Comparative Prognostic Significance of CEA and CA15-3 in Breast Cancer

International Journal of Advanced Pharmaceutical Sciences and Research (IJAPSR) ISSN: 2582-7618 (Online), Volume-5 Issue-6, October 2025 30 Published By: Lattice Science Publication (LSP) © Copyright: All rights reserved. Retrieval Number: 100.1/ijapsr.A409706011225 DOI:10.54105/ijapsr.A4097.05061025 Journal Website: www.ijapsr.latticescipub.com Comparative Prognostic Significance of CEA and CA15-3 in Breast Cancer Riham Mohammad Aljouji, Issa Radwan Yusuf, Rama Hussein Ibrahim Abstract: Breast cancer is a leading cause of cancer-related mortality worldwide, particularly among women. Thus, it is critical to have reliable biomarkers for prognosis and metastasis detection. This retrospective study compared the prognostic utility of serum tumour markers CEA and CA15-3 in 117 female breast cancer patients admitted to Lattakia University Hospital. Patients were stratified by histopathological type, molecular subtype, tumour stage, size, and metastasis location. Patients were stratified by histopathological type, molecular subtype, tumour stage, size, and metastasis location. Elevated CA15-3 levels were significantly associated with advanced tumour stage (P<0.05) and metastatic disease (P<0.0001), but not with specific metastatic sites, tumour size, or molecular subtype (P>0.05). In contrast, while CEA levels were not significantly elevated in advanced tumour stages, they correlated with larger tumour size (P<0.05) and metastasis (P<0.001), particularly liver metastasis (P<0.05).Kaplan-Meier analysis revealed that elevated CEA (>5 ng/mL) was significantly associated with worse 5-year overall survival (27% vs. 68%, P<0.001), whereas CA15-3 (>35 IU/mL) was not (50% vs. 75%, P>0.05). These findings highlight CEA’s potential as a prognostic biomarker, particularly for liver metastasis. The controversial results of our study support using CEA in clinical surveillance for breast cancer. Keywords: Breast Cancer, Ca15-3, Cea, Prognostic Biomarkers Nomenclature: AJCC: American Joint Committee on Cancer CA15-3: Carbohydrate Antigen 15 3 CEA: Carcinoembryonic antigen CRC: Colorectal Cancer ER: Estrogen Receptor IDC: Invasive Ductal Carcinoma IDLC: Invasive Ductal and Lobular Carcinoma ILC: Invasive Lobular Carcinoma PR: Progesterone Receptor I. INTRODUCTION Breast cancer is the second most frequently diagnosed malignancy around the world, with approximately 2.3 Manuscript received on 28 September 2025 | Revised Manuscript received on 07 October 2025 | Manuscript Accepted on 15 October 2025 | Manuscript published on 30 October 2025. *Correspondence Author(s) Riham Mohammad Aljouji, Faculty of Pharmacy, Al-Sham Private University, Lattakia, Syria, Email ID: reehamaljou[email protected], ORCID ID: 0009-0007-0683-8110 Dr. Issa Radwan Yusuf*, Faculty of Pharmacy, Lattakia University, Lattakia, Syria (Research Assistant), Email ID: [email protected], ORCID ID: 0009-0006-6466-9338 Dr. Rama Hussein Ibrahim, Faculty of Pharmacy, Al-Sham Private University, Lattakia, Syria, (Supervisor), Email ID: [email protected], ORCID ID: 0009-0007-1516-6870 © The Authors. Published by Lattice Science Publication (LSP). This is an open-access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Million new cases reported worldwide, according to GLOBOCAN (2022) [1]. Breast cancer is the most commonly diagnosed cancer and the leading cause of death among female patients [2]. In Syria, breast cancer accounted for about 4,100 new cases in 2022 among females, representing 35% of all female cancer cases [3]. Breast cancer is a heterogeneous disease classified histologically into invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). IDC is the most common histologic subtype, accounting for 70–80% of all breast cancer cases, whereas ILC occurs in 5–15% of patients [4]. Additionally, there exists a mixed subtype known as mixed invasive ductal and lobular carcinoma (IDLC), which represents 3–5% of breast cancer cases. This variant exhibits both ductal and lobular morphological features, with the ductal component constituting 10–49% and the lobular component comprising at least half of the tumour [5]. As outlined in the 8th edition of the American Joint Committee on Cancer (AJCC) guidelines, breast cancer staging