Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Abstract

BACKGROUND. The heterogeneity of stage II colon cancer underlines the need for identifying high‐risk, lymph node‐negative patients. The objective of this study was to define a multimarker prognostic model of 5‐year survival in patients with lymph node‐negative, mismatch repair (MMR)‐proficient colorectal cancer (CRC). METHODS. Immunohistochemistry for 13 tumor markers was performed on 587 lymph node‐negative, MMR‐proficient CRC samples by using a tissue microarray. Immunoreactivity was evaluated semiquantitatively. A receiver‐operating characteristic‐based approach was used to detect clinically relevant tumor markers and to determine cutoff scores for tumor positivity. Univariate and multivariate analyses stratified by pathologic T3 (pT3) or pT4 tumor classification were performed. RESULTS. In univariate analysis, the absence of CD8+ tumor infiltrating lymphocytes (TILs) (P < .001), loss of p27 (P = .006), positive urokinase‐type plasminogen activator (uPA) expression (P = .002), and positive uPA receptor (uPAR) expression (P = .037) were associated with an adverse prognosis. In multivariate analysis, CD8 (P = .001), p27 (P = .031), and uPA (P = .014) were independent prognostic factors. The multimarker phenotype of negative CD8, loss of p27, and positive uPA expression led to significantly worse survival compared with all other combinations of these features. Stratified by pT3 or pT4 stage, CD8 (P = .006) and uPA (P = .011) had independent prognostic value. Combined CD8 negativity and uPA positivity led to a more adverse prognosis in both patients with pT3 tumors and patients with pT4 tumors (P < .001). No difference was observed in the length of survival between patients with pT3 tumors who had CD8 negativity and uPA positivity and patients with pT4 tumors (P = .267). CONCLUSIONS. The multimarker phenotype of the absence of CD8+ TILs, loss of p27, and positive uPA expression was predictive of an adverse prognosis in patients with lymph node‐negative, MMR‐proficient CRC. The current findings suggested that a subgroup of patients with high‐risk, lymph node‐negative pT3 tumors should be considered for adjuvant therapy. Cancer 2008. © 2007 American Cancer Society.

Local Recurrence in Mismatch Repair–Proficient Colon Cancer Predicted by an Infiltrative Tumor Border and Lack of CD8+ Tumor-Infiltrating Lymphocytes

“…The inherent abundance of TILs in microsatellite instability-high colorectal cancers as well as the less frequent occurrence of tumor budding in these patients again underlines the possible role of tumor immunity in conferring an improved prognosis in colorectal cancer. We have also highlighted previously the importance of CD8 + TILs in improved survival in patients with MMR-proficient nodenegative colorectal cancer (22). In this study, an infiltrative tumor margin and absence of CD8 + TILs were highly predictive of local recurrence in patients with MMR-proficient colon cancer.…”

“…Positivity for all three markers was required for the tumor to be considered MMR proficient (20). Immunostaining protocols have been detailed elsewhere (21,22). Evaluation of immunoreactivity for all tumor markers was done semiquantitatively by assessing the proportion of immunoreactive tumor cells over the total number of tumor cells per tissue microarray punch resulting in scores from 0% to 100%.…”

CD133 expression predicts for non-response to chemotherapy in colorectal cancer

“…The good prognosis associated with p27 expression confirms previous reports with this marker. 28 The major finding of this study was that colorectal cancers with the CD133 þ immunophenotype show resistance to 5-fluorouracil-based chemotherapy. Two separate lines of evidence were obtained in support of this.…”

Expression of p16 in lymph node metastases of adjuvantly treated stage III colorectal cancer patients identifies poor prognostic subgroups

“…To date, this goal largely has not been reached, although a series of markers has been associated with a greater probability of observing lymph node metastasis and has sparked interest as a possible indicator of poor outcome in patients with lymph node-negative disease. [11][12][13][14][15] Prognostic biomarker studies in colorectal cancer clearly focus on the expression of proteins in primary tumor and correlating that expression with clinical endpoints. However, to date, very few reports have focused on the comparison of protein markers between primary tumor and corresponding lymph nodes, 16 and a systematic evaluation of prognosis based on lymph node expression of protein markers has yet to be performed.…”