The Landscape of Circulating Tumor DNA (ctDNA) in Appendiceal Adenocarcinoma

• Published in: Clinical cancer research 2024-12
• Main Authors: White, Michael G, Zeineddine, Mohammad A, Fallon, Eleanor A, Zeineddine, Fadl A, Dansby, Julia, Chowdhury, Saikat, Hornstein, Nicholas, Yousef, Abdelrahman, Yousef, Mahmoud, Bhutiani, Neal, Gu, Yue, Kee, Bryan, Dasari, Arvind, Overman, Michael J, Raghav, Kanwal, Kopetz, Scott, Uppal, Abhineet, Taggart, Melissa, Newhook, Timothy, Fournier, Keith, Helmink, Beth, Drusbosky, Leylah M, Shen, John Paul
• Format: Article
• Language: English
• ISSN: 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-24-2474

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. 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. 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%). Although metastatic AA tumors are less likely to shed tumor DNA into the blood relative to CRC, ctDNA profiling in AA has clinical utility.