Department of Nuclear Medicine, Jilin University Second Hospital [Combined Application of Tumor Markers] Phase III - Colorectal Tumor Marker Panel

Author: Zhang Mengxian

First review: Tai Jing

Final judge: Zhao Yinlong

As the second most common malignant tumor in my country and the fourth most common malignant tumor in terms of mortality, colorectal cancer has always attracted public attention. According to the latest data released by the National Cancer Center in 2022, there were 517,000 new cases of colorectal cancer (as shown in Figure 1) and 240,000 new deaths (as shown in Figure 2), which seriously threatens the health and quality of life of Chinese residents.

Figure 1 Number of new cancer cases in 2022

Figure 2 New number of cancer deaths in 2022

Currently, the commonly used tumor markers for diagnosing colorectal cancer include: carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), carbohydrate antigen 242 (CA242), carbohydrate antigen 50 (CA50), and carbohydrate antigen 724 (CA724).

CEA

Carcinoembryonic antigen (CEA) is an acidic glycoprotein with human embryonic antigen properties and is used as a marker for the diagnosis and monitoring of recurrence of colorectal cancer [1-3].

Studies have shown that patients with negative CEA in stage T1 have the best prognosis, with a 5-year tumor-specific survival rate of 99.6%; patients with positive CEA in stage T1 have the worst prognosis, with a 5-year tumor-specific survival rate of 88.4%; patients with negative CEA in stage T2 have a similar prognosis to patients with negative CEA in stage T1, with a 5-year tumor-specific survival rate of 94.5%. Patients with positive CEA in stage T2 have a similar prognosis to patients with positive CEA in stage T1, with a 5-year tumor-specific survival rate of 88.7% (as shown in Figure 3).

Figure 3 Relationship between follow-up months and tumor-specific survival rate in patients with colorectal cancer stage T1 and T2

Carbohydrate antigen 19-9

The relationship between the sensitivity of carbohydrate antigen 19-9 (CA19-9) and the Dukes staging of colorectal cancer is: 0-7% in stage A, 17% in stage B, 47% in stage C, and 75% in stage D. The sensitivity of CA19-9 in the diagnosis of early rectal cancer is not high, but because of its high specificity, positive results should be taken seriously.

The "Chinese Colorectal Cancer Diagnosis and Treatment Guidelines" released in 2023 clearly states that colorectal cancer patients must be tested for peripheral blood carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 199 at the time of diagnosis, before treatment, during efficacy evaluation and follow-up. It is recommended that patients with suspected peritoneal or ovarian metastasis should be tested for CA125.

Carbohydrate antigen 125

Elevated serum carbohydrate antigen 125 (CA125) levels can detect tumor recurrence 1 to 14 months earlier than clinical findings, which is helpful for follow-up of the condition and can serve as an important reference for the second treatment. CA125 has the lowest positive rate compared with CEA and CA19-9. It is expressed at a low level in the first three stages of colorectal cancer and increases rapidly in the late stage, lagging behind the expression of CEA and CA19-9 in serum, suggesting that elevated CA125 may better reflect tumor dissemination and metastasis. Therefore, the combination of CA125 and the first two markers is more clinically meaningful than single detection.

Carbohydrate antigen 242

Carbohydrate antigen 242 (CA242) is mainly present in the malignant tumor cells of the pancreas and colon. It is a glycosphingolipid antigen. As a tumor marker, it has a higher specificity and is conducive to the identification of benign and malignant tumors of the digestive tract. The positive rate of CA242 in patients with colorectal cancer is 73.2%, and in patients with benign colorectal diseases, it is only 8-3%. The positive rate of CA242 in patients with non-metastatic colorectal cancer is 44.4%, and in patients with metastatic colorectal cancer, its positive rate is 88.6%.

Related studies have shown that the serum CA242 level in colorectal cancer patients is correlated with the clinical pathological stage, that is, the deeper the tumor infiltration, the higher the stage, the more advanced the disease, and the higher the average CA242 serum level in colorectal cancer patients[4]. Wang Qilong[5] et al.'s study showed that the overall survival rate of CA242-negative patients was significantly higher than that of positive patients, suggesting that higher serum CA242 levels may indicate a poor prognosis (as shown in Figure 4).

