p53 status and response to radiotherapy in rectal cancer: a prospective multilevel analysis

Abstract

The aim of this study was to evaluate, in a prospective study, the predictive role of p53 status analysed at four different levels in identifying the response to preoperative radiotherapy in rectal adenocarcinoma. Before treatment, 70 patients were staged and endoscopic forceps biopsies from the tumour area were taken. p53 status was assessed by total cDNA sequencing, allelic loss analysis, immunohistochemistry, and p53 antibodies. Neoadjuvant treatment was based on preoperative radiotherapy or radiochemotherapy. Response to therapy was evaluated after surgery by both pathologic downstaging and histologic tumour regression grade. In all, 35 patients (50.0%) had p53 gene mutations; 44.4% of patients had an allelic loss; nuclear p53 overexpression was observed in 39 patients (55.7%); and p53 antibodies were detected in 11 patients (16.7%). In the multilevel analysis of p53 status, gene mutations correlated with both nuclear protein overexpression (Po0.0001) and loss of heterozygosity (P ¼ 0.013). In all, 29 patients (41.4%) were downstaged by pathologic analysis, and 19 patients (29.2%) were classified as tumour regression grade 1. Whatever the method of evaluation of treatment response, no correlation between p53 alterations and response to radiotherapy was observed. Our results do not support the use of p53 alterations alone as a predictive marker for response to radiotherapy in rectal carcinoma.

Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy

“…Recently, microarray gene expression profiling was successfully used to predict complete responses to preoperative chemoradiotherapy with advanced-stage rectal cancer (Ghadimi et al, 2005;Kim et al, 2007). Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), the p53 tumour suppressor and key mediators of cell-cycle arrest (p21, p27) and apoptosis (Bcl-2, apoptosis protease-activating factor-1 (APAF-1)) are among the immunohistochemical protein markers currently of interest as potential predictors of pathologic response, prognosis and recurrence-free survival in rectal cancer following neoadjuvant therapy (Giralt et al, 2005(Giralt et al, , 2007Lopez-Crapez et al, 2005;Kim et al, 2006;Lin et al, 2006;Smith et al, 2006;Bertolini et al, 2007).…”

Desenlaces del manejo no quirúrgico posterior a neoadyuvancia del cáncer localmente avanzado de recto

“…Aunque esten aún en investigación y no sea clara su significacia como factores pronósticos, la determinación de marcadores inmunohistoquímicos como p53, Ki67 y moleculares como Kras podrian correlacionarse con el comportamiento del tumor y la respuesta a los tratamientos sobre él [42][43][44][45][46][47][48][49][50] . En un reporte de Lin et al 46 , los autores comparan la expresión de p53, p27 y bcl-2 antes y después de la terapia neoadyuvante, mostrando un incremento de p27 y bcl-2 en los especímenes resecados, al compararse con la biopsia inicial, considerándose que la positividad de p27 parece mejorar el pronóstico.…”

“…En un reporte de Lin et al 46 , los autores comparan la expresión de p53, p27 y bcl-2 antes y después de la terapia neoadyuvante, mostrando un incremento de p27 y bcl-2 en los especímenes resecados, al compararse con la biopsia inicial, considerándose que la positividad de p27 parece mejorar el pronóstico. Estudios in vitro 45 , demuestran que un p53 normal es requerido en el tejido tumoral, para que responda adecuadamente a la quimioterapia basada en 5-FU. Su determinación antes de la neoadyuvancia, podría contribuir como predictor de respuesta a la quimioterapia [45][46] .…”

“…Estudios in vitro 45 , demuestran que un p53 normal es requerido en el tejido tumoral, para que responda adecuadamente a la quimioterapia basada en 5-FU. Su determinación antes de la neoadyuvancia, podría contribuir como predictor de respuesta a la quimioterapia [45][46] . Sin embargo, otros estudios hablan que el p53 es poco útil como buen predictor de respuesta a la quimioterapia y que para el bcl2 y ki67 no hay suficiente evidencia que avale su utilidad 47 .…”

Usefulness of two independent histopathological classifications of tumor regression in patients with rectal cancer submitted to hyperfractionated pre-operative radiotherapy

“…This finding may prove to be of significance during planning of surgical treatment. The percentage of patients with "T-downstaging" in the group submitted to long-term radiotherapy and radiochemotherapy ranged from 23/88 (26.0%) to 15/20 (75.0%) [14,17,[20][21][22][23][24]27,[34][35][36]39,[46][47][48][49]51,52] . Among patients submitted to short-term preoperative radiotherapy "T-downstaging" ranged between 10/28 (35.7%) and 44/104 (43%) [11,14,18,19] .…”