DNA mismatch repair status and site of tumor recurrence in stage II and III colon cancers treated in 5-fluorouracil-based adjuvant therapy trials.

11093 Background: Defective DNA mismatch repair (MMR) results in microsatellite instability (MSI) and is detected in approximately 15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information in primary colon cancers. We sought to develop a model to predict MMR deficiency using clinically available data, and thereby facilitate patient selection for MMR or MSI testing. Methods: TNM stage II and III colon carcinomas (n= 982) were studied from six 5- fluorouracil-based adjuvant therapy trials conducted by the North Central Cancer Treatment Group. MMR status in tumors had been analyzed by MSI (using mono- and dinucleotide markers) or by immunohistochemistry for MMR proteins (hMLH1 and hMSH2). Logistic regression and a recursive partitioning and amalgamation (RPA) analysis was used to identify important predictive factors of MMR status. Factors explored included age, gender, histologic grade, tumor site, stage, lymph node metastases, and T-stage. Results: Defective MMR was found in147 (15%) cancers. Tumor site was the most important predictor of MMR status followed by histologic grade. Distal tumors had a low likelihood of defective MMR (3% rate overall; 13/468), whereas proximal tumors had a greater likelihood of defective MMR (26%; 130/506). For patients with proximal tumors, the addition of histologic grade and gender increased the prediction of defective MMR ( Table ). Using tumor site, histologic grade, and gender, the logistic regression model showed excellent discrimination (c- statistic = 0.81). Conclusions: Tumor site is an important predictor of defective MMR that is rare in distal and increased in proximal tumors. The combination of proximal site, poor differentiation, and female gender resulted in a 51% likelihood of defective MMR. Therefore, this model can facilitate the selection of sporadic colon cancers for MMR or MSI testing to enable its use in clinical decision-making. [Table: see text] No significant financial relationships to disclose.

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Detecting deficient DNA mismatch repair in stage II and III colon cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.419 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 419-419

Author(s):

F. Sinicrope ◽

P. Benatti ◽

N. R. Foster ◽

S. Marsoni ◽

G. Monges ◽

...

Keyword(s):

Logistic Regression ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Histologic Grade ◽

Stage Ii ◽

Lymph Node Status ◽

Tumor Site ◽

Dna Mismatch ◽

Colon Cancers ◽

Mmr Deficiency

419 Background: Deficient DNA mismatch repair (MMR) results in microsatellite instability (MSI) that is detected in ∼15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information. We developed a model to predict MMR deficiency using clinically available data, and thereby facilitate the selection of patient tumors for MMR testing. Methods: Data were utilized from stage II and III colon carcinoma patients (n = 2016) who participated in 5-fluorouracil-based adjuvant studies (NCCTG, FFCD, NCIC, GIVIO, NSABP) and an Italian cohort. MMR status in tumors had been determined by MSI testing or by immunohistochemistry for hMLH1 and hMSH2 proteins. Logistic regression and a recursive partitioning and amalgamation analysis was used to identify factors (histologic grade, gender, tumor site, stage, age, lymph node status, T-stage) predictive of MMR status. Results: Of the cancers, 357 (17.7%) showed deficient MMR. Tumor site was the most important predictor of MMR status followed by histologic grade, then stage (II vs. III) and then gender. Distal tumors had a low likelihood of deficient MMR (5% rate overall), whereas proximal tumors had a greater likelihood of deficient MMR (30%). For patients with proximal tumors, the addition of histologic grade and stage increased the prediction of deficient MMR (Table). Using tumor site, histologic grade, and stage, the logistic regression model showed excellent discrimination (c-statistic = 0.80). Conclusions: Routine clinicopathological data can facilitate the identification of MMR deficient cases. Tumor site and histologic grade were the strongest predictors of MMR deficiency. Within proximal, poorly differentiated tumors, stage was highly predictive. These findings suggest that our model can assist in selecting sporadic colon cancers for MMR testing for use in clinical decision-making, especially for stage II patients. [Table: see text] [Table: see text]

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