p53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma

Purpose: We recently presented evidence for tumor site and gender-specifici ty in the survival benefit from adjuvant chemotherapy in Stage III colorect al cancer (CRC), In the current study, we examined whether p53 alteration o r the microsatellite instability (MSI) phenotype provide additional predict ive information in CRC patients. Experimental Design: A retrospective series of 891 Stage m CRC patients wit h negative surgical margins was investigated. Thirty percent (270 of 891) r eceived postoperative adjuvant chemotherapy with curative intent and compri sing of 5-fluorouracil/levamisole. Adjuvant treatment and nontreatment pati ent groups were well matched for tumor site, grade, p53 alterations, and MS I, Surgical tumor specimens were investigated for p53 overexpression using immunohistochemistry and for p53 mutation and MSI using single-strand confo rmation polymorphism analysis. The predictive value of these markers was ev aluated by comparing the survival of adjuvant-treated and nonadjuvant treat ed patients. Results: A strong inverse correlation was observed between p53 alteration a nd MSI (P < 0,0001), In univariate analysis, the factors of sex, site, p53 alteration, and MSI were each strong predictors of a survival benefit from chemotherapy, Multivariate analysis revealed that chemotherapy provided max imal survival benefit for female patients (P = 0.005) and for patients whos e tumors contained normal p53 (P = 0.041). Males whose tumors contained a p 53 alteration and were negative for MSI appeared not to benefit from chemot herapy. Conclusions: Our findings suggest that p53 alteration and MSI could be clin ically useful molecular predictive markers for the identification of CRC pa tients who might benefit from 5-fluorouracil-based chemotherapy.