Images of immunhistochemical staining in resection specimens of rectal cancer: A SRC cytosolic staining intensity 0 in 40x magnification, B SRC cytosolic staining intensity in 40x magnification, C SRC cytosolic staining intensity in 40x magnification, D SRC cytosolic staining intensity III in 40x magnificationon.

Figure 3

A) Correlation between SRC expression in pretherapeutic biopsies and the nodal status in cytosolic staining: high SRC expression is associated with fewer lymph node metastases (p=0.005). B) Correlation between pretherapeutic SRC expression under preoperative CRT with 5-FU/oxaliplatin and the nodal status: On the basis of the ROC curve (receiver operating characteristic curve) there is a high specificity and sensitivity regarding the correlation between the pretherapeutic SRC expression for patients receiving preoperative CRT with 5-FU and oxaliplatin and the nodal status. The AUC (area under curve) is 81.2%, representing the quality of the test.

Figure 4

Correlation between cytosolic SRC expression in resection specimens and the occurrence of distant metastases: high SRC expression is associated with fewer distant metastases (p=0.048).