The Clinical Significance of CEA, CA19-9, and CA125 in Management of Appendiceal Adenocarcinoma

Abstract

Importance: Serum tumor markers CEA, CA19-9, & CA125 have been useful in the management of gastrointestinal and gynecological cancers, however there is limited information regarding their utility in patients with appendiceal adenocarcinoma.

Objective: Assessing the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes, pathologic, and molecular features in patients with appendiceal adenocarcinoma.

Design: This is a retrospective study with results reported in 2023. The median follow-up time was 43 months.

Setting: Single tertiary care comprehensive cancer center.

Participants: Under an approved Institutional Review Board protocol, the Palantir Foundry software system was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least one tumor marker measured at MD Anderson between 2016 and 2023.

Results: A total of 1,338 patients with appendiceal adenocarcinoma were included, with a median age of 56.5 years. The majority of the patients had metastatic disease (80.7%). CEA was elevated in more than half of the patients tested (56%), while CA19-9 and CA125 were elevated in 34% and 27%, respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; 82% vs 95%, 84% vs 92%, and 69% vs 93% elevated vs normal for CEA, CA19-9, and CA125 respectively (all p<0.0001). Quantitative evaluation of tumor markers increased prognostic ability. Patients with highly elevated (top 10^th percentile) CEA, CA19-9 or CA125 had markedly worse survival with 5-year survival rates of 59%, 64%, and 57%, respectively (HR vs. normal : 9.8, 6.0, 7.6, all p<0.0001). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease elevated CEA, CA19-9 or CA125 were all still associated worse survival (HR vs. normal : 3.4, 1.8, 3.9, p<0.0001 for CEA and CA125, p=0.0019 for CA19-9). Interestingly tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high relative to low-grade tumors (18.3 vs. 15.0, p=0.0009). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with a 11-fold increased risk of death in patients with all three tumor markers elevated relative to those with none elevated. Mutation in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9.

Conclusions: These findings demonstrate the utility of measuring CEA, CA19-9, and CA125 in the management of appendiceal adenocarcinoma. Given their prognostic value, all three biomarkers should be included in the initial workup of patients diagnosed with appendiceal adenocarcinoma.

Keywords: Appendiceal adenocarcinoma; Appendix cancer; CA125; CA19–9; CEA; Tumor marker.

Figure 1.

Flowchart diagram showing cohort patients selection. Abbreviations include MDACC (MD Anderson Cancer Center).

Figure 2.

(A) Violin plot showing the distribution of all patients CEA, CA19–9, and CA125 tumor markers levels, each point represents one patient. (B) Pie charts for the three tumor markers showing the distribution of normal, elevated, and highly elevated in each. (C) Violin plot showing the distribution of all patients CEA, CA19–9, and CA125 tumor markers levels split by disease stage (metastatic vs localized), lines represent median levels (D) Violin plot showing the distribution of all patients CEA, CA19–9, and CA125 tumor markers levels split by grade. lines represent median levels (E) Bar graph showing the percentage of elevated tumor markers in different histopathological groups. (F) Venn diagram showing the overlapping of elevated (highly elevated included) levels of the three tumor markers.

Figure 3.

(A) KM survival plot of all patients with normal, elevated, and highly elevated levels of CEA. (B) KM survival plot of stage IV metastatic disease patients with normal, elevated, and highly elevated levels of CEA (C) KM survival plot of all patients with normal, elevated, and highly elevated levels of CA19–9. (D) KM survival plot of stage IV metastatic disease patients with normal, elevated, and highly elevated levels of CA19–9. (E) KM survival plot of all patients with normal, elevated, and highly elevated levels of CA125. (F) KM survival plot of stage IV metastatic disease patients with normal, elevated, and highly elevated levels of CA125. (F) KM survival plot of all patients with number of elevated tumor markers. (G) Forest plot for multivariable analysis showing HR for death in all patients on a log2 axis.

Figure 4.

(A-C) Bar graphs showing the percentage of patients with elevated CEA (red), CA19–9 (blue), and CA125 (green) in mutant and wildtype KRAS, GNAS, and TP53. (D) Scattered plots for KRAS mutant vs wildtype with CEA, CA19–9 and CA125 levels, lines represents the median levels. (E) Scattered plots for GNAS mutant vs wildtype with CEA, CA19–9 and CA125 levels, lines represents the median levels. (F) Bar graph showing the prevalence of KRAS, GNAS, TP53, SMAD4, PIK3CA, and FBXW7 (Genes that are most frequently mutated in our cohort) mutations in patients with the 3 tumor markers elevated (pan-elevated) vs. patients with normal levels of the 3 tumor markers (pan-normal). (G) Oncoplot showing the 3 tumor markers elevated levels on the left and normal levels on the right, and the mutation status of KRAS, GNAS, TP53, SMAD4, PIK3CA, and FBXW7.