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PURPOSE: In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. MATERIALS AND METHODS: Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. RESULTS: MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. CONCLUSION: Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

Abstract Background: Cetuximab, an EGFR inhibitor used to treat multiple cancer types, including colon cancer, causes severe skin toxicity in 5%–20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity. Methods: Our study included 1,209 patients with stage III colon cancer randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating approximately 10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade ≥ 3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as P < 5 × 10−8. Results: Participants were predominantly middle-aged white men; 20% (n = 243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity [OR, 3.93; 95% confidence interval (CI), 2.47–6.25; P < 7.8 × 10−9]. Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions. Conclusions: Identified variants could represent a potential target for risk stratification of patients with colon cancer receiving cetuximab. Impact: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.

11088 Background: Obesity is associated with an increased risk of colon cancer. However, the influence of body mass index (BMI) upon the prognosis of patients with established colon cancer remains unknown. Methods: We conducted a retrospective study of 1,803 patients with surgically resected stage III colon cancer who were enrolled in five randomized trials of 5-fluorouracil-based adjuvant chemotherapy conducted by the North Central Cancer Treatment Group. Patient height and weight were recorded at study entry and BMI (kg/m2) was calculated and categorized. Cancer recurrence or death were monitored during 5 years of follow-up. The score and likelihood ratio p-values were determined from univariate and multivariate Cox regression models respectively, after stratifying by study. Results: Among stage III colon cancer patients, 19% were obese (BMI 30 kg/m2), 37% were overweight (BMI, 25 to 29.9 kg/m2), 38% were of normal-weight (BMI, 20 to 24.9 kg/m2), and 6% were underweight (BMI < 20 kg/m2). Obese versus normal-weight patients showed higher rates of lymph node (LN) metastasis (>3 LNs; 38% vs. 29%, p <0.01) and tumor site was more likely to be distal versus proximal (52% vs. 45%, p= 0.03). No differences in age, gender, or histologic grade were found. In a univariate analysis, obese patients had significantly worse disease-free survival (DFS) compared with normal-weight patients (hazard ratio 1.25 (95% CI: 1.04 -1.51; p= 0.02). The 5 year DFS rates were 49% in obese patients versus 57% in normal weight subjects. Furthermore, poorer DFS was observed for obese patients after adjusting for age, sex, histologic grade, and tumor site (p= 0.03). Neither overweight nor underweight patients (vs. normal-weight) had significantly different DFS. Analysis of the predictive impact of BMI for 5-FU-based adjuvant therapy is in progress. Conclusions: Obesity (BMI 30 kg/m2) was associated with a greater number of metastatic lymph nodes and poorer disease-free survival in patients with stage III colon cancer, suggesting that obesity influences tumor progression. No significant financial relationships to disclose.

4627 Background: E4201 compared radiation and gemcitabine (RT+Gem) versus Gem alone in LAPC. The primary endpoint was overall survival; secondary objectives included: objective response rate (RR), progression-free survival (PFS), toxicity and QOL. We previously reported that RT+Gem was associated with improved overall survival compared with Gem alone [median survival time, 11 months and 9.2 months, respectively; p=0.034], without impact in RR or PFS. (ASCO 2008, abstract # 4506). We now report on QOL as measured by the Hep subscale from the FACT-Hepatobiliary [FACT-Hep] between both arms. Methods: Eligible patients had LAPC adenocarcinoma, PS <2, without prior therapy. They were randomized to Arm A: Gem alone (1,000 mg/m2/week x 3, every 4 weeks, 7 cycles), or Arm B: RT (50.4Gy/28 fractions) plus Gem (600 mg/m2/weekly x 6) followed by 5 cycles of Gem alone (1,000 mg/m2/weekly x 3 every 4 wks). The FACT-Hep was administered at baseline (before starting induction), 6 weeks (immediately after completing induction), week 16 (Arm A) or week 15 (Arm B) mid-consolidation, and at 9 months. Results: From April, 2003 to December, 2005, 74 patients were enrolled, 71 were eligible [37 Arm A; 34 Arm B]. Grade ≥3 was reported in 80% and 82.4% in ARM A and B, respectively (p=1.00). Grade IV toxicities, mainly gastrointestinal and hematologic, were more common in ARM B (41.2% vs 5.7%, p=<0.0001). QOL compliance declined over time, most commonly attributable to either patients or staff choosing not to complete or administer the instrument due to declining health (96%, 69%, 60%, and 40% at baseline, week 6, 15/16 weeks and 9 months, respectively). Within Arm B, QoL scores dropped significantly from baseline to 6 weeks. By week 15, QoL scores for patients on Arm B rebounded to levels similar to baseline. Two-sided Wilcoxon rank sum tests failed to suggest differences in median FACT-Hep subscale score between treatment arms at any of the four time-points (alpha = 0.10). Conclusions: RT+Gem is associated with an overall survival benefit without apparent long term adverse impact on QOL when compared with Gem alone. No significant financial relationships to disclose.

