Tumor Markers

• Now there is a discussion of the following tumor markers.
  1. CA 15-3.
  2. CA 549.
  3. CA 125.
  4. CA 72-4
  5. CA 27.29.
  6. CA 19-9

Tumor Markers:

Definition of Cancer antigen (CA antigen)

1. The tumor marker is the carbohydrate antigen (CA) or cancer antigen (CA).
2. These antigens are released by the tumor cells.
3. These CA (cancer antigens) are released in the blood circulation, giving information about the tumor spread.
4. These markers can also be increased in benign conditions, like infection or inflammation, or benign tumors.

CA 15-3 (Cancer antigen 15-3)

1. These are abbreviated as CA for carbohydrate antigen or cancer antigen.
2. This is detected by the use of two antibodies.
   1. Murine monoclonal antibody against the membrane-rich extract of human breast cancer metastasis to the liver.
   2. The second monoclonal antibody was developed against the human milk fat globule membrane.
3. This tumor marker 15-3 is used to stage breast cancer and monitor the treatment.
4. In <50% of the cases, the level is high in localized breast cancer or in the case of a small tumor.
5. In the case of metastatic breast cancer, 80% of cases have raised CA-15-3 levels.
6. For the screening of breast cancer, CA 15-3 is limited.
7. CA 15-3 was the first breast tumor available.
8. CA 15-3 is raised in benign breast diseases and other malignancies like lung, pancreas, ovary, and prostate.
9. CA 15-3 is used not for the diagnosis but for monitoring the treatment effect.

The normal CA 15-3

1. The upper limit is 25 kU/L.

An elevated level is seen in the following:

1. Primary Breast cancer (23 %).
2. Metastatic breast cancer (69 %).
3. Pancreatic tumors (80 %).
4. Lung tumors (70 %).
5. Ovarian tumors (64 %).
6. Colorectal tumors (64 %).
7. Liver cancer (28 %).

Elevated level in Benign conditions like:

1. Benign liver (42 %).
2. Benign breast diseases (16 %).

CA 549 (Cancer antigen 549)

1. This is an acidic glycoprotein abbreviated as CA from carbohydrate antigen.
2. This is a carcinoma-associated mucin antigen, which is a tumor marker for breast cancer.
3. It has two species with a molecular weight of 400 kD and 512 kD.

Normal CA 549

1. In the healthy women population, 95% is below 11 kU/ L.
2. Another source: The upper limit of normal was established as 15.5 U/mL.

Benign conditions when CA 549 is positive:

1. Pregnancy.
2. Benign breast diseases.
3. Benign liver diseases.

The malignant condition when CA 549 is positive:

1. Metastatic carcinoma of:
   1. Ovary (50%).
   2. Lung (33 5).
   3. Prostate (40%).
   4. Breast
2. This is a better marker in the monitoring of breast carcinoma treatment.

Drawbacks of CA 549:

1.  CA 549 lacks the sensitivity and specificity to act as an effective screening tool.
2. CA 549 is elevated in some pregnancies, liver diseases, and in benign breast diseases.
3. It may be raised in the ovarian, lung, and even prostate cancers.
4. It has limited value in detecting early breast cancer because of its low values in the early stages of breast cancer.

CA 27.29 (Cancer antigen 27.29)

1. This is also the breast carcinoma marker.
2. It is approved by the FDA.
3. This is used for the staging of breast cancer and the monitoring of its treatment.
4. In <50%, its level is high in localized breast cancer or in a small tumor burden.
5. In the case of metastatic breast cancer, 65% show an elevated level.
6. This test is not useful for the screening of breast cancer.
7. It is useful in recurrent breast tumors in stages II and stages III.
8. It is proven better than CA 15-3 in detecting recurrent breast cancer.

The normal level of CA 27-29

1. <38 units/mL (<38 kU/L).

CA 125 (Cancer antigen 125)

Introduction of CA 125:

1. This is a high molecular mass glycoprotein.
2. This is recognized by the monoclonal antibody OC- 125.
3. It has a 24% carbohydrate.
4. Its physiological function is unknown.

Normal CA 125

1. 0 to 35 units/mL (<35 kU/L).
2. Another source: The normal level in the healthy population is up to 35 kU/L.

