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4012 Background: Identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) other than for N1c designation. The aim of this study was to determine the prognostic impact, beyond AJCC N1c designation, of TD among primary CRC patients. Methods: Patients with stage 1 to 3 primary CRC diagnosed between 2010 and 2015 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Cancer specific survival (CSS) stratified by TDs and nodal status was calculated, and Kaplan-Meier method and multivariable COX proportional hazards regression analyses were performed. Results: A total of 74,494 patients with primary CRC were identified. Mean age was 66.4 (SD+/-13.2) years, 36,988 (49.7%) were female and 40,651 (54.6%) were right-sided. TDs were present in 4,481 patients (6.0%) and 26,603 (35.7%) had lymph node metastases. The presence of TDs were significantly associated with adverse tumor characteristics including advanced pathological stage, nodal and metastasis status, higher grade and perineural invasion. Incorporating TDs into each nodal status was independently associated with worse CSS and supported reclassification of nodal status to incorporate TDs following multivariable regression analysis as outlined in the table. Following multivariable regression analysis, the proposed AJCC nodal reclassification incorporating TDs, in combination with tumor stage was a strong predictor of CSS, and also represents a new summary staging. Conclusions: TDs are an independent predictor of worse outcome in CRC. The presence of TDs have distinctly different CSS and these data support modification of the current N classification. This study proposes a reclassification of the AJCC system for CRC to incorporate TDs and informs an updated node and summary stage. [Table: see text]

3592 Background: Lynch-like syndrome (LLS) is characterized by a diagnosis of mismatch repair deficient (dMMR) malignancy where somatic bi-allelic mutations in canonical MMR pathway genes ( MLH1, MSH2, MSH6, PMS2) have been identified as the main cause. Yet, a substantial proportion of cases remain unexplained by MMR somatic bi-allelic events or germline mutations. We hypothesize that LLS cases with young-onset cancers carry cryptic germline alterations in other pathways. To explore this contribution, we performed analyses of the germline and tumor mutation landscapes in LLS patients diagnosed with dMMR cancers. Methods: 18 probands with young-onset (age

298 Background: Appendiceal adenocarcinomas (AAs) are orphan tumors. Little is known about their molecular profile limiting understanding of their biology and development of novel targeted therapies. The purpose of this study was to delineate the molecular landscape of AAs. Methods: We performed a retrospective review of AAs patients (pts) who were evaluated at MD Anderson Cancer Center between October 2012 and April 2017 and underwent next-generation sequencing (NGS) with internal or external assays (at least 45 genes) using either tumor tissue specimens or peripheral blood for circulating cell-free DNA (cfDNA). The primary outcome was to assess the prevalence of genomic alterations (GAs) in AAs. We then performed comparative exploratory analyses of GAs using TCGA colorectal cancer (CRC) sequencing. Results: A total of 78 patients were identified of which 57 (73%) and 18 (23%) underwent tissue based and ctDNA based sequencing, respectively (3 cases had both). At least 1 GA was found in 61 (78%) of AA specimens, with a mean (SD) of 2.8 (1.6) GAs per case. Of these 44 (72%) had ≥ 2 GAs and 31 (51%) had ≥ 3 GAs. The most frequent GAs were KRAS (38 [62%]), TP53 (22 [36%]), GNAS (17 [28%]), SMAD4 (11 [18%]), PIK3CA (10 [16%]), APC (9 [15%]), ATM (8 [13%]), BRAF (5 [8%]), KIT (5 [8%]), NRAS (3 [5%]) and MET (3 [5%]). GNAS mutations frequently co-occurred with KRAS mutations (42% v 5%, OR 14.3, P < 0.001). No GA was associated with grade, mucinous histology or overall survival (OS). Besides these mutations, we also found unusual cases with targetable mutations such as ALK, EGFR, MET, IDH1 and ERBB2. In our comparative analyses, mutations in KRAS (p = 0.009), TP53 (p = 0.020), GNAS (p < 0.001) and APC (p < 0.001) genes were significantly different from CRC whereas there was no difference in prevalence of PIK3CA, SMAD4 and ATM genes. Conclusions: To date, our analysis of one of the largest cohorts of AAs, demonstrate a majority of AAs harbor at least 1 GAs. Although treatment paradigms in AAs are extrapolated from CRC, the molecular profile of these tumors differs significantly. Molecular characterization of these rare tumors is a necessary first step towards discovery of opportunities for use of targeted therapies in these patients.