is categorised into two tables: the anatomic staging system, known as the TNM classification, and the prognostic staging system, which is based on molecular subtypes [6]. The anatomic staging system includes three key parameters: primary tumour size (T), regional lymph node involvement (N), and distant metastasis (M), as determined by clinical examination and/or pathological analysis. These three categories are combined to determine the overall five anatomic stages (0, I, II, III, IV) [7]. Stage 0 represents noninvasive breast cancer, while stages I and II indicate early invasive breast cancer. The last two stages involve more advanced disease with poorer prognosis and metastasis [8]. The prognostic staging system is not based on the histological features of the tumour but instead on the expression of three molecular receptors (ER, PR, HER2), which define four distinct subtypes: Luminal A, Luminal B, HER2-enriched, and Triple-Negative Breast Cancer [9]. Luminal A tumours are ER-positive and/or PR-positive and HER2-negative. This subtype has a good prognosis, as it is a low-stage, slow-growing tumour. On the other hand, Luminal B tumors are of a higher stage and have a poorer prognosis. This subtype is ER-positive and/or PR-positive, with or without HER2 receptors. Additionally, the Luminal B subtype is characterized by high expression of the marker of proliferation (Ki-67) [10]. The HER2-enriched subtype is characterised by high HER2 expression in the absence of ER and PR. HER2-enriched cancers grow faster than luminal cancers and have a worse prognosis. Triple-negative breast cancer (TNBC) is negative for ER, PR, and HER2, and has the worst prognosis among all subtypes [11]. Comparative Prognostic Significance of CEA and CA15-3 in Breast Cancer 31 Published By: Lattice Science Publication (LSP) © Copyright: All rights reserved. Retrieval Number: 100.1/ijapsr.A409706011225 DOI:10.54105/ijapsr.A4097.05061025 Journal Website: www.ijapsr.latticescipub.com Carbohydrate Antigen 15 3 (CA15-3) is a transmembrane glycoprotein encoded by the muc1 gene. CA15-3 is considered a key biomarker for detecting cancer progression and metastasis, due to its overexpression in many cancers [12]. Elevated serum CA15-3 values at diagnosis are associated with higher breast cancer stage, tumour size, positive axillary lymph nodes, and worse overall survival [13]. CEA is a glycoprotein primarily expressed during fetal development, with minimal production after birth. Adults may have elevated CEA levels in several pathological conditions. CEA is most commonly used as a tumour biomarker for monitoring colorectal cancer (CRC) recurrence [14]. Furthermore, CEA has also been used as a tumour marker for many tumours, such as lung, uterine, and ovarian cancers [15]. CEA is used in breast cancer patients for surveillance after surgery and monitoring in the advanced stage [16]. CEA, CA 15-3, and CA 27-29 may be used as adjunctive assessments to contribute to decisions regarding therapy for metastatic breast cancer [17]. However, CEA has not been widely investigated as a prognostic biomarker for breast cancer and metastasis. Thus, our study aims to examine the predictive utility of CEA compared with CA 15-3. II. MATERIALS AND METHODS We conducted a retrospective study on 117 female patients diagnosed with breast cancer at the oncology department of Lattakia University Hospital. We analysed the medical records of patients, which were selected based on the availability of complete clinical and laboratory data, including tumour marker results (CA 15-3 and CEA), histopathological tumour type, stage, size, presence and location of metastases, as well as estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor status. Records lacking essential data or containing unclear laboratory results were excluded to ensure the reliability of statistical analysis. Concurrent bilateral breast cancers, and male breast cancers were excluded from the study. We obtained the official approval from the institutional ethics committee, and full compliance with patient confidentiality and data privacy was maintained throughout data collection and analysis. III. STATISTICAL ANALYSIS The Shapiro-Wilk test was used to assess the normality of continuous variables. Categorical variables were presented as