URINARY BLADDER CANCER RECURRENCE AND EXPRESSION OF LYNCH AND HER MARKERS: SEARCHING FOR IMMUNOHISTOCHEMICAL PATTERNS AMONG 113 TUMORS FROM 33 PATIENTS

The aim was to identify immunohistochemical (IHC) markers able to predict recurrence of urinary bladder tumors. The method of multivariate adaptive regression splines (MARS) was applied to IHC data of 33 patients with urinary bladder cancer that relapsed one to six times (24 male and nine female, age 57-87 years). The MARS analysis was used to predict the total number of recurrences and the Ki-67 value by nine IHC markers (epidermal growth factor receptor (EGFR), HER2, HER3, E-cadherin, Ki-67, MLH1, MSH2, MSH6 and PMS2). Data were divided as initial tumors, first and subsequent recurrences, and tumors that relapsed within nine months of previous surgery or later. The IHC markers were semiquantitatively classified into four groups, as follows: 0 means no positive cells; 1, 10% of positive cells; 2, 11%-30% of positive cells; and 3, 31%-100% of positive cells. In predicting the overall number of recurrences, as a surrogate marker of tumor biology, the R(2) value for all tumors was 0.423, for initial tumors 0.686, for first recurrence 0.700, and for subsequent recurrences only 0.233. The key predictors for initial tumors were HER2 and MSH2, while for the first recurrence it was EGFR. For quick recurrences (within nine months), the R(2) was 0.474 with EGFR and HER3 as predictors, while for slow recurrences R(2) was 0.640 due to EGFR and PMS2. In predicting the Ki-67 value of that tumor, the R(2) value for all tumors was 0.300, for initial tumors 0.262, for first recurrence 0.360, and for subsequent recurrences only 0.533. The key predictors for first recurrences were EGFR and MSH6, and for subsequent recurrences HER2, EGFR and all Lynch markers. The R(2) was 0.266 for quick recurrences and 0.370 for slow recurrences. The finding of E-cadherin was not found relevant by any of these MARS models. In conclusion, the MARS results associated multiple IHC markers with the number of recurrences and with Ki-67 values. It is important that differences in predictive markers were found between initial tumors and first recurrences, and between quick and slow recurrences, thus suggesting that tumor biology is different among these subgroups regarding the total number of recurrences and Ki-67 values.