650 Background: Peritoneal mesothelioma (PeM) is an orphan disease with approximately 300-400 cases diagnosed in the United States each year. Due to its rarity, data on its presentation and prognostic factors is limited. The purpose of this study was to investigate the clinicopathological profile and outcome of Malignant PeM (MPeM). Methods: We retrospectively reviewed 128 PeM patients (pts) seen at UTMDACC (2011 - 2017) comprised of 111 MPeM and 17 variants (VPeM) [9 well-differentiated papillary and 8 multicystic]. Kaplan-Meier method was used to estimate median overall survival (mOS) and compared with log-rank tests. Results: Median age at diagnosis was 57 yrs. with a higher proportion of women (61%). The mOS for MPeM was significantly shorter than VPeM (HR 3.7, 95% CI: 1.6 – 8.4, P = 0.002). Among pts with MPeM, median age at diagnosis was 56 yrs. and 58% were women. Only 22% had prior exposure to asbestos. Epithelioid subtype was seen in 94 (85%) pts. Calretinin and WT-1 IHC were positive in 98% and 96% of cases. BerEP4 and MOC-31 IHC were negative in 90% and 84% of cases. After median follow-up of 31 months (m), the mOS for MPeM cohort was 78 m. In univariate analysis, age, prior asbestos exposure, ECOG PS, histologic subtype, CA125, neutrophil-lymphocyte ratio (NLR) and cytoreductive surgery (CRS) were found to be associated with OS. In multivariate analyses, age ≥ 65 years (HR 4.5, 95% CI: 1.3 - 15.2, P = 0.02), prior asbestos exposure (HR 4.1, 95% CI: 1.1 – 15.6, P = 0.04), poor PS (ECOG 2/3) (HR 8.9, 95% CI: 1.7 – 47.7, P = 0.01), elevated CA125 ( > 3X upper limit of normal) (HR 4.5, 95% CI: 1.3 – 15.5, P = 0.02), and high NLR (HR 3.8, 95% CI: 1.1 – 12.6, P = 0.03) were found to be independently associated with poor OS. A total of 50 (45%) pts underwent CRS and among these the completion of cytoreduction score (CCS) was strongly associated with OS (mOS: 201 m, 53 m and 36 m for CCS 0, 1, 2/3, respectively, P = 0.005). Conclusions: MPeM is associated with poor survival outcomes. Prognostic factors include age, history of asbestos exposure, CA-125 level, NLR, and PS. CRS with CCS 0 results in favorable survival. Further understanding of molecular genetics is warranted to improve prognostication and outcomes.

773 Background: Histological grade is a key prognostic factor in appendiceal adenocarcinomas (AAs) and has been incorporated in classification of stage IV AAs (IVA – Grade 1: Well; IVB – Grade 2/3: Moderately/Poorly differentiated) in AJCC Cancer Staging (8th edition). The purpose of the study was to corroborate the prognostic impact of this staging classifier. Methods: We performed a retrospective review of 98 AA patients (pts) at UTMDACC (2013 - 2017). Kaplan-Meier method was used to estimate median overall survival (mOS), compared with log-rank tests with emphasis on stage and grade. Results: The cohort included 18, 8, 14, 47 and 11 cases of stage II, III, IVA, IVB and IVC AAs. Histologically, 75 were mucinous (21 non mucinous) and 19, 35 and 42 were grade 1, 2 and 3 respectively. Median age of cohort was 54 years. Median follow-up was 46 months (m). The mOS of stage II, III, IVA, IVB and IVC was 136, 106, 140, 48, 23 m, respectively (P < 0.0001). The mOS of grade 1, 2 and 3 was 160, 75 and 33 m, respectively (P < 0.0001). In univariate analysis (restricted to stage IV pts), grade, AJCC stage, and cytoreductive surgery (CRS) were found to be associated with OS. In multivariate analyses (restricted to stage IV pts), only AJCC stage (HR 3.9, 95% CI: 1.5 - 10.6, P = 0.005) and CRS (HR 3.4, 95% CI: 1.4 – 8.3, P = 0.009) were found to be independently associated with poor OS. In subgroup of mucinous AAs, mOS of grade 3 (32 m) was significantly shorter than grade 2 (54 m) (P = 0.02). In non-mucinous AAs, mOS of grade 3 and grade 2 pts was 38 and 29 m, respectively (P = 0.97). Conclusions: AJCC staging classification has a strong prognostic value in AAs. Beyond the well differentiated AAs which are regarded as a distinct entity in stage IV disease, moderate and poor differentiation also has strong and dissimilar prognostic impact which appears to be dependent on mucinous or non-mucinous subtype in stage IV AAs. Further efforts are needed to incorporate the complex interplay of all grades and mucinous characteristics within the staging system for better prognostication and management.

3605Background: Response to nCRT is a key prognostic indicator for rectal cancer and may be influenced by the systemic inflammatory response. The purpose of this study was to determine the relation...