counts and percentages, while continuous variables were reported as mean ± standard deviation or median and interquartile range (25th–75th percentile). The MannWhitney test was used for continuous variables. Correlations were evaluated using Pearson’s correlation test. To determine the prognostic utility of CEA compared with CA15-3, we conducted Kaplan-Meier analyses and log-rank tests. Results were considered statistically significant when P < 0.05. All statistical analyses were performed using the R statistical programming language. IV. RESULTS The study included 117 female patients diagnosed with breast cancer, with a mean age of 51.6 ± 11.8 years. The majority of patients (n=108, 92%) were diagnosed with invasive ductal carcinoma (IDC), while invasive lobular carcinoma (ILC) accounted for 8% (n=9) of cases. Patients were further categorised by tumour stage, tumour size, and the presence and location of metastasis. Additionally, the cohort was stratified into the four molecular subtypes of breast cancer—Luminal A, Luminal B, HER2-positive, and triple-negative—based on the expression status of estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor, as detailed in tables 1 to 4. The levels of CA 15-3 and CEA were analysed in patients, as detailed in Table 5. Table 1: General Characteristics of the Study Population Characteristic Values n (%) Tumor Type IDC 108 (92.3%) ILC 9 (7.7%) Tumor Stage I 1 (1.2%) II 57 (67.9%) III 25 (29.8%) IV 1 (1.2%) Tumor Size T1 6 (7%) T2 61 (70.9%) T3 12 (14%) T4 7 (8.1%) Metastasis Metastatic 76 (81%) Non-Metastatic 18 (19%) Table 2: Location of Metastasis Location of Metastasis Bone Brain Liver Lung n (%) 55 (73.3%) 4 (5.3%) 28 (37.3%) 21 (28%) Table 3: Tumor Biomarker Status Type Positive n (%) Negative n (%) Estrogen Receptors 49 (53.8%) 42 (46.2%) Progesterone Receptors 40 (44%) 51 (56%) HER2 Receptors 63 (69.2%) 28 (30.8%) Table 4: Subtype Subtype Luminal A Luminal B HER2Positive Triple Negative n (%) 16 (17.6%) 40 (44%) 23 (25.3%) 12 (13.2%) Table 5: Levels of CA15-3 and CEA Biomarker Values Median (Q1-Q3) Pearson Correlation CA 15-3 IU/ml 57.7 (25-208) 0.7 (P<0.01) CEA ng/ml 10.13 (2.59-37.26) A. Relationship between CA15-3 Levels and the Tumour Parameters CA15-3 levels were measured several times upon admission, so we calculated the mean for each patient and compared it with the research variables. We found that CA15-3 levels were significantly higher in patients with advanced-stage International Journal of Advanced Pharmaceutical Sciences and Research (IJAPSR) ISSN: 2582-7618 (Online), Volume-5 Issue-6, October 2025 32 Published By: Lattice Science Publication (LSP) © Copyright: All rights reserved. Retrieval Number: 100.1/ijapsr.A409706011225 DOI:10.54105/ijapsr.A4097.05061025 Journal Website: www.ijapsr.latticescipub.com disease than in those with early-stage disease (P<0.05). Furthermore, CA15-3 values were elevated in with larger tumor sizes, but without significant differences (P>0.05). We also found that metastatic patients had significantly higher CA15-3 levels than non-metastatic patients (P<0.01). However, there was no significant difference in CA 15-3 levels by metastasis location or breast cancer subtype (P > 0.05; Table 6). Table 6: Levels of CA15-3 Across Study Parameters Characteristics CA15-3 Values P Value Tumor Stage I+II 33 (21-84.3) 0.023 III+IV 84.52 (41.95-253) Tumor Size T1 26 (22.7-42.3) 0.68 T2 38.8 (21.-126.7) T3 39 (25.2-299.1) T4 65.4 (38.9-87.5) Metastasis Metastatic 57.78 (28.5-226.4) <0.0001 Nonmetastatic 16.9 (14-30.1) Bone Metastasis yes 57.86 (33-312.8) 0.706 no 73.25 (27.34-196) Brain Metastasis yes 219.7 (34-551.2) 0.65 no 57.86 (30-216.5) Liver Metastasis yes 113.3 (43.7-243.3) 0.08 no 51.58 (27-137.2) Lung Metastasis yes 63 (29.95-247.43) 0.995 no 57.78 (31.5201.37) Subtype Luminal A 171 (22.78-317.74) 0.32 Luminal B 34.8 (22.44-92.38) Triplenegative 37.8 (22.9-59.48) HER2-positive 39.9 (26.78-96.6) B. Relationship between CEA Levels and the Tumour Parameters CEA levels were measured several times upon admission, so we calculated the mean CEA level for each patient and compared it with the research variables. We found higher CEA levels in patients with advanced disease, but the difference was not significant (P>0.05). We found that larger tumours, especially