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PURPOSE Appendiceal adenocarcinomas (ACs) are rare, histologically diverse malignancies treated as colorectal cancers despite having distinct biology and clinical behavior. To guide clinical decision making, we defined molecular subtypes of AC associated with patient survival, metastatic burden, and chemotherapy response. PATIENTS AND METHODS A comprehensive molecular analysis was performed in patients with AC to define molecular subtypes. Associations between molecular subtype and overall survival, intraoperative peritoneal cancer index, and first-line chemotherapy response were assessed adjusting for histopathologic and clinical variables using multivariable Cox proportional hazards, linear regression, and logistic regression models. RESULTS We defined distinct molecular lineages of mucinous appendiceal adenocarcinoma (MAAP) from co-occurring mutations in GNAS, RAS, and TP53. Of 164 MAAP tumors, 24 were RAS-mutant (mut) predominant ( RAS-mut/ GNAS-wild-type [wt]/ TP53-wt) with significantly decreased mutations and chromosomal alterations compared with tumors with GNAS mutations (GNAS-mut predominant) or TP53 mutations (TP53-mut predominant). No patient with RAS-mut predominant subtype metastatic MAAP died of cancer, and overall survival in this subgroup was significantly improved compared with patients with GNAS-mut ( P = .05) and TP53-mut ( P = .004) predominant subtypes. TP53-mut predominant subtypes were highly aneuploid; increased tumor aneuploidy was independently ( P = .001) associated with poor prognosis. The findings retained significance in patients with any metastatic AC. RAS-mut predominant metastases exhibited reduced peritoneal tumor bulk ( P = .04) and stromal invasion ( P < .001) compared with GNAS-mut or TP53-mut predominant tumors, respectively. Patients with RAS-mut predominant MAAP responded more to first-line chemotherapy (50%) compared with patients with GNAS-mut predominant tumors (6%, P = .03). CONCLUSION AC molecular patterns identify distinct molecular subtypes: a clinically indolent RAS-mut/GNAS-wt/TP53-wt subtype; a chemotherapy-resistant GNAS-mut predominant subtype; and an aggressive, highly aneuploid TP53-mut predominant subtype. Each subtype exhibits conserved clinical behavior irrespective of histopathology.

Purpose: Over 10% of assessed patients with appendiceal adenocarcinoma (AC) have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch Syndrome. We defined the clinical and molecular impact of heritable alterations in AC to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants. Experimental Design: We performed an integrated germline and somatic molecular analysis for patients with confirmed AC. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer-risk genes and 505 genes for somatic mutation profiling. We defined the co-occurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated. Results: Twenty-five out of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and AC-specific survival were similar in patients with or without germline variants. Most (92%, N=23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However only one patient tumor exhibited APC-mediated WNT-signaling dysregulation; a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch Syndrome, yet their cancers were microsatellite-stable. Conclusions: Germline variants are likely incidental without a contributory driver role in AC. AC screening in patients with germline variants is not clearly merited.

160 Background: ICARuS is a randomized phase II, multicenter trial to evaluate the relative efficacy of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with mitomycin C vs. Early Postoperative Intraperitoneal Chemotherapy (EPIC) with floxuridine (FUDR), after cytoreductive surgery (CRS), for the treatment of peritoneal metastases (PM) from colorectal (CRC) or appendiceal cancer (AC). PRODIGE7 results failed to demonstrate benefit of HIPEC therapy after complete gross resection of CRC PM, prompting termination of CRC accrual and early cohort analysis. Methods: Patients with isolated, confirmed PM were eligible for 1:1 randomization to CRS plus HIPEC with mitomycin C or CRS plus EPIC with FUDR. Patients were stratified by recent systemic chemotherapy and disease (AC vs. CRC). The trial was originally powered to evaluate 212 patients for a 20% gain in a primary endpoint of 3-year progression free survival (PFS: HR = 1.75). Results: Seventy-five CRC patients were included between 4/2013 and 12/2018 for HIPEC (N = 40) or EPIC (N = 35) treatment. Baseline characteristics were well balanced. After a median follow up of 36 months, the median PFS was 7.7 months (95% CI: 6.3-11.1) in the HIPEC arm and 8.8 months (95% CI: 7.1-21.9) in the EPIC arm, HR = 0.69 (95% CI: 0.42-1.14) p = 0.14. In the 42 left-sided primary cancers, the median PFS was 8.4 months (95% CI: 6.4-17.7) in the HIPEC arm and 12.5 months (95% CI: 8.1-NR) in the EPIC arm, HR = 0.60 (95% CI: 0.29-1.22) p = 0.14. In the 33 right-sided primary cancers, the median PFS was 6.5 months (95% CI: 5.5-14.1) in the HIPEC arm and 8 months (95% CI: 5.8-24.1) in the EPIC arm, HR = 0.80 (95% CI: 0.39-1.64) p = 0.53. PFS was significantly better in the EPIC arm among patients with BRAF wildtype (WT) tumors and patients with higher PM burden (PCI > 7). There was no difference between HIPEC and EPIC in the primary toxicity endpoint of complications grade 3 or above (23 vs. 34%, p = 0.3). Conclusions: Three-year PFS did not significantly differ between treatment arms. The lack of survival benefit of HIPEC in the entire cohort and in subset analysis is consistent with the findings of PRODIGE7. ICARuS remains open to accrual for AC. These data support further investigation of the potential benefit of EPIC with CRS in carefully selected patients with CRC PM. Clinical trial information: NCT01815359 .

Appendiceal adenocarcinoma (AC) are rare gastrointestinal tumors that exhibit a heterogeneous spectrum of tumor histology and differentiation patterns. Personalized AC treatments are limited by the lack of robust histopathological or genomic predictors of disease behavior. We utilized the MSK IMPACT sequencing panel to profile genomic signature patterns in somatic mutations, copy number alterations, and germline mutations in a large curated dataset of patients with AC. We evaluated co-occurrence and clonality patterns between frequently altered genes in AC (RAS, GNAS, TP53) to establish five molecular subtypes of mucinous appendiceal adenocarcinoma (MAAP): RAS mutated-only, GNAS mutated, TP53 & KRAS mutated, TP53 mutated-only, and none (all wild-type). In multivariable Cox regression models, patients with RAS mutated-only tumors exhibit a nearly non-lethal disease course compared to other molecular subtypes, including TP53 mutated-only tumors (hazard ratio for death: 75.6, p Molecular characterization of AC also reveals differences in tumor biology and behavior. In addition to an improved prognosis, RAS mutated-only MAAP tumors exhibit significantly lower tumor mutational quantity and aneuploidy compared to other subtypes in multivariable models (p Overall, through a comprehensive profiling of the AC mutational landscape we introduce a unique disease entity of RAS-only mutated MAAP that exhibits dramatically low lethality, low peritoneal spread, and decreased tissue invasiveness despite high-risk histological characteristics. The behavior of this clinically-metastatic, but molecularly-young subtype introduces a new characterization of metastatic pathogenesis and risk that may apply to other premalignant and malignant diseases. Citation Format: Michael B. Foote, Henry Walch, Walid Chatila, Efsevia Vakiani, Chris Chandler, Felix Steinrucke, Garrett Nash, Zsofia Stadler, Sebastian Chung, Yelena Kemel, Anna Maio, Margaret Sheehan, Nikolaus Shultz, Luis A. Diaz, Andrea Cercek. Molecular subtypes characterize appendiceal adenocarcinoma genomic evolution and disease behavior [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3474.

BackgroundResidual renal function (RRF) is an important prognostic indicator in continuous ambulatory peritoneal dialysis (CAPD) patients. We determined the predictors of RRF loss in a cohort of incident CAPD patients.MethodsWe reviewed the record of 645 incident CAPD patients. RRF loss is represented by the slope of decline of residual glomerular filtration rate (GFR) as well as the time to anuria.ResultsThe average rate of residual GFR decline was -0.083 ± 0.094 mL/min/month. The rate of residual GFR decline was faster with a higher proteinuria (r = -0.506, p < 0.0001) and baseline residual GFR (r = -0.560, p < 0.0001). Multivariate analysis showed that proteinuria, baseline residual GFR, and the use of diuretics were independent predictors of residual GFR decline. Cox proportional hazard model showed that proteinuria, glucose exposure, and the number of peritonitis episodes were independent predictors of progression to anuria, while a higher baseline GFR was protective. Each 1 g/day of proteinuria is associated with a 13.2% increase in the risk of progressing to anuria, each 10 g/day higher glucose exposure is associated with a 2.5% increase in risk, while each peritonitis episode confers a 3.8% increase in risk.ConclusionsOur study shows that factors predicting the loss of residual solute clearance and urine output are different. Proteinuria, baseline residual GFR, and the use of diuretics are independently related to the rate of RRF decline in CAPD patients, while proteinuria, glucose exposure, and the number of peritonitis episodes are independent predictors for the development of anuria. The role of anti-proteinuric therapy and measures to prevent peritonitis episodes in the preservation of RRF should be tested in future studies.