1525 Background: Universal testing of resected CRC for Microsatellite Instability (MSI) status has been widely advocated. While PCR-based MSI analysis is the current gold standard test, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is more commonly performed. At present, it remains un-established whether PCR-based MSI analysis remains reliable when performed on post-neoadjuvant treated specimens. Our goal was to examine the effect of neoadjuvant therapy on MSI analysis using both in vitro and clinical data. Methods: MSI analysis was performed using the standard panel of 7 markers. In vitro, MMR deficient (HCT116) and proficient (HCT116+Ch3) isogenic cell lines were exposed to 3 cycles of single agent 5-Fluorouracil, Oxaliplatin and Irinotecan and MSI analysis was tested after each cycle. To evaluate the induction of genomic instability, 3 additional coding microsatellite tracts in ATR, BLM and CHK1 were assessed by fragment analysis. In parallel, clinical data from 238 CRCs that were resected after neoadjuvant chemoradiation (n=191) or chemotherapy (n=47) between 9/2009 and 8/2011 were queried for MSI results. MSI analysis performed on paired pre-treatment and post-treatment resection tissues was compared. Results: No changes in MSI status were detected and there was no increase in genomic instability post-treatment in cell line models. In the clinical setting, pre-neoadjuvant MSI testing was limited by the availability of pre-treatment biopsy tissue. 3 patients found to be MMR proficient based on MSI analysis performed on pre-treatment biopsy remained microsatellite stable when analyzed on post-treatment resection tissue. 7 patients were MMR deficient based on MSI analysis performed on post-treatment resection tissue but most had strong clinical evidence to expect MMR deficiency. Conclusions: Based on both preclinical in vitro and clinical data, results of the MSI analysis does not appear to be affected by neoadjuvant therapy for both MMR proficient and deficient cases. In addition, preclinical results do not suggest that neoadjuvant chemoradiation induces an increase in genomic instability. Therefore, MSI analysis remains a reliable gold standard test on post-treatment specimens.

4134 Background: AA is a rare malignancy ranging from well-differentiated to poorly differentiated carcinoma, including those with signet ring cells. Optimal therapy for low grade peritoneal disease is cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC). However, some patients (pts) are suboptimal for CRS/HIPEC, and are considered for systemic chemotherapy (SC) alone, or SC + CRS. In light of our previously reported overall survival (OS) benefits for the role of SC in metastatic AA, here we explore the impact of surgical intervention on OS in these pts. Our aim was to clarify the OS benefit of multidisciplinary therapy (SC + CRS + HIPEC) in those pts with aggressive tumor biology. Methods: A retrospective chart review of AA pts registered in our tumor registry between Jan. 2005 to Dec. 2009 was undertaken to identify patients with AA who received SC. Electronic medical records (EMR) were reviewed for CRS, HIPEC, histology, SC, and OS. The K-M method and Log-Rank test were used for statistical analysis. Results: Of 143 AA pts, 52 (36%) pts were high grade with 33 (23%) having signet ring cells. After a median follow-up of 35M, high grade tumors were noted to have worse OS overall (24M vs 56M, p

199 Background: The natural history, clinical presentation, and impact of cytoreductive surgery (CRS) or systemic chemotherapy for high grade MAA has been poorly studied. Methods: A retrospective chart review of patients (pts) with moderate or poorly differentiated AA was completed from 1994-2010. Radiographic response was assessed semi-quantitatively form physician records and complete cytoreductive surgery (CRS) was defined as a completeness of cytoreduction score of 0 or 1. For CRS and chemotherapy subgroups efficacy endpoints were calculated from date of CRS or first chemotherapy dose, respectively. Results: 288 (136 moderate and 152 poor grade) pts were identified with a median age of 52 years (range: 25-82). Mucinous histology was present in 110 pts (38%) and differed by grade: 55% of moderate and 23% of poor. Stage IV presentation (n=163) occurred in 76% of poor grade but only 35% of moderate grade. Both median OS (4.5 vs. 2.7 yrs, P=0.04) and median OS for the stage IV subgroup (3 vs 1.9yrs, P=0.005) were improved for MAA vs. non-MAA. Moderate compared to poor grade had improved median OS (3.7 vs 1.9 yrs, P=0.002) for Stage IV disease, but this differed by mucinous histology (moderate mucinous 6.2yr vs. poor mucinous 1.6yr, P=0.001; moderate nonmucinous 1.4yr, poor nonmucinous 2yr). 39 MAA pts underwent a complete CRS (30 moderate and 9 poor) with a median time to recurrence of 1.5yrs and median OS of 9.2yrs. Improved OS was seen for pts with a complete CRS compared to pts with an incomplete CRS, Pth edition use of a single mucinous high-grade category. The use of systemic chemotherapy appears to be a viable treatment option for these pts and a complete CRS is associated with improved OS.

