Model‐based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients

BACKGROUND: Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5‐fluorouracil–based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data. METHODS: TNM stage II and III colon carcinomas (n = 982) from 6 5‐fluorouracil–based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor‐infiltrating lymphocytes (TILs) were quantified (n = 326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status. RESULTS: Defective MMR was detected in 147 (15%) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3%; 13 of 468); proximal tumors had a greater likelihood (26%; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic = 0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51% for defective MMR. In a patient subset (n = 326), a model including proximal site, TILs (>2/high‐power field), and female sex showed even better discrimination (c statistic = 0.86), with a PPV of 81%. CONCLUSIONS: Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51% of tumors with defective MMR; substituting TILs for grade increases the PPV to 81%. These data can increase the efficiency of MMR testing to assist in clinical decisions. Cancer 2010. © 2010 American Cancer Society.