Response of CA 125 to treatment:

1. CA 125 is a highly accurate tumor marker of a nonmucinous epithelial tumor of the ovary.
2. It is raised in 80% of females with ovarian cancer.
3. This tumor marker has high sensitivity and specificity for ovarian cancer.
4. CA 125 is also used to determine the response of the patient to the treatment.
5. The serial determination of CA 125, a progressive decrease in the value, indicates the response of the tumor to the treatment.
6. A second look laparotomy will be positive in 97% of the patients where the CA 125 value is >35 units/mL.
7. Whereas only 56% positive second-look laparotomy when the value is <35 units/mL.
8. After two courses of chemotherapy, if there is a remarkable fall in the CA 125 value is a very good indicator of the response to chemotherapy. This is a good prognostic sign.
9. In patients with a response to radiation, chemotherapy, or surgery, a delayed rise in the CA 125 level indicates recurrence in 93% of the patients.
10. Raised in malignant conditions like:
    1. Ovarian carcinoma.
    2. Endometrial carcinoma.
    3. Pancreatic Tumors.
    4. Lung Tumors.
    5. Breast Tumors.
    6. Colorectal and other GI tract tumors.
    7. Lymphoma.
    8. Peritoneal carcinomatosis.
11. Benign conditions are in which is positive:
    1. The follicular phase of the menstrual cycle.
    2. Cirrhosis.
    3. Hepatitis.
    4. Endometriosis.
    5. Pericarditis.
    6. Early pregnancy.
12. Useful for the prognosis of endometrial carcinoma.

Important facts:

1. This is not useful for screening for ovarian cancer.
2. This can not be used to differentiate ovarian cancer from other malignancies.
3. CA 125 is raised in ovarian cancers:
   1. 50 % positive in stage I.
   2. 90 % positive in stage II.
   3. > 90 % positive in stages III and IV.
4. The increasing level of CA 125 correlates with the tumor size and staging.
5. This can differentiate ovarian benign from malignant conditions.
6. Postoperative falls in the level of CA 125 predict survival.
7. CA 125 can help to diagnose the residual disease after the treatment.
8. Persistent rise after the 3 cycles of chemotherapy indicates a poor prognosis.
9. The detection of recurrent metastasis is 75% accurate.

CA 19-9 (Cancer antigen 19-9)

1. This is glycolipid. This carbohydrate antigen exists on the surface of cancer cells.
   1. In serum, it exists as a mucin glycoprotein complex.
2. This is synthesized by:
   1. Normal human pancreatic cells
   2. Biliary ductular cells.
   3. Gastric epithelial cells.
   4. Colon epithelial cells.
   5. Endometrial cells.
   6. Salivary gland epithelial cells.

CA 19-9 response to tumors:

1. There is raised the level of CA 19-9 in pancreatic cancer compared to benign pancreatitis.
2. If a patient has ascites, jaundice, and raised CA 19-9 level, there is the possibility of hepatobiliary cancer.
3. CA 19-9 may not be raised in all cases of pancreatic cancer.
   1. Around 70% of pancreatic carcinoma and 65% of hepatobiliary cancer shows CA 19-9 elevated level.
4. If the patient has a positive response to surgery or radiation, or chemotherapy, then there will be a decrease in the CA 19-9 level.
   1. A rapid rise in CA 19-9 level may be associated with recurrent or progressive tumor growth.
5. There may be a mild raised level of CA 19-9 in gastric cancer, colorectal cancer, hepatoma, and 6% to 7% of non-gastrointestinal cancers.
6. There is a very mild increase of CA 19-9 in cases of pancreatitis, gallstones, inflammatory bowel disease, cystic fibrosis, and cirrhosis.

Normal (Source 2):

1. <37 units/L  (<37 kU/L).

CA 19-9 increased level is seen in:

1. Colorectal carcinoma (30 %).
2. Pancreatic tumors(80 %).
3. Hepatobiliary tumors (67 %).
4. Stomach cancers (40 to 50 %).
5. Hepatocellular carcinoma (30 to 50 %).
6. Breast cancer (15 %).

CA 19-9 Useful for:

1. In the monitoring of pancreatic and Colorectal carcinoma.
2. CA 19-9 is a tumor marker for diagnosis and response to treatment and the surveillance of pancreatic or hepatobiliary cancers.

CA 72-4 (Cancer antigen 72-4)

1. This is a marker of the GI tract and ovary.
   1. Elevated levels of CA 72-4 are found in gastric cancer.
   2. This is also raised in benign diseases like:
      1. Pneumonia.
      2. Pancreatitis.
      3. Cirrhosis.
      4. Ovarian cyst.

Advantages of CA 72-4:

1. CA 72-4 level after curative surgery of gastric cancer remains in the normal range.
   1. In 70% of the cases in recurrence, its level is increased prior to the clinical diagnosis.
2. Along with CA 125, Ca- 72-4 increases the diagnostic value for ovarian cancer.
3. There is a correlation between colorectal carcinoma with dukes classification.

CA 72-4 Positive in:

1. Lung cancer (40 %).
2. Ovarian cancer (36 %).
3. GI tract cancer (6.7 %).
4. Another source:
   1. 40% sensitivity for colorectal and gastric carcinoma diagnosis and overall 95% specificity.
   2. 50% sensitivity for ovarian cancer and overall 95% specificity.

Tumor markers

Test	marker for tumor
CA 125	Ovarian carcinoma
CA- 549	Breast cancer
CA 15-3	Breast cancer
CA 72-4	Gastric