The Landscape of ctDNA in Appendiceal Adenocarcinoma

Appendiceal adenocarcinoma is a rare malignancy with distinct histopathologic subtypes and a natural history with metastasis primarily limited to the peritoneum. Little is known about the molecular pathogenesis of appendiceal adenocarcinoma relative to common tumors.

We analyzed molecular data for patients within the Guardant Health database with appendix cancer (n = 718). We then identified patients with appendiceal adenocarcinoma at our institution (from October 2004-September 2022) for whom ctDNA mutation profiling (liquid biopsy) was performed (n = 168) and extracted clinicopathologic and outcomes data. Of these 168 patients, 57 also had tissue-based tumor mutational profiling, allowing for evaluation of concordance between liquid and tissue assays.

The mutational landscape of ctDNA in appendiceal adenocarcinoma is distinct from tissue-based sequencing, with TP53 being the most frequently mutated (46%). Relative to other tumors, appendiceal adenocarcinoma seems less likely to shed ctDNA, with only 38% of patients with metastatic appendiceal adenocarcinoma having detectable ctDNA (OR = 0.26; P < 0.0001 relative to colorectal cancer). When detectable, the median variant allele frequency was significantly lower in appendiceal adenocarcinoma (0.4% vs. 1.3% for colorectal cancer; P ≤ 0.001). High-grade, signet ring, or colonic-type histology, metastatic spread beyond the peritoneum, and TP53 mutation were associated with detectable ctDNA. With respect to clinical translation, patients with detectable ctDNA had worse overall survival (HR = 2.32; P = 0.048). In the Guardant Health cohort, actionable mutations were found in 93 patients (13.0%).

Although metastatic appendiceal adenocarcinoma tumors are less likely to shed tumor DNA into the blood relative to colorectal cancer, ctDNA profiling in appendiceal adenocarcinoma has clinical utility.