526 Background: Cyclooxygenase-2 (COX-2), an inducible isoenzyme, is upregulated in inflammation and involved in cancer progression by promoting angiogenesis, cell proliferation and migration and by inhibiting apoptosis. COX-2 is implicated in colorectal tumorigenesis and by extension COX-2 expression testing and therapeutic inhibition has been considered in appendiceal adenocarcinomas (AAs). However, its role in this setting has never been well studied. The purpose of our study was to investigate COX-2 expression in AAs and to evaluate its prognostic and predictive significance. Methods: We performed a retrospective review of 607 patients with AAs treated at MD Anderson Cancer Center between 2002 and 2010. Immunohistochemistry was performed for COX-2 expression (COX2 mAb Clone CX229, Cayman Chemical) in 49 (8%) patients. Thirty (61%) stained positive and 19 (39%) showed no staining. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine association between OS, COX-2 expression and other characteristics. Results: Median age at diagnosis was 47 yrs (range 34-78 yrs). Grade (P = 0.003), completeness of cytoreduction score (P = 0.010) and stage (P = 0.023) were significantly associated with OS. Median OS for patients with COX-2 positive and COX-2 negative tumors was 58.3 and 42.8 months, respectively (P = 0.232). Nine COX-2 positive patients received celecoxib (selective COX-2 inhibitor) in combination with other chemotherapy. Mean treatment duration was 5.5 months with best radiographic response being stable disease in 7 patients. Reduction in tumor markers (CEA or CA19-9) was seen in 7 cases (median reduction of 30%). Similar treatment duration (6.6 months), rate of stable disease (6/8 pts) and tumor marker reduction (7/8 pts) was seen on the preceding non-celecoxib containing chemotherapy in these patients. Median OS, with and without COX-2 inhibition, was 55.7 and 57.6 months respectively (P = 0.57). Conclusions: In this cohort, COX-2 expression is not a significant prognostic factor in AAs. Benefit from COX-2 inhibition in COX-2 expressing AAs is unclear. Current data does not support the routine use of either COX-2 testing or COX-2 inhibition therapy in AAs.

575 Background: Microsatellite instability (MSI) testing in colorectal cancer (CRC) provides prognosis, predicts chemotherapy response, and guides diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. MSI can be sporadic or hereditary, arising from somatic or germline mutations in DNA mismatch repair (MMR) genes respectively. The clinical implications of these distinct mechanisms are uncertain. Methods: Patients who underwent MSI testing for CRC between 2000 and 2011 were identified. MSI-high (MSH) CRCs were defined by: pathogenic mutation in MMR genes; >30% of markers with allelic shift in PCR-based MSI testing; or loss of expression in at least 1 MMR protein on immunohistochemistry. The subset with MLH1 gene promoter methylation, BRAF mutation, or EPCAM mutation was considered sporadic. Clinicopathologic features and disease-free survival (DFS) were examined in reference to microsatellite stable (MSS) CRCs. Results: MSH CRC’s, 92 germline and 49 sporadic, were compared with 105 MSS CRCs. Compared to MSS CRCs, both germline and sporadic MSH CRCs more commonly arose in the proximal colon (63% and 92%, vs. 30%; p Conclusions: Patients with sporadic MSH CRCs exhibit distinct clinicopathologic features compared to those with germline MSH tumors. Despite poor prognostic features, no apparent survival difference was observed. Further characterization of these distinct groups is warranted to explain the discordance between risk factors and outcomes.

402 Background: Though histological grade is known to have a major prognostic impact in metastatic mucinous appendiceal adenocarcinomas; the prognostic impact of grade in localized disease, and the validity of the AJCC Cancer Staging Manual 7th edition decision to combine moderately and poorly differentiated mucinous adenocarcinomas into a single mucinous high-grade category, is not known. Methods: Patients with adenocarcinoma of the appendix diagnosed between 1988-2007 were identified from the SEER database. Cancer-specific survival (CSS) stratified by histological subtype, stage and grade were calculated; and Cox proportional hazards regression analyses were performed. Results: We analyzed a total of 2,469 appendiceal adenocarcinomas, of which 1,375 had mucinous histology, 860 had non-mucinous histology, and 234 had signet-ring cell histology. Though overall CSS was similar for mucinous and non-mucinous subtypes, differences in stage distribution and stage-stratified CSS were seen. Female gender (57% vs.45%, P Conclusions: The strong prognostic impact of histological grade for mucinous adenocarcinomas is primarily restricted to stage IV disease. Stage IV moderately and poorly differentiated mucinous adenocarcinomas have distinctly different CSS and this data does not support the combination of these two histological grades in the recent AJCC 7th edition.