P-022 Predictive biomarkers of pathologic response to preoperative chemoradiotherapy in locally advanced rectal cancer

Abstract

Introduction: Preoperative chemoradiotherapy (CRT) is the standard treatment option in locally advanced rectal cancer (LARC). The tumor response is estimated trough tumor and nodal down staging and the tumor regression grade. Currently, there is no method to predict a tumor response to CRT, and finding the accurate one would have a great clinical utility. Both p53 and p21 proteins belong to the cell cycle-regulating family of proteins and the loss of their activity seems to be one of the most important regulatory mechanisms of carcinogenesis in colorectal cancer. EGFR and VEGF expressions are also known to be correlated with disease outcome in patients with LARC. We aimed to evaluate whether p21, p53, VEGF and EGFR expressions could be the reliable predictors of pathological response to preoperative CRT. Methods: 50 patients with locally advanced rectal cancer (T3 stage -76%, T4 stage - 24%) were treated with preoperative radiotherapy with total dose of 45 Gy combined with concomitant chemotherapy 5-FU and leucovorin. Surgery was performed six to eight weeks after the end of chemoradiation. p21, p53, EGFR and VEGF immunohistochemical staining was performed on pretreatment biopsy specimens and results were compared with histopathological tumor regression according to a standardized semiquantitative score grading systems by Dworak (TRG grades) and Wheeler (RCRG grades). Results: Higher p21 expression was correlated with lower histopathological grade, i.e. better differentiated tumors (p = 0.009). Testing RCRG grades in relation to p21 expression, showed statistically significant difference (p = 0.021). RCRG 3 (poor response) was significantly more frequent in the group of patients with p21-, which was registered in 41.38%, compared to p21 + , found in 14.29% of patients. Frequency of p21+ and p21- expression was also compared with five stage regression grades according to Dworak. Grade 4 (complete regression) was more frequent in the group of patients with positive p21 expression (p21- vs. p21 + : 3.45% vs. 33.33%, p = 0.032). Statistically significant difference in p21 expression in Grade 4 group compared with all other grades groups was also found (p = 0.007). In other words, patients with elevated expression of p21 had statistically significantly higher percentage of complete regression in comparison to the patients with low expression of p21. According to Dworak grading system, complete regression was more frequent in the group of patients with negative EGFR and VEGF expression compared with other grades (p = 0.017 and p = 0.041 respectively). These results were not confirmed testing RCRG grades in relation to EGFR and VEGF expression. We haven't found any correlation between p53 expression and histopathological as well as regression grades. Conclusion: According both grading systems, results obtained in our setting suggest that unlike p53 expression, p21 expression could predict pathological response to preoperative CRT. The association of higher EGFR and VEGF expression with unfavorable outcome according to Dworak grading system is also reported.