4044 Background: To aid in decisions regarding adjuvant therapy (AT) for resected high-risk CC, two prog models are in common use: the Mayo Clinic NUM calculator developed from a pooled data analysis of 7 randomized 5FU-based AT trials, and ADJ! developed using SEER data. This study examines the accuracy of NUM and ADJ! utilizing a cohort of patients (pts) referred to the BC Cancer Agency (BCCA). Methods: Demographic, disease and treatment data for pts with stage II/III CC referred to the BCCA from 1995–1996 + 1999–2003 were collected. Observed (obs) 5-year relapse free survival (RFS) and overall survival (OS) were compared to predicted estimates (pred) using NUM and ADJ!, both overall and for all prog subgroups with ≥ 10pts, as stratified by T stage, N stage, tumor grade and age. Data are presented in a descriptive manner and using confidence intervals. Results: Median follow-up was 5.6 yrs for 2,033 pts - 53% male, median age 68y, 40% N0. The mean percentages of 5 year pred outcomes for each of the two models and the actual Kaplan Meier mean survivals are presented in the table . The percentage correct predictions of 5 y status is also presented, with correctness deemed accurate if the pt was alive and predicted to be alive by ≥ 50% as determined by each model or dead while the respective tool predicted < 50% possibility of being alive. For surgery alone pts, ADJ!pred were more often closer to what was observed, as compared to NUMpred, in the prog subgroups (for RFS 56%, OS 88%). For surgery + 5-FU pts, within these subgroups, NUMpred were more often closer to what was observed, as compared to ADJ!pred, for RFS (62%) and for OS (55%). Conclusions: In this independent population-based validation, NUM and ADJ! have acceptable and similar reliability with modest over-estimations of 5y RFS and OS. Both models thus appear to be useful adjuvant decision-aids. [Table: see text] No significant financial relationships to disclose.

e15031 Background: Two web based prognostic calculators, Adjuvant! and Numeracy (JCO 22:1797–1806, 2004) are widely used to provide individual patient outcome predictions to aid decisions regarding adjuvant therapy for colon cancer. The comparability of these tools has not been studied yet. The aim of this project was to assess whether the Numeracy and Adjuvant! Colon cancer prognostic tools produced similar results for patients with resected stage II and III colon cancer based on a set of hypothetical patients. Methods: All possible hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were applied to three post- surgical therapy choices: observation, 5-FU (5-fluorouracil), or FOLFOX (5-FU, leucovorin and oxaliplatin). Predictions for these hypothetical scenarios (N= 192 for males and 192 for females) were also entered into the Adjuvant! Program. Predicted relapse free survival (RFS) and overall survival (OS) were obtained using both calculators. Wilcoxon signed rank tests were used to compare the numerical predictions between the calculators for each outcome. Results: In the majority of the 384 hypothetical patient scenarios, predictions for RFS and OS from Adjuvant! were statistically significantly higher than from Numeracy (p value < 0.05), except for age≥70 for FOLFOX, and the number of positive nodes of 0 and 1–4 using FOLFOX, among males. The net estimate of benefit for RFS and OS for 5-FU over surgery, obtained from Adjuvant! and Numeracy, were similar (for both males and females), but the benefit in RFS and OS for FOLFOX over 5-FU obtained from Adjuvant! was significantly lower than the estimate obtained from Numeracy (p value < 0.05). Conclusions: Based on a hypothetical set of patients with resected stage II and III colon cancer, the estimated benefit in RFS and OS of FOLFOX over 5-FU based chemotherapy is lower in Adjuvant! than in the Numeracy tool (but benefit for 5-FU over surgery alone is similar). Further studies are needed to clarify the discrepancy and to assess which of these tools most accurately reflects actual patient outcome. No significant financial relationships to disclose.

Abstract Background Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. Methods The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). Results Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P &lt; .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P &lt; .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P &lt; .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P &lt; .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P &lt; .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P &lt; .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P &lt; .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P &lt; .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P &lt; .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P &lt; .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P &lt; .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P &lt; .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P &lt; .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P &lt; .001]) were observed, with women being consistently at increased risk. Conclusions Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

4099 Background: Colorectal cancer (CRC) incidence and mortality has decreased since the 1970s but the incidence is increasing in young adults (age 20-49). The incidence of early onset CRC (eoCRC) will keep increasing significantly based on the trends of the SEER CRC registry data. There is limited data suggesting eoCRC may have different behaviors compared to traditional CRC (tCRC, age ≥ 50). Methods: Individual pt data of 47184 stage II/III CRC pts from 25 randomized studies in the ACCENT database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and treatment-related data were summarized by age group. Overall survival (OS), disease-free survival (DFS), recurrence-free rate (RFR), and survival after recurrence (SAR) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for stage, performance status (PS), BMI and grade. Results: Using 5% difference between age groups as clinically meaningful cutoff, eoCRC had similar gender, race, ethnicity, PS, risk group, disease sidedness and T stage as tCRC. eoCRC were less likely overweight (30 vs 36%) and more pts had ≥ 12 lymph nodes resected (63 vs 51%). eoCRC had more frequent dMMR status (18 vs 12%), less BRAF mutations (5 vs 13%), and more dMMR/BRAF wild type (WT) status (17 vs 7%). Overall, eoCRC had better OS, DFS, and SAR, with the most significant differences between the < 30 and > = 70 age groups. Similar results were observed within pMMR pts. eoCRC experienced less hematological side effects, diarrhea, and stomatitis, but had more nausea and/or vomiting. Conclusions: eoCRC have unique characteristics; although statistically significant, the clinical differences in outcomes between eoCRC and tCRC are potentially due to the difference seen in extremely young and old pts. eoCRC have a different adverse events panel compared to tCRC. [Table: see text]

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]

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial