Aberrant P53 expression lacks prognostic or predictive significance in colorectal cancer: results from the VICTOR trial.

AIM: Biomarkers with prognostic and predictive value can help stratify patients with colorectal cancer (CRC) into appropriate treatment groups. We sought to evaluate the clinical utility of P53 protein expression as a biomarker in VICTOR, a large phase III trial of rofecoxib in stage II and III CRC. PATIENTS AND METHODS: Tissue micro arrays were constructed from 884 tumors and the expression of P53 was examined by immunohistochemistry. Tumors were dichotomised as either P53-positive (nuclear expression in >10% of cells or the 'absent' pattern, both representing TP53 mutation) or P53-negative (nuclear expression in <10% of cells). RESULTS: Aberrant P53 expression was found in 65% (482/740) of patients. It was associated with distal location (p<0.001) and stage III disease (p<0.001). No effect was observed on disease-free or overall survival, and there was no interaction with chemotherapy or radiotherapy. CONCLUSION: Analysis of P53 expression in the patients recruited to the VICTOR trial confirmed that P53 expression is associated with site and stage of CRC. However, independently, this biomarker has neither prognostic nor predictive utility in this cohort of patients.

Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer.

PURPOSE: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin. METHODS: We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status. RESULTS: We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2; 95% CI, 0.53 to 2.72; P = .66; (P)INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87; 95% CI, 0.64 to 1.16; P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11; 95% CI, 0.001 to 0.832; P = .027; (P)INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92; 95% CI, 0.60 to 1.42; P = .71). CONCLUSION: Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.

Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial.

PURPOSE: Laboratory and case-control studies suggest a pivotal role for the cyclooxygenase-2 (COX-2) pathway in colorectal carcinogenesis. The purpose of this study was to test whether the COX-2 inhibitor rofecoxib could reduce recurrence and improve survival when administered in the adjuvant setting of colorectal cancer (CRC). PATIENTS AND METHODS: Patients who had undergone potentially curative surgery and completion of adjuvant therapy for stage II and III CRC were randomly assigned to receive rofecoxib (20 mg daily) or placebo. The primary end point was overall survival (OS). Where formalin-fixed paraffin-embedded tumor tissue samples were available, COX-2 expression was evaluated by immunohistochemistry and correlated with clinical outcome. RESULTS: Two thousand four hundred thirty-four patients were entered onto the study. The trial was terminated early because of the worldwide withdrawal of rofecoxib. At this point, 1,167 patients had received rofecoxib and 1,160 patients had received placebo for median treatment durations of 7.4 and 8.2 months, respectively. For the rofecoxib and placebo arms, median follow-up times were 4.84 and 4.85 years, with 241 and 246 deaths and 297 and 329 recurrences, respectively. No difference was demonstrated in OS (hazard ratio [HR] = 0.97; 95% CI, 0.81 to 1.16; P = .75) or recurrence (HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) comparing the two groups. Tumor COX-2 expression by immunohistochemistry was assessed for 871 patients, but neither prognostic nor predictive effects were observed. CONCLUSION: In this study of abbreviated therapy in the adjuvant setting of CRC, rofecoxib did not improve OS or protect from recurrence in unselected patients. In addition, COX-2 expression did not correlate with prognosis overall or predict effectiveness of COX-2 inhibitors.

Evolution of nonsurgical therapy for colorectal cancer.

The management of colorectal cancer (CRC) has changed considerably in the past 15 years with the introduction of multiple novel active therapeutic agents. Chemotherapy regimens combining a fluoropyrimidine with either oxaliplatin or irinotecan are standard first-line and second-line therapy for advanced and metastatic disease. The first-line use of these combinations produces tumor response rates of approximately 50% and a median overall survival of approximately 20 months. Addition of bevacizumab to first-line treatment and addition of cetuximab to salvage therapy for patients who fail to respond to irinotecan have contributed to further increases in tumor response rates and enhanced progression-free survival. Such approaches have produced only marginal overall survival benefits, however, and entail considerable cost. Adjuvant chemotherapy, delivered after surgical resection of the primary tumor, increases cure rates by approximately 10% for stage III disease and approximately 3-4% for stage II disease. Encouraging reductions in local relapse rates have been observed in patients with early rectal cancer who have undergone chemoradiotherapy, and increasingly complex regimens are currently being explored in phase II clinical trials in an attempt to increase both the operability and long-term local control of CRC. The greater the therapeutic choice, the greater the cost (both financial and in terms of toxicity), thus the keener the clinical community becomes to develop biomarkers to select patient populations who will be most likely to benefit from a specific agent.

Modified Irinotecan/5FU/Leucovorin therapy in advanced colorectal cancer and predicting therapeutic efficacy by expression of tumor-related enzymes.

OBJECTIVE: To evaluate the efficacy and safety of a regimen using Irinotecan, 5FU and Leucovorin for patients with advanced or recurrent colorectal cancer. MATERIAL AND METHODS: Irinotecan (75 mg/m(2)) was administered biweekly, while 5FU (600 mg/m(2)) and Leucovorin (250 mg/m(2)) were administered weekly, for 6 weeks. RESULTS: The 21 consecutive patients subjected to this regimen showed a good response rate (43%) with minimal toxicity (incidence of grade 3/4: leukopenia and neutropenia, 5%, respectively, and vomiting, 10%). The mean survival time of all 21 patients was 15.7 months. This regimen could be a valid option for patients with advanced colorectal cancer, especially those seeking a good QoL (quality of life) for the remainder of their lives. We evaluated the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) mRNAs, and sialyl Lewis X on formalin-fixed, paraffin-embedded colorectal tumor samples. Expression of TS mRNA or sialyl Lewis X was negatively correlated with the response from chemotherapy. Patients with low DPD mRNA expression in the tumor showed a significant longer survival than those with high expression. In patients with high TP mRNA expression, there was a tendency towards a high incidence of leukopenia. CONCLUSIONS: Some predictive factors elucidated in this study could contribute to the progress of the tumor-biology based, individualized chemotherapy for colorectal cancer patients.