Fig. 4 Survival curves of CA242 positive and negative colorectal cancer patients

Carbohydrate Antigen 50

Carbohydrate antigen 50 (CA50) is a sialic acid ester and sialic acid glycoprotein and a broad-spectrum tumor-associated antigen [6]. It is not present in normal tissues, but its expression is significantly elevated in patients with colorectal cancer [7].

Carbohydrate antigen 50 (CA50) has a high positive rate in metastatic colorectal cancer and malignant pleural effusions and ascites. Studies have also shown that the positive expression of CA50 is related to the degree of differentiation, stage and lymph node metastasis of colorectal cancer (as shown in Table 1).

Table 1 TNM staging of colorectal cancer and serum CA50, CA242, CA199, and carcinoembryonic antigen

Carbohydrate Antigen 724

Carbohydrate antigen 724 (CA724) is a mucin-like high molecular weight glycoprotein recognized by two monoclonal antibodies, cc49 and B72.3.

Studies have shown that CA724 is an independent risk factor for progression-free survival and overall survival in patients with elevated CEA before colorectal cancer surgery, and its specificity for colorectal cancer diagnosis is significantly higher than its sensitivity [8]. Studies have also found that the areas under the receiver operating characteristic curves (ROC curves, AUCs, range 0-1, 0 for the worst, 1 for the best) for CEA, CA199, CA724, and CA242 in diagnosing colorectal cancer are 0.840, 0.735, 0.648, and 0.703, respectively. The AUC for the combined diagnosis of the four is 0.990, and the diagnostic value is greatly improved (as shown in Figure 5) [9].

Fig.5 ROC curves of CEA, CA199, CA724, CA242 and combined diagnosis

Compared with single detection, the combined detection of colorectal cancer tumor markers has better sensitivity, specificity, AUC and higher diagnostic performance. It can also provide clinicians and patients with data for disease diagnosis, treatment and prognosis, thus facilitating subsequent diagnosis and treatment of patients.

In summary, since colorectal cancer has a high incidence and mortality rate in my country, regular physical examinations are particularly important. Don't panic when you find that certain indicators are elevated. Consult a specialist in time to make a comprehensive judgment based on the elevated levels, personal circumstances and family history. Monitor the dynamic changes of tumor markers regularly and combine imaging examinations when necessary.

References:

[1] Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues[J]. Semin Cancer Biol, 1999, 9(2): 67-81.

[2] Kim H, Jung HI, Kwon SH, et al. Preoperative neutrophil-lymphocyte ratio and CEA is associated with poor prognosis in patients with synchronous colorectal cancer liver metastasis[J]. Ann Surg Treat Res, 2019, 96(4): 191-200.

[3] Lin JK, Lin CC, Yang SH, et al. Early postoperative CEA level is a better prognostic indicator than is preoperative CEA level in predicting prognosis of patients with curable colorectal cancer[J]. Int J Colorectal Dis, 2011, 26(9): 1135-1141.

[4] PAN Lifeng, LIANG Junlin. Expression characteristics of serum CA242 levels in patients with newly diagnosed colorectal cancer[J]. Chinese Practical Medicine, 2015, (10): 58-60.

[5] Wang Qilong, Chen Nanzheng, Lü Tiesheng. Evaluation value of serum CEA, CA19-9 and CA242 for colorectal cancer metastasis and prognosis[J]. Journal of PLA Medicine, 2020, 32(6): 29-33.

[6] Gao Shuping. Clinical significance of serum CA50, CEA and CA242 detection in patients with colorectal cancer before and after surgery [J]. Journal of Radioimmunology, 2010, 23(1):26-27.

[7] Li Hai, Shi Minghai, Ma Xiaoqiang, et al. Research progress on colorectal cancer related markers [J]. Journal of Ningxia Medical College, 2006, 28(3): 263-265.

[8] Zhao Xiaopeng, Zhao Meng, Ren Li. Predictive value of combined detection of preoperative serum CEA, CA19-9, and CA724 for the prognosis of patients undergoing surgery for stage I to III colorectal cancer [J]. Shandong Medicine, 2019, 59(34): 66-69.

[9] Zhong Meiwen, He Huiping, Xu Haosheng. Diagnostic value of CEA, CA199, CA724 and CA242 for colorectal cancer[J]. Chinese Journal of Modern Medicine, 2022, 24(01): 6-9.