Purpose: Appendiceal adenocarcinoma (AA) 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 AA relative to common tumors.
Experimental design: We analyzed molecular data for patients within the Guardant Health database with appendix cancer (n = 718). We then identified patients with AA at our institution (from 10/2004-9/2022) for whom circulating tumor DNA (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.
Results: The mutational landscape of ctDNA in AA is distinct from tissue-based sequencing, with TP53 being the most frequently mutated (46%). Relative to other tumors, AA appears less likely to shed ctDNA, with only 38% of metastatic AA patients having detectable ctDNA (OR 0.26, p < 0.0001 relative to CRC). When detectable the median VAF was significantly lower in AA (0.4% vs. 1.3% for CRC, 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%).
Conclusions: Although metastatic AA tumors are less likely to shed tumor DNA into the blood relative to CRC, ctDNA profiling in AA has clinical utility.