Sha, Dan

4065 Background: Tumor infiltrating lymphocytes (TILs) and tumor budding (linked to epithelial mesenchymal transition) may influence metastatic potential and patient prognosis. We analyzed these features and their relative contribution to survival among low (T1-3 N1) and high (T4 and/or N2) risk groups, defined by the IDEA study, used to inform the duration of adjuvant chemotherapy in stage III colon cancer. Methods: Among 1,532 patients (low risk n=804; high risk n=728) treated in a phase III adjuvant trial of FOLFOX + cetuximab (x 6 months), intraepithelial TIL densities and tumor budding were quantified at microscopy in routine histologic sections. Optimal cutpoints were determined in association with 5-yr disease-free survival (DFS). Relative contribution of variables to DFS was calculated using χ2 from Harrell’s rms R package based on multivariable Cox regression models. Results: In the overall cohort, the tumor budding/TILs combined variable was more robust for predition of DFS than either alone. Budding/TILs was significantly associated with DFS in both low (HRadj, 1.59; 95% CI, 1.02-2.48; p=.0273) and high (HRadj, 2.82; 95% CI, 1.72-4.63; p<.0001) risk patients. We then determined its relative contribution (%) to DFS (Table). Among low risk, budding/TILs ranked second (24.4%) behind KRAS status (45.5%) and ahead of treatment arm (7.2%) and mismatch repair (MMR) status (6.1%). Among high risk, budding/TILs contributed the most to DFS (45.4%) followed by primary tumor sidedness (13.0%), performance status (12.0%), and MMR (10.4%). Conclusions: Tumor budding/TILs provides robust prognostic stratification by risk group to improve anatomic tumor staging. The relative contribution of budding/TILs to DFS was second only to KRAS status in low risk patients, and was the most important predictor of DFS in high risk patients. Evaluation in patients treated with 3 vs 6 mos of adjuvant chemotherapy is warranted. [Table: see text]

3564 Background: Lethal-7 (let-7) microRNA has been shown to inhibit colon cancer cell proliferation by inducing KRAS downregulation after binding to specific sites in the 3’- UTR. Recent studies identified a KRAS 3’-UTR polymorphism in the let-7 complimentary site (LCS6) that has been shown to weaken let-7 binding and alter KRAS expression. Carriers of the LCS6 G-allele showed worse survival in metastatic colorectal cancer from prior studies of limited sample size. In the current study, we evaluated the LCS6 variant in 2,834 Stage III colon cancer patients and its association with disease-free survival (DFS), KRAS mutation status, and other clinicopathological features. Methods: In the NCCTG phase III trial (N0147), the LCS6 variant was assayed in germline DNA extracted from whole blood using RT-PCR. Extracted tumor DNA was analyzed for KRAS exon 2 mutations. Chi-squared and two-sample t test were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed the unadjusted and adjusted associations between LCS6 status and DFS, respectively. Results: We identified 432 (15.2%) patients heterozygous or homozygous for the LCS6 G-allele and 2402 (84.8%) patients homozygous for the LCS6 T-allele. G-allele carriers were significantly more frequent in Caucasians than other races (Chi-Squared Test, p<0.0001). No associations were found between the LCS6 genotype and T stage, positive lymph node number, tumor differentiation, or primary tumor location (all p>0.2). Moreover, the LCS6 genotype was not associated with DFS (hazard ratio = 0.93, p=0.49) even after combining LCS6 genotype with KRAS mutation status. Conclusions: We report the largest association study investigating the LCS6 polymorphism and colon cancer outcome. There is no significant evidence that the germline LCS6 genotype was associated with DFS in stage III colon cancer patients. Additional studies are needed to determine if LCS6 genotype differs between tumor and germline DNA which may further clarify its prognostic value.

Abstract Abundant epidemiologic evidence indicates that regular and long-term use of aspirin is associated with a significant reduction in the incidence of colorectal cancer. The long duration of aspirin needed to prevent colorectal cancer is believed to be due to inhibition of precursor lesions known as adenomas, the recurrence of which is inhibited by aspirin in randomized trials. Aspirin intake has also been associated with a statistically significant improvement in patient survival after curative resection of colorectal cancer in large observational studies. In these cohorts, the survival benefit of aspirin was shown to depend upon the level of COX-2 expression in the primary colorectal cancer. More recent analysis of patient tumors from these observational cohorts suggests that the benefit of aspirin may be limited to specific molecular subtypes. Aspirin intake following colorectal cancer resection was associated with a significant improvement of survival in patients whose tumors carried mutant, but not wild-type, copies of the phosphoinositide 3-kinase (PI3KCA) gene, especially tumors that overexpressed COX-2. A mechanistic explanation is suggested by the finding that inhibition of COX-mediated prostaglandin E2 synthesis by aspirin attenuates PI3K signaling activity that is known to regulate cancer cell proliferation and survival. Aspirin has also been shown to reduce the incidence of colorectal cancers bearing wild-type, but not mutant alleles of the BRAFV600E oncogene. Although provocative, the potential utility of these molecular markers for predicting aspirin efficacy awaits prospective evaluation in clinical trials. If validated, these findings may support a personalized approach to using aspirin for the therapy of colorectal cancer. Clin Cancer Res; 20(5); 1087–94. ©2013 AACR.