T3 tumours, were associated with a notable increase in CEA levels (P<0.05). Metastatic patients had significantly higher CEA levels than nonmetastatic patients (P<0.01). Regarding metastasis location, CEA levels do not appear to be associated with metastasis to the lungs, bones, or brain (P>0.05). However, CEA levels were significantly elevated in patients with liver metastasis (P<0.05). There was no significant difference in CEA values between the subtypes of breast cancer (P>0.05). Table 4 demonstrates the relationship between CEA levels and the tumor parameters. Table 7: Levels of CEA Across Study Parameters. Characteristics CEA Values P Value Tumor Stage I+II 4.55 (1.83-31.8) 0.2 III+IV 8.6 (2.66-119.7) Tumor Size T1 3.2 (2.58-4.08) 0.024 T2 12 (2.02-34.24) T3 22.08 (5.84120.79) T4 3.3 (1.37-8.65) Metastasis Metastatic 12.6 (4.26-51.3) 0.00017 Nonmetastatic 1.81 (1.2-3) Bone Metastasis yes 18.4 (3.4-101.96) 0.239 no 9.62 (6.22-18.35) Brain Metastasis yes 276.45 (16.81546.75) 0.13 no 12.55 (4.14-51.08) Liver Metastasis yes 32.8 (7.9-119.9) 0.023 no 9.73 (3.8-28.2) Lung Metastasis yes 12.5 (2.78-90.3) 0.77 no 13.2 (4.52-46.85) Subtype Luminal A 14.75 (2.75-62.4) 0.47 Luminal B 4.48 (1.92-26.2) Triplenegative 5.27 (1.46-11.55) HER2positive 12.5 (3.56-40.65) C. The Prognostic Significance of CEA Compared to CA15-3 in Breast Cancer Among the dead patients, the 5-year survival rate among the patient cohort was 60%. To evaluate the impact of CA15-3 and CEA levels on 5-year survival, patients were stratified into groups based on the prognostic cut-off values: 35 IU/mL for CA15-3 and 5 ng/mL for CEA. Analysis revealed that patients with CA15-3 levels exceeding 35 IU/mL had a lower 5-year survival rate than those with lower levels, but the difference was not significant (P > 0.05; Figure 1). Patients with CEA levels above 5 ng/mL had a significantly lower 5-year survival rate than those with lower levels (P<0.001), as shown in Figure 2. [Fig.1: Kaplan-Meier Survival Analysis by CA15-3 Levels (Log-Rank P:0.1)] Comparative Prognostic Significance of CEA and CA15-3 in Breast Cancer 33 Published By: Lattice Science Publication (LSP) © Copyright: All rights reserved. Retrieval Number: 100.1/ijapsr.A409706011225 DOI:10.54105/ijapsr.A4097.05061025 Journal Website: www.ijapsr.latticescipub.com [Fig.2: Kaplan-Meier Survival Analysis by CEA Levels (Log-Rank P <0.001)] V. DISCUSSION We found that CA15-3 levels were significantly elevated in patients with III and IV tumours compared with those with I and II tumours (P<0.05). Similarly, CA15-3 levels increased with larger tumour size, but this result did not reach statistical significance (P>.05). Furthermore, metastatic patients had significantly higher CA15-3 levels than the non-metastatic group (P<0.01). As noted, CA15-3 is used as a biomarker for breast cancer progression. Our findings align with multiple studies, including a 2014 study by Hashim et al. in Iraq, which reported significantly elevated CA15-3 levels in advanced-stage tumors, and a 2021 study by Uygur et al. in Turkey, which demonstrated substantially higher CA15-3 values in patients with metastatic breast cancer [18, 19]. Regarding metastatic sites, no significant differences in CA 15-3 values were observed among bone, liver, lung, and brain metastasis (P>0.05). Although some studies have shown that CA15-3 levels are higher in breast cancer patients with certain types of secondary metastasis—such as Baqir et al., who found elevated CA15-3 in cases of bone metastasis—others, like Fakhari et al., reported no association between CA15-3 and secondary metastasis [20, 21]. This might reflect the conflicting results regarding the association between CA15-3 and secondary metastasis in breast cancer patients. As mentioned, CA 15-3 is derived from the MUC1 gene product, which is overexpressed in many cancers and metastases, leading to elevated CA 15-3 levels [22]. We found that CA 15-3 levels were significantly increased in Luminal A patients. Similar to our findings, Sinha et al. showed that elevated CA153 levels were most frequently seen in luminal subtypes, while they were less common in the HER2-enriched subtype [23]. Also, Salih et al. demonstrated that luminal breast cancer patients have a higher likelihood of elevated CA15-3 levels at relapse