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.