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Measurement of circulating tumor DNA (ctDNA) in appendiceal adenocarcinoma (AA): Prevalence, predictors, and correlation with clinical outcome
Background
Appendiceal adenocarcinoma (AA) is a rare and heterogenous cancer with marked differences in clinical course between high- and low-grade tumors. Unlike colorectal cancer (CRC) and other gastrointestinal malignancies, AA virtually never has hematogenous metastases, rather, metastasis is limited to the peritoneum. Here we present a retrospective, single institution study of AA to identify the prevalence of detectable ctDNA, evaluate the predictive value of positive ctDNA, and assess what clinical, pathologic, or molecular features predict positive ctDNA.
Methods
69 blood samples from 63 patients with AA metastatic to the peritoneum were profiled with a CLIA approved 73 gene mutational panel (Guardant 360) as part of routine clinical practice. Paired tumor sequencing was available for 23 patients to allow for concordance testing.
Results
Out of 69 ctDNA samples, 43 were taken in the setting of radiographically apparent metastatic disease. Of these only 12 (27.9%) had any detectable mutation while 31 (72.1%) had no detectable ctDNA. High-grade tumors were more likely to have measurable ctDNA with detection rates of 3/16 (18.7%), 4/15 (26.7%), and 5/12 (41.7%) for well, moderately, and poorly-differentiated tumors, respectively. Detectable ctDNA was associated with worse overall survival (29.4 months for positive ctDNA vs not yet reached for negative ctDNA, HR = 4.7, p = 0.02), although not powered for subgroup analysis this association appeared to hold for both low- and high- grade tumors (HR 4.4, 2.8 respectively). Restricting analysis to the 23 patients with paired tissue and blood samples and 72 genes sequenced in both, of 44 mutations detected in tumor only 3 (GNAS, KRAS and TP53) were detected in blood (sensitivity of 6.8%). Six mutations (BRCA1, KIT, KRAS and TP53) were seen in blood but not tissue, which may represent either clonal hematopoiesis or somatic mutations missed in tissue sequencing. Overall, the sensitivity of ctDNA detection in metastatic AA was markedly less than what was observed in a cohort of 274 metastatic CRC patients from the same institution (288/581 = 49.6%). 26 AA patients with No Evidence of Disease (NED) clinically or radiographically after complete cytoreduction had ctDNA testing done. Of the 26, 7 had positive ctDNA (26.9%), while 19 were negative (73%). High-grade tumors were somewhat more likely to have detectable ctDNA with detection rates of 2/12 (16.7%), 2/9 (22.2%) and 3/7 (43%) for well, moderately, and poorly-differentiated tumors, respectively. Detectable ctDNA was a risk factor for recurrence (5/7, 71.4% detectable ctDNA vs. 5/19, 26.3% undetectable, HR = 4.5, p = 0.007). Restricting to high-grade patients, the three with detectable ctDNA had markedly shorter median duration to recurrence (4.0 vs. 26.9 months, HR = 3.8, p = 0.13).
Conclusions
Sensitivity of ctDNA detection in metastatic AA is overall markedly lower than other metastatic gastrointestinal tumors, with detection more likely in high-grade tumors relative to low-grade. The presence of detectable ctDNA is associated with worse survival and increased risk of relapse in NED patients. The development of more sensitive ctDNA assays may improve ctDNA detection in AA.
Legal entity responsible for the study
The author.
Funding
This work was supported by the National Cancer Institute (L30 CA171000 and K22 CA234406 to J.P.S., and the Cancer Center Support Grant (P30 CA016672), the Cancer Prevention & Research Institute of Texas (RR180035 to J.P.S., J.P.S. is a CPRIT Scholar in Cancer Research), and the Col. Daniel Connelly Memorial Fund.
Disclosures
M. Overman: Advisory / Consultancy: AbbVie and Takeda Pharamceuticals (Japan), AgilVax and Merck Sharp & Dohme Corp, Acrotech Biopharma and Novartis Pharmaceuticals corp. A. Dasari: Research grant / Funding (institution): Guardant Health, Natera. All other authors have declared no conflicts of interest.
