Senescence, a new concept in pathologic response evaluation of rectal carcinomas (RC) after neoadjuvant treatment.

Abstract

e21021 Background: Available protocols of response evaluation after therapy are based on the presence of viable cells, fibrosis and necrosis. Senescence is an irreversible cell cycle arrest that can be activated by different kinds of stress like DNA damage and cytotoxic drugs. Senescent cells are histologically very similar to viable neoplasic cells and usually evaluated alike. Our hypothesis is that neoadjuvant treatment can induce senescence as part of the therapeutic response and its presence may impact the prognosis. Methods: Tumor samples of 45 consecutive patients (pts) with RC treated between sept/02 and feb/2007 with fluorouracil-based chemotherapy and neoadjuvant radiotherapy, and of 33 non-treated colon cancer pts (controls), were selected. p53 and P16-ki67 double immunostaining were retrospectively evaluated in endoscopic-pretreatment biopsies, post-therapy specimens, and controls. P16+/ki67- malignant glands were considered as senescent-like glands. SPSS v20.0 (Kruskal-Wallis, Cox regression and log-rank test) was employed for analysis. Results: After a median follow up of 60 months 13 pts had relapsed. Significant differences in the percentage of senescent-like glands were observed between treated carcinomas and their pre-treatment samples (p=0.0001) and also with the colonic-non-treated carcinomas (p=0.0001). A tendency toward a better disease free survival (DFS) (p=0.236) in those patients with more than 30% of senescent glands after treatment was observed. No differences in p53 were found between the 3 groups. However, low levels of p53 expression in pretreatment-rectal biopsies correlate with a better pathologic response (GR) (p=0.029), and better DFS (p=0.0958). Conclusions: The number of senescent-like glands increases after neoadjuvant therapy. There was a tendency for a better DFS in the pts with treatment-induced senescence. Moreover, an inverse correlation between p53 expression in pretreated endoscopic-samples and pathologic response and DFS was observed. Further and larger studies should be performed to confirm the prognostic implications of evaluating senescence markers in treated rectal carcinomas.