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4089 Background: Consensus molecular subtypes (CMS) categorize colorectal cancer (CRC) into groups based on gene transcription and are prognostic in early-stage and first-line metastatic settings. Their impact on treatment history is unknown. We hypothesized that the best prognosis CMS2 would have higher utilization of liver-directed therapies and maintenance chemotherapy over the worst prognosis CMS4. Methods: Primary surgical resection specimens were annotated for CMS on a translational protocol in a 5FU-refractory metastatic CRC population. Specimens that had neoadjuvant chemotherapy or radiation were excluded. CMS1, CMS3 and indeterminate CMS were also excluded. Liver-directed therapies were defined as any surgery, direct injection of cytotoxics or microspheres, radiation or radiofrequency ablation. Multiple occurrences of liver-directed therapies or maintenance chemotherapy in the same patient were recorded once for statistical tests of association. Results: CMS1 (7.4%), CMS3 (8.2%) and indeterminate calls (4.1%) accounted for 20% of all samples tested. There were 43 (44%) CMS2 and 55 (56%) CMS4 patients eligible. Age, stage at diagnosis, mismatch repair and RAS mutational status were similar in both groups. Left-sided tumors were more common in CMS2 (79%) than CMS4 (42%), p = .001. The median overall survival (OS) from stage IV diagnosis was 40 [34 - 51] versus (vs) 28 [21 – 33] months (p < .0001) for CMS2 vs CMS4 respectively. Liver-directed therapy was greater in CMS2 (53%) vs CMS4 (31%), p = .024. The number further increased when multiple treatments in a single patient were taken into account. Microsphere injection, radiation and liver surgery combined with RFA were the most skewed towards CMS2 over CMS4. No difference in median OS was seen from first liver-directed therapy in CMS2 vs CMS4 (29 vs 27 months, p = .31). There was a trend towards greater maintenance chemotherapy in CMS2 (47%) vs CMS4 (29%), p = .076. Conclusions: Better prognosis with CMS2 is consistent with other studies. Significantly increased liver-directed therapy was observed in CMS2. Selection criteria for liver-directed therapy such as slowly progressing, oligometastatic and hepatic-confined disease may be enriching for CMS2 and gives insight into the natural history of this subtype.

Background Adenomas and serrated lesions represent heterogeneous sets of early precursors in the colorectum with varying malignant potential. They are often distinguished by their histopathologic differences, but little is known about potential differences in regulation of epithelial proliferation and apoptosis. Methods We conducted a protein expression analysis using tissue microarrays of 625 colorectal adenomas and 142 serrated lesions to determine potential differences in regulation of epithelial proliferation and apoptosis. We quantitated proliferation with Ki-67; apoptosis with activated caspase-3 (CASP3); up- and down-regulators of proliferation with cyclin D1, p16INK2, and p21Cip1; and apoptosis regulators with BAX, BCL2, and survivin. Linear mixed effects models and circos diagrams were used to determine relationships among expression and lesion characteristics. Results Adenomas had a significantly higher CASP-3 labeling index (LI) than serrated lesions, resulting in a lower net growth ratio (Ki-67 LI/activated CASP-3 LI, p-value<0.0001). Cyclin D1 LI, p16 LI and p21 LI were lower in adenomas compared to serrated lesions, while expression of both BCL2 and BAX were higher (p <0.001). Among adenomas, cyclin D1 LI and p16 LI levels increased with greater villous component, and the highest BAX expression was detected in adenomas larger than 2 cm (both p<0.0001). Right-sided adenomas had higher CASP3 LI than left colorectal adenomas (p = 0.008). Significant differences in cyclin D1 LI, p21 LI and survivin LI were also observed across histopathologic subtypes of serrated lesions. Conclusions Our findings demonstrate different patterns of regulatory protein expression in adenomas than serrated lesions, especially involving apoptosis. ClinicalTrials.gov Identifier: NCT00272324

606 Background: Colorectal signet ring cell carcinoma (SRCC) has been shown to be associated with advanced tumor stage at presentation and worse outcomes. Due to the rarity of this subtype, 1% of all colorectal adenocarcinoma (CRC), little is known about its molecular characteristics. We aimed to characterize the molecular alterations of this subgroup. Methods: Metastatic CRC (mCRC) patients (pts) with signet ring cell (SC) histology who had tumors evaluated with next generation sequencing between February 2009 and November 2015 were reviewed. SC mCRC were classified into 2 groups; SRCC (>50% of signet cells) and adenocarcinoma (AC) with SC component. Genomic alterations, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) status noted in SC mCRC were compared to non-SC mCRC pts from the Assessment of Targeted Therapies Against Colorectal Cancer program at MD Anderson Cancer Center using Pearson’s χ 2 test. Results: A total of 665 mCRC pts were included in this study. 93 pts (14%) had SC histology of which 30 (32.3%) pts were SRCC. The Table below shows key cancer genes mutation frequencies. Conclusions: Colorectal SRCC has distinct molecular features compared with non-SC and AC with SC component CRC. The frequencies of KRAS, PIK3CA and APC mutations were lower than the frequencies reported in non-SC CRC. SRCC was not associated with MSI-H or CIMP-H tumor in this study. Further studies on identification of activated pathways underlying this worse prognosis and potential therapeutic targets are required. [Table: see text]