than patients with HER2-enriched and basal-like breast cancers [24]. This can be attributed to the higher expression of the MUC1 protein in luminal subtypes compared to others, as CA15-3 is derived from proteolytic cleavage of MUC1’s extracellular domain [25]. We found that CEA levels were not significantly elevated in patients with advanced stages (P>0.05). However, CEA levels increased substantially with larger tumour size (P<0.05). Furthermore, metastatic patients had significantly higher CEA levels than the non-metastatic group (P<0.01). Shao et al. demonstrated that patients with elevated CEA and CA15-3 levels had larger tumours, more advanced axillary lymph node involvement, and higher TNM stage [26]. Also, Luan et al. found that CEA levels were elevated in patients with the most advanced stages and larger tumours [27]. Our study showed significantly higher CEA levels in patients with liver metastasis compared with those without (P<0.05). In fact, overexpression of CEA is closely associated with liver metastasis. CEA triggers Kupffer cells to produce pro-inflammatory cytokines, which creates a favourable hepatic micro-environment for cancer cell implantation [28]. This process occurs when CEA interacts with a specific receptor on Kupffer cells, promoting hepatic metastatic initiation and facilitating the mesenchymalepithelial transition (MET) of circulating tumor cells in the liver [29]. The OS of patients with high CEA levels (CEA-high: n = 61, 5-year OS 27%) was significantly worse (P<0.001) than that of CEA-low patients (n = 43, 5-year OS 68%). There was no significant difference in OS (P>0.05) between CA15-3-high and CA15-3-low patients (n=66 and n = 37, respectively; 5-year OS 50 vs. 75%). Our findings demonstrated that CEA might be a useful prognostic biomarker for breast cancer patients. Our study was similar to Imamura et al., who found that CEA and CA15-3 levels might help predict the prognosis of patients with breast cancer irrespective of the subtype [30]. However, unlike the Imamura study, we did not find a statistically significant association between CA15-3 levels and 5-year OS. The Imamura study supports the use of CEA and CA15-3 as prognostic biomarkers. However, our study showed that CEA rather than CA15-3 is a better prognostic biomarker for breast cancer. This study has several limitations. First, CA 15-3 and CEA analyses were performed in different laboratories, which may have introduced modest variations in biomarker measurements due to inter-laboratory differences in protocols and calibration. Second, the results lack a comprehensive screening and diagnostic panel for breast cancer, potentially limiting the broader clinical applicability of our findings. Finally, the retrospective nature of the study design may weaken the conclusions; a prospective study would allow for better-controlled investigations and more robust validation of the results. Also, large-scale studies that include treatment regimens among patients would be advisable, as they would provide stronger outcomes. VI. CONCLUSION In conclusion, our study demonstrates that both CA15-3 and CEA levels were significantly elevated in metastatic breast cancer, with CEA showing a specific increase in liver metastasis. In addition, we found International Journal of Advanced Pharmaceutical Sciences and Research (IJAPSR) ISSN: 2582-7618 (Online), Volume-5 Issue-6, October 2025 34 Published By: Lattice Science Publication (LSP) © Copyright: All rights reserved. Retrieval Number: 100.1/ijapsr.A409706011225 DOI:10.54105/ijapsr.A4097.05061025 Journal Website: www.ijapsr.latticescipub.com that patients with high levels of CEA _rather than CA15-3_ have significantly worse OS, reflecting better prognostic utility than CA15-3. ACKNOWLEDGEMENTS We sincerely appreciate the commitment and efforts of the medical staff and healthcare professionals at "Latakia University Hospital”. DECLARATION STATEMENT After aggregating input from all authors, I must verify the accuracy of the following information as the article's author. ▪ Conflicts of Interest/ Competing Interests: Based on my understanding, this article has no conflicts of interest. ▪ Funding Support: This article has not been funded by any organizations or agencies. 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