ABSTRACT
BACKGROUND & AIMS: Genomic instability in colon cancers is a consequence of chromosomal instability characterized by aneuploidy or defective DNA mismatch repair (MMR) indicated by microsatellite instability (MSI). Given that high-frequency MSI (MSI-H) and diploidy are correlated, we determined whether they are independent prognostic variables. METHODS: Astler-Coller stage B2 and C colon cancers (N = 528) from patients treated in 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for hMLH1, hMSH2, and p53 proteins was performed. DNA ploidy was analyzed by flow cytometry. Associations with disease-free and overall survival were determined. RESULTS: MSI-H was detected in 95 tumors (18%), and 70 (74%) of these were diploid. Tumors showing MSI-H (hazard ratio, 0.65; 95% confidence interval, 0.44-0.96; P = .023) or loss of MMR proteins (P = .024) were associated with better overall survival. Improved disease-free and overall survival were found for diploid versus aneuploid/tetraploid tumors (overall survival: hazard ratio, 0.59; 95% confidence interval, 0.43-0.79; P = .0003). In the subgroups of MSI-H and microsatellite stable (MSS)/low-frequency MSI (MSI-L) tumors, diploidy was associated with better survival. The prognostic impact of ploidy was similar in stage B2 and C tumors. Ploidy did not predict the benefit of 5-fluorouracil-based treatment. When ploidy, MSI, and MMR proteins were analyzed in the same multivariate model, only ploidy remained significant. CONCLUSIONS: DNA ploidy and MSI-H status were independent prognostic variables, yet ploidy was the strongest marker. Diploidy was associated with better survival in MSI-H and in MSS/MSI-L patient subgroups.
Subject(s)
Carcinoma/genetics , Colonic Neoplasms/genetics , DNA, Neoplasm/genetics , Microsatellite Repeats/genetics , Ploidies , Adaptor Proteins, Signal Transducing , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Carcinoma/metabolism , Carcinoma/pathology , Carrier Proteins/metabolism , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Female , Flow Cytometry , Humans , Immunohistochemistry , Male , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein/metabolism , Neoplasm Staging , Nuclear Proteins/metabolism , Prognosis , Survival Rate , Tumor Suppressor Protein p53/metabolismABSTRACT
PURPOSE: Colon cancer cells with high-frequency microsatellite instability (MSI-H) display resistance to 5-fluorouracil (5-FU) that can be reversed by restoring DNA mismatch repair (MMR) proficiency. Given that thymidylate synthase (TS) is inhibited by 5-FU, we studied the relationship between MSI and TS expression, and the prognostic effect of these and other markers (i.e., p53 and 17p allelic imbalance). EXPERIMENTAL DESIGN: Dukes' stage B2 and C colon carcinomas (n = 320) from participants in 5-FU-based adjuvant therapy trials were analyzed for MSI and 17p allelic imbalance. Expression of MMR (hMLH1, hMSH2), TS, and p53 proteins were analyzed by immunohistochemistry. Correlations between markers and associations with overall survival were determined. RESULTS: Of 320 cancers studied, 60 (19%) were MSI-H. TS expression variables were similar in MSI-H and microsatellite stable/low-frequency MSI (MSS/MSI-L) cancers, and unrelated to MMR proteins. MSI-H tumors had lower stage (P = 0.0007), fewer metastatic lymph nodes (P = 0.004), and improved overall survival (P = 0.01). Loss of MMR proteins was also associated with better overall survival (P = 0.006). None of the TS variables were prognostic. Histologic grade (P = 0.0008) and nodal status (P = 0.0002) were associated with overall survival, in contrast to 17p allelic imbalance or p53. Only MSI status or loss of MMR proteins, histologic grade, and tumor stage were independent markers for overall survival. CONCLUSIONS: MSI-H tumors show earlier stage at presentation and better stage-adjusted survival rates. MSI status and TS expression were unrelated and TS was not prognostic, suggesting that TS levels cannot explain therapeutic resistance to 5-FU reported in MSI-H colon cancers.
Subject(s)
Colonic Neoplasms/enzymology , Colonic Neoplasms/genetics , Genomic Instability , Microsatellite Repeats/genetics , Thymidylate Synthase/genetics , Antimetabolites, Antineoplastic/therapeutic use , Chemotherapy, Adjuvant , Colonic Neoplasms/drug therapy , Colonic Neoplasms/mortality , Colonic Neoplasms/surgery , Fluorouracil/therapeutic use , Humans , Immunohistochemistry , Neoplasm Staging , Prognosis , Survival Analysis , Survivors , Time FactorsABSTRACT
One of the challenges of interpreting a Quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) analysis is examining the sensitivity of conclusions that may be drawn to varying values of the utility coefficients for days with toxicity and days after disease progression. We present a graphic that parsimoniously displays the impact on median Q-TWiST survival across treatment groups of varying values of the utility coefficients. The goal of the graphic is to present a concise Q-TWiST analysis. We use Zhao and Tsiatis (Biometrika 1997; 84(2): 339-348) to adjust for the bias in Kaplan-Meier (K-M) estimates. The graphic contains bounds that approximate points for which statistical significance would be achieved by comparing the median Q-TWiST survival between treatment alternatives for each value of the utility coefficients. The plot may be generalized to compare Q-TWiST means, medians or percentiles across treatment groups. We demonstrate the application of the Q-TWiST plot through a re-analysis of a randomized phase III North Central Cancer Treatment Group (NCCTG) clinical trial of recombinant Interferon-2alpha in patients with malignant melanoma. We explore alternative options to customize the graphic representation for other data sets drawn from several NCCTG clinical trials.
