Next-Generation Sequencing Identifies Key Targetable Mutations in the Treatment of Appendiceal Neoplasms

Abstract Background Appendiceal neoplasms are a group of rare, heterogeneous tumors that exhibit varying malignant potential. Systemic treatment options for disseminated appendiceal cancer are limited. We sought to review rates of mutations that may indicate potential roles for routine next-generation sequencing to identify targetable therapies. Methods An analysis of 916 appendiceal tumor samples submitted to American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) consortium was performed to compare patient demographics and the rates of mutations that may confer drug susceptibility. Results Low-grade appendiceal mucinous neoplasms (LAMNs) had the lowest mutations per specimen (4.5 ± 4.6, p = 0.01) and the highest percentage of KRAS mutations (88.9%, p < 0.01). In KRAS-mutated LAMNs, 92% occurred at codon G12, with 56.5% at G12V and 39.1% at G12D. In total, 5.7%, 29.7%, 53.0%, and 71.8% of goblet cell, signet ring cell, appendiceal, and mucinous adenocarcinomas, respectively, had KRAS mutations. Across all appendiceal tumors, only a limited number had drug-targetable mutations within each gene evaluated: 7.0% KRAS G12C mutations, 26.4% GNAS mutations, 6.9% PIK3CA mutations, and 3.5% DNA mismatch repair gene (MLH1, MSH2, MSH6, and PMS2) mutations. Collectively, 21.5% of appendiceal cancer cases were associated with at least one or more gene mutations with drug targeting potential, and 4.3% of cases had multiple targetable mutations. Conclusions Although mutations suggesting available drug targeting occur at low frequencies in appendiceal tumors, minimal overlap of these mutations results in a sizeable subpopulation of patients that may benefit from targeted therapies. Next-generation sequencing may enable tailored therapeutic approaches for disseminated appendiceal cancer.