Goldberg, R. M.

10022 Background: Patients with colon cancers displaying high frequency microsatellite instability (MSI-H) are reported to have a favorable prognosis compared to microsatellite stable (MSS) tumors. However, prognostic factors underlying this observation are poorly understood. We studied apoptotic and proliferative indices and their relationship to MSI status, clinicopathological features, and patient survival rates. Methods: Archival Dukes’ stage B2 (n=83) and C (n=246) primary colon adenocarcinomas from patients enrolled in five 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using a PCR-based assay (MSI-H: ≥30% of loci with instability), and expression of hMLH1, hMSH2 and p53 proteins by immunostaining. Apoptosis was analyzed by the TUNEL assay and the proliferative index (PI: S phase + G2M) and DNA ploidy by flow cytometry. Correlations between markers and associations with overall survival (OS) censored at 8 yrs were sought. Results: MSI-H (n=58.18%) tumors were more likely proximal, diploid, high grade, p53 negative (vs. MSS/MSI-L; all p<0.0001), and from women (p=0.002). Of 58 MSH-H cases tested, 54 showed loss of hMLH1 (n=50) or hMSH2 (n=4) proteins. Median proliferative index (PI) [12.6 vs. 17.4; p=0.0002] was reduced in MSI-H versus MSS/MSI-L tumors. Lower PI was associated with diploidy (p<0.0001) and negative p53 expression (p=0.003). Apoptotic indices (AIs) were increased in MSI-H cancers (vs. MSS/MSI-L, p=0.082), as was the AI/PI ratio (p=0.0065). Interestingly, AI (p=0.02) and AI/PI (p<0.0001) were significantly increased in diploid versus nondiploid tumors, and after removal of MSI-H cases, relationships held for PI and AI/PI with ploidy. Better OS was related to MSI-H (p=0.032), loss of hMLH1 or hMSH2 (p=0.024), diploidy (p=0.0015), and lower PI (p=0.078), but not AI, AI/PI, nor p53 (adjusting for stage, grade, treatment and stratifying by study). Conclusions: MSI-H tumors are characterized by reduced proliferative indices and a higher ratio of apoptosis to proliferation, reflecting slower tumor growth rates compared to MSS/MSI-L tumors. These features may contribute to their better survival. Lower PI and increased AI/PI are also features of diploid MSS cancers. [Table: see text]

3520 Background: This report examines UGT1A1*28, toxicity, and outcome in trial NCCTG N9741 patients (pts) receiving combination chemotherapy for advanced colorectal cancer. Methods: Blood samples were collected from 520 pts randomized between 2/18/00 and 7/18/02. Pts were treated with irinotecan/5-fluorouracil (5FU)/leucovorin (LV) (IFL, n=114), oxaliplatin/5FU/LV (FOLFOX, n=299), irinotecan/oxaliplatin (IROX, n=107). 19% of IFL pts received full-dose (125 mg/m2) irinotecan; the rest received a reduced dose (100 mg/m2). Toxicity was evaluated every cycle. Correlation of dichotomous outcomes and genotype status used Fisher’s exact tests. Univariate logistic regression was used to test the association between continuous variables and binary outcomes, including a test of trend, and multivariate logistic regression to adjust for known risk factors: performance status, age, gender. Time to progression (TTP) and overall survival (OS) were tested for association with UGT1A1 using the log-rank test. Statistical significance was prospectively set at .01 to control for multiple comparisons. Results: Frequency of UGT1A1 genotype was 44% 6/6, 42% 6/7, and 9% 7/7. In all arms, the rate of grade (G) 4 neutropenia (neut) ( Table ) and G3+ febrile neut (FN) was higher in pts with the 7/7 than in pts with 6/7 and 6/6. No association was seen between UGT1A1 and diarrhea, tumor response, TTP, or OS overall or for any treatment arm. The odds ratios for pts with 7/7 developing G4 neut and G3+ FN compared with pts with 6/6 are shown ( Table ). Statistically significant associations between the 7/7 polymorphism and G4 neut were seen in pts treated with IROX (P=.004) and in all pts (P=.007). The association between 7/7 and G3+ FN was also significant for IROX (P=.006). Conclusions: There is a higher risk of neut in 7/7 pts. Due to low frequency of the 7/7, exclusion of all pts with 7/7 reduces the overall G4 neut rate from 18% to 17%. UGT1A1 was not a predictor of response, TTP, or OS for any arm. [Table: see text] [Table: see text]