Targeted Next-Generation Sequencing Improves the Prognostication of Patients with Disseminated Appendiceal Mucinous Neoplasms

Abstract Appendiceal mucinous neoplasms (AMNs) with disseminated disease are a heterogeneous group of tumors with variable clinicopathologic behavior. Despite the development of prognostic systems, objective biomarkers are needed to accurately stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients with respect to currently used prognostic systems. Therefore, targeted NGS was performed for 183 patients and correlated with patient demographics, AJCC/WHO histologic grade, lymphovascular and perineural invasion, regional lymph node metastasis, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS). Genomic alterations were identified for 179 (98%) disseminated AMNs and consisted of KRAS (84%), GNAS (59%), TP53 (24%), SMAD4 (19%), PIK3CA (4%), ATM (4%), PTEN (2%), NRAS (2%), BRAF (2%), and CDKN2A (1%). Excluding mitogen activated protein kinase (MAPK) genes and GNAS due to their ubiquitous nature among AMNs, collective genomic alterations in TP53 , SMAD4 , CDKN2A , and the mTOR genes were associated with older mean age (p = 0.019), higher AJCC/WHO histologic grade (p < 0.001), lymphovascular invasion (p < 0.001), perineural invasion (p = 0.003), regional lymph node metastasis (p < 0.001), and lower mean PCI (p = 0.038). Patients harboring TP53 , SMAD4 , ATM , CDKN2A , and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, as compared to 88% at 5 years and 88% at 10 years for patients without the aforementioned genomic alterations (p < 0.001). Based on univariate and multivariate analyses, genomic alterations in TP53 , SMAD4 , ATM , CDKN2A , and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (p = 0.006). In summary, targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients that may require increased surveillance and/or more aggressive management.