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. 2024 Feb 5;7(2):e240260.
doi: 10.1001/jamanetworkopen.2024.0260.

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

Abdelrahman Yousef  1 , Mahmoud Yousef  1 , Mohammad A Zeineddine  1 , Aditya More  1 , Mohammad Fanaeian  1 , Saikat Chowdhury  1 , Mark Knafl  2 , Paul Edelkamp  3 , Ichiaki Ito  1 , Yue Gu  1 , Vinay Pattalachinti  1 , Zahra Alavi Naini  1 , Fadl A Zeineddine  4 , Jennifer Peterson  1 , Kristin Alfaro  1 , Wai Chin Foo  5 , Jeff Jin  6 , Neal Bhutiani  7 , Victoria Higbie  1 , Christopher P Scally  8 , Bryan Kee  1 , Scott Kopetz  1 , Drew Goldstein  9 , Madeleine Strach  10   11   12 , Andrew Williamson  13 , Omer Aziz  10   11 , Jorge Barriuso  10   11 , Abhineet Uppal  7 , Michael G White  7 , Beth Helmink  8 , Keith F Fournier  8 , Kanwal P Raghav  1 , Melissa W Taggart  5 , Michael J Overman  1 , John Paul Shen  1
Affiliations

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

Abdelrahman Yousef et al. JAMA Netw Open. .

Abstract

Importance: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (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: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma.

Design, setting, and participants: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023.

Main outcomes and measures: Association of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival).

Results: A total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P < .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P < .001 for all). 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 for CEA, 3.4; 95% CI, 2.5-4.8; P < .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P < .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P < .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9.

Conclusions and relevance: In this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kee reported holding Medtronic stock outside the submitted work. Dr Kopetz reported serving as a consultant for Genentech, EMD Serono, Merck, Holy Stone Healthcare, Novartis, Lilly, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Redx Pharma, Ipsen, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, Abbvie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotech, Bicara Therapeutics, Endeavor BioMedicines, Numab, Johnson and Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol-Myers Squibb-Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Oncology, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics Laboratories, Accademia Nazionale Di Medicina, and Tachyon Therapeutics; doing research for Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, and Daiichi Sankyo; and having ownership in Lutris, Iylon, Frontier Medicines, Xilis, and Navire outside the submitted work. Dr Strach reported receiving personal fees from European Society of Medical Oncology for a Translational Research Fellowship and from Royal Australasian College of Physicians during the conduct of the study; receiving grants from Royal Prince Alfred Hospital Cancer Services, The Christie Charitable Fund, and the Chris O'Brien Lifehouse Philanthropic Fund; receiving personal fees from Australia and New Zealand Sarcoma Association for the ANZSA Clinical Research Fellowship and Specialised Therapeutics outside the submitted work. Dr Barriuso reported receiving personal fees from Ellipses pharma, Nutricia, Rand Spa, and Medicover; receiving travel accommodation for meetings from AAA, Novartis, Pfizer, Nanostring, and Ipsen outside the submitted work. Dr Uppal reported receiving personal fees from Bayer Pharmaceuticals outside the submitted work. Dr Shen reported receiving personal fees from Nadeno Nanoscience and Engine Bioscience; receiving grants from Celsius Therapeutics outside the submitted work; holding a patent for small molecule GNAS inhibitors; and serving on the Medical Advisory Board for Appendix Cancer Pseudomyxoma Peritonei Research Foundation (unpaid). No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Distribution of Carcinoembryonic Antigen (CEA), Carbohydrate Antigen 19-9 (CA19-9), and Cancer Antigen (CA125) Tumor Marker Levels
A, Distribution of all patients CEA, CA19-9, and CA125 tumor markers levels; each point represents one patient. B, Distribution of all patients CEA, CA19-9, and CA125 tumor markers levels split by disease stage (metastatic vs localized); lines represent median levels. C, Distribution of all patients CEA, CA19-9, and CA125 tumor markers levels split by grade; lines represent median levels. D, Percentage of elevated tumor markers in different histopathological groups. aLaboratory upper limit of normal (CEA 3.8 ng/mL, CA19-9 35 U/mL, and CA125 38 U/mL). bP < .001.
Figure 2.
Figure 2.. Survival Plots of Patients With Metastatic Disease by Tumor Markers
A, Stage IV metastatic disease patients with normal, elevated, and highly elevated levels of carcinoembryonic antigen (CEA). B, Stage IV metastatic disease patients with normal, elevated, and highly elevated levels of carbohydrate antigen 19-9 (CA19-9). C, Stage IV metastatic disease patients with normal, elevated, and highly elevated levels of cancer antigen 125 (CA125). D, All patients with number of elevated tumor markers. KM indicates Kaplan-Meier; OS, overall survival.
Figure 3.
Figure 3.. Survival Plots for Patients With Low and High Tumor Grades
A, Patients with low grade tumor for normal, elevated, and highly elevated levels of carcinoembryonic antigen (CEA). B, Patients with high grade tumor for normal, elevated, and highly elevated levels of CEA. C, Multivariable analysis showing HR for death in all patients on a log2 axis. KM indicates Kaplan-Meier; OS, overall survival.
Figure 4.
Figure 4.. Somatic Mutation Landscape and Association With Tumor Markers
A, KRAS somatic mutation vs wildtype with carcinoembryonic antigen (CEA) levels; lines represent the median levels. B, GNAS somatic mutation vs wildtype with CEA levels; lines represent the median levels. C, Prevalence of KRAS, GNAS, TP53, SMAD4, PIK3CA, and FBXW7 (most common genes with somatic mutations in our cohort) somatic mutations in patients with the 3 tumor markers elevated (pan-elevated) vs patients with normal levels of the 3 tumor markers (pan-normal). D, 3 Tumor markers elevated levels on the left and normal levels on the right, and the somatic mutation status of KRAS, GNAS, TP53, SMAD4, PIK3CA, and FBXW7. aP < .001.
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