Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given the localization of AA to the peritoneal space, intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here, we tested the efficacy of paclitaxel given by IP administration using three orthotopic patient-derived xenograft (PDX) models of AA established in immunodeficient NSG mice. Weekly IP paclitaxel treatment dramatically reduced AA tumor growth in all three PDX models. Comparing the safety and efficacy of intravenous (IV) to IP administration, IP delivery of paclitaxel was more effective with reduced systemic side effects in mice. Given the established safety record of IP paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of IP paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of IP paclitaxel in a prospective clinical trial.

Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, and in part because of this AA remains an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases, but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given its localization to the peritoneal space we hypothesized that intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here we tested the efficacy paclitaxel given by IP administration using three orthotopic PDX models of AA established in NSG mice. Weekly treatment of 25.0 mg/kg of IP paclitaxel dramatically reduced AA tumor growth in TM00351 (81.9% reduction vs. control), PMP-2 (98.3% reduction vs. control), and PMCA-3 (71.4% reduction vs. control) PDX models. Comparing the safety and efficacy of intravenous (IV) to IP administration in PMCA-3, 25.0 mg/kg of IV paclitaxel was a lethal to mice shortly after administration and neither 6.25 nor 12.5 mg/kg of IV paclitaxel significantly reduced tumor growth. These results suggest that IP administration of paclitaxel is favorable to IV administration. Given the established safety record of IP paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of IP paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of IP paclitaxel in a prospective clinical trial.

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223 Background: Goblet Cell tumors (GCTs) of the appendix are a rare, distinct, and under studied malignancy. Since 2019 the preferred World Health Organization (WHO) terminology is Goblet Cell Adenocarcinoma (GCA), but previously many terms have been used to describe these tumors including Goblet Cell Carcinoid and Adenocarcinoma ex goblet cell carcinoid as these tumors have a histological appearance that blends neuroendocrine and adenocarcinoma features. Historically goblet cell tumors have been considered one of the more aggressive subtypes of appendiceal cancer, but limited data exists and is mostly in the form of case reports. Here we present the retrospective analysis of a large single institution cohort. Methods: The internal database of the University of Texas MD Anderson Cancer Center (MDACC) was queried to identify all patients diagnosed with goblet cell appendiceal tumor. Patients were classified to two different histopathological groups, GCA (n=220) and GCA with signet ring adenocarcinoma (SRA) (n=146). Clinical, histopathological, and molecular data were extracted from the database in semi-automated fashion. Survival analysis were performed using Kaplan Meier methodology. Results: 366 patients with GCTs were identified from 1986 to 2022. 132 (36%) patients were seen during the last five years, with an average of 26 patients per year. Median follow up time was 54 months, while median age at diagnosis was 57 years. Tumor grade data was available for 294 patients. 95% of the patients had high grade tumors (moderately, moderately to poorly and poorly-differentiated) (n= 278), and 5% had low grade tumors (well and well to moderately-differentiated (n=16). The median overall survival was 85 months, and significantly different between the two groups, 118 months for the GCA group and 57 months for the GCA with SRA (p= 0.003). Lymph node (LN) status was known for 168 patients, rate of LN involvement was 53% (n=89) and significantly different between the two groups with 41% (n=39) for GCA and 68% (n=50) for GCA with SRA (p= <0.0006). The internal database of MDACC was queried for LN status of Mucinous adenocarcinoma (MA) (n=242) and SRA (n=104) for comparison purposes, rate of LN positivity was 13% in MA and 76% in SRA. Node positive patients had significantly worse overall survival with median overall survival of 51 months vs 85 months for node negative patients (p<0.004). By multivariate analysis, both LN status and SRA component were independent predictors of overall survival. 107 patients had gene mutation analysis tested, TP53, SMAD4, GNAS and KRAS were the most commonly mutated with 13%, 9%, 4%, and 3% respectively. Conclusions: This study highlights the heterogenicity of GCTs of the appendix and the importance of the histopathological classification in this distinct entity. GCT are much more likely to spread to LN and have a distinct somatic mutation profile relative to MA.

221 Background: Due to the rarity of appendiceal adenocarcinomas (AA), systematic study of these tumors has been limited. Thus, guidelines for the diagnosis and treatment of AA are often based on other related tumor types such as colorectal cancer. However, given that AA has been shown to be molecularly and functionally distinct, there is a need for focused clinical data to guide disease management. In AA, tumor marker levels are used by some practitioners to monitor response to treatment and aid in diagnosis. This study evaluates the association of elevated tumor marker levels with survival outcomes. Methods: The MDACC database was queried to identify patients with AA between 1997 to 2022. Patients with reported values for the tumor markers CA-125 (n=1076), CA 19-9 (n=1060), and CEA (n=1249) were then selected for analysis. Elevation of tumor markers was defined as above the laboratory upper limit of normal (CA-125 > 37 U/mL, CA 19-9 > 37 U/mL, and CEA > 3 ng/mL and survival outcomes were compared with a log-rank (Mantel-Cox) test. This analysis was repeated while controlling for tumor grade, which was defined by low-grade: well, well to moderately differentiated and high-grade: moderate, moderate to poor, and poorly differentiated. Results: Elevated CA-125 was predictive of overall survival in all patients with median survival not-yet-reached for those with normal CA-125 vs. 87.4 months for those with elevated CA-125 (HR: 5.8, p < 0.0001). Similarly, elevated CA 19-9 and CEA were also predictive of overall survival (HR: 2.8, 4.6, respectively, p < 0.0001 for each). Given that tumor grade is the primary driver of prognosis in AA, survival analysis was repeated while controlling for tumor grade. While elevated levels of all tumor markers were predictive of overall survival for both low-grade and high-grade tumors, elevated CA-125 was an especially strong predictor of survival in patients with high-grade tumors (OS: 69.8 months vs. not-yet-reached, HR: 14.3, p < 0.0001). Moreover, high-grade patients with elevated CA-125 had a reduced 5-year survival rate of 56% vs. 91%. Elevated CA-125 also stratified 5-year survival rate in low-grade patients (83% vs. 99%). Elevated levels of CA 19-9 and CEA were strongly predictive of overall survival for patients with low-grade tumors (HR: 10.6, 26.8, respectively, p < 0.0001 for each). Notably, patients with low-grade tumors expressing normal levels of CA 19-9 or CEA had excellent 5-year survival rates of 99% and 100%, respectively. Conclusions: These results highlight the utility of using tumor marker levels in conjunction with tumor grade to more accurately predict prognosis in AA. CA 19-9 and CEA were particularly useful indicators of outcome in patients with low-grade AA, while CA-125 had greatest prognostic value in high-grade tumors.