Abstract 3474: Molecular subtypes characterize appendiceal adenocarcinoma genomic evolution and disease behavior
Authors: Foote Michael B. , Walch Henry , Chatila Walid , Vakiani Efsevia , Chandler Chris , Steinrucke Felix , Nash Garrett , Stadler Zsofia , Chung Sebastian , Kemel Yelena , Maio Anna , Sheehan Margaret , Shultz Nikolaus , Diaz Luis A. , Cercek Andrea 
Published: June 2022

Abstract
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&lt;0.001). Inclusion of tumor molecular subtype in conventional multivariable models improves model prognostic strength. In addition, MAAP-derived molecular subtypes prognosticate patient survival in a separate cohort of 248 patients with right-sided, mismatch-repair-proficient metastatic colorectal cancer.
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&lt;0.001). Together with clonality patterns, this suggests that RAS mutated-only tumors exhibit a relatively younger molecular age. In a subset of patients with MAAP who underwent cytoreductive surgery, patients with RAS-only tumors demonstrate significantly lower intra-operative assessed peritoneal cancer indices (PCI) compared to patients with other molecular subtypes (p=0.049). Microscopic assessment of surgical samples reveals that RAS mutated-only tumors are significantly less likely (p&lt;0.001) to exhibit destructive metastatic stromal invasion compared to GNAS and TP53 mutated subtypes. Molecular subtype is also a significant independent predictor of both radiographic and biochemical response to first line chemotherapy for patients with AC.
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.