Prognosis Prediction For Locally Advanced Colorectal Cancer: Implication Of Clinical Characteristics And Molecular Markers

Prognosis Prediction for Locally Advanced Colorectal Cancer: Implication of Clinical Characteristics and Molecular MarkersObjectives:To explore the value of clinicopathological characteristics,immunohistochemical protein markers and gene expression profiling in prediction prognosis of locally advanced colorectal cancer,and to explore the clinical implication of integrating molecular marker to clinical prognostic factors for more individualized treatment and outcome evaluation.Materials and Methods:PartⅠ:Retrospectively collecting colorectal cancer patients in Department of Surgery of Fudan University Cancer Hospital between the year 1990 and 2004.Prognostic factors of clinicopathological features were studied by Cox multivariate analyses.PartⅡ:A consecutive group of 259 Patients in the database who were treated between 1999 and 2004 were explored the prognostic value of immunohistochemical proteins,including P53,P21, PCNA and CD44v6.Multivariate analyses was performed to study the relationship among clinicopathological features,proteomic markers and patients outcome.PartⅢ:Between June to December 2004,95 curative treated patients with locally advanced colorectal cancer were accrued in the following prospective study.All the patients were tested their gene expression profiling of 502 genes by DASL technique.Genetic signature was analyzed and simulated by method of genetic statistics,and hazards models were established to integrating clinicopathological prognostic factors to genetic signature for a better prediction model.Results:PartⅠ:For all the patients of stageⅠ,Ⅱ,Ⅲ,the 5-year disease-free survival(DFS) rates were 91.3%,79.4%and 57.5%,and the 5-year overall survival(OS) rates were 94%,83.1%and 60.1%, respectively.73.9%of patients whose tumors were over 5cm in the largest tumor diameter had T3-4 disease,and 33.1%of patients had lung metastasis after surgery,in which 22%of all patients had lung metastasis as the only recurrence.For node-positive rectal cancers,metastatic lymph node ratio (LNR) was independent prognostic factors for local recurrence(LR),DFS and OS,the hazard ratio was 8.50(95%CI 2.25-32.03,P=0.002),3.59(95%CI 1.83-7.03,P=0.0002) and 3.11(95%CI 1.47-6.58,P=0.003),respectively.By choosing 0.14 and 0.5 as cutoff,the node-positive rectal cancer patients could be classified into three groups of significantly different outcomes(＜0.14, 0.14-0.49,and 0.5-1),and the 5-year DFS rates were 72.57%,58.54%and 34.75%(P=0.0001),the 5-year OS rates were 72.19%,61.92%and 38.47%(P=0.002),respectively.PartⅡ:The 5-year OS,DFS rate and overall LR rates were 75.4%,70.3%and 6.7%for all the 259 patients of stageⅠ-Ⅲrectal cancer,while the rates were 66.8%,65.8%and 8.1%for 179 patients of stageⅡ-Ⅲlocally advanced rectal cancer.Multivariate analysis revealed that expression of CD44v6,TNM stage and preoperative CEA value were independent risk factors for prediction 5-year DFS and OS in the 259 patients.For the group of 179 locally advanced rectal cancers,CD44v6 and lymph node metastasis were independent risk factors for 5-year DFS(P=0.009 and 0.016)and OS(P=0.048 and 0.034),and lymph node metastasis was the only independent risk factor for LR. For 112 cases of stageⅢrectal cancer,CD44v6 was the only risk factor for predicting LR,the hazard ratio was 6.02.The LR rate was significantly higher in stage HI patients with overexpression of CD44v6(17.63%:6.62%,P=0.026).PartⅢ:Multivariate analysis for 95 prospectively studied patients with locally advanced colorectal cancer revealed that TNM stage,invasion depth(T4 vs T1-3),and adjuvant chemotherapeutic regimen was independent risk factors for predicting 3-year DFS,the hazard ratio was 3.7(95%CI 1.6-8.4,P=0.002),2.9(95%CI 1.4-6.2,P=0.006) and 0.46(95%CI 0.21-0.98, P=0.046).Cox univariate analyses were performed for 502 gene expression by DASL technique.An 8-gene signature were obtained and the score of genetic signature was calculated by expression value and regression coefficient.Multivariate analysis revealed the score of genetic signature was independent risk factors for 3-year DFS(HR 1.48,95%CI 1.26-1.73;P=2×10^-6).A further risk model was performed by integrating score of genetic signature to TNM stage system to establish an integrated risk factor.The integrated risk factor reclassified the 95 patients into three groups(high, medium and low risk).The 3-year DFS rates were 92.3%,60.9%and 30.4%(P=8×10^-6), respectively.ROC curved also proved that our integrated risk factor had the best value of predicting 3-year DFS,compared to sole-use of TNM stage system or score of genetic signature.Conclusion:PartⅠ:For stageⅠ-Ⅲrectal cancer,histopathology and TNM stage were important prognostic factors.And for node-positive rectal cancer,metastatic lymph node ratio was independent risk factors,which may be valuable for making multidisciplinary treatment protocols.PartⅡ:The expression of CD44v6 was an important prognostic factor for locally advanced rectal cancer.In node-positive rectal cancer,CD44v6 was an independent risk factor for predicting local recurrence.As all the patients in the study didn't had adjuvant radiotherapy,CD44v6 may be served as an important molecular marker for selecting patients with radiotherapy.PartⅢ:Gene expression profiling study by DASL technique was an prospective method in colorectal cancer.The score of genetic signature,derived from 8-gene signature,was an independent prognostic factor.The integrated risk factor,which combined genetic signature and TNM staging system together,was an more valuable prognostic factor than TNM staging system, which may confer better prediction for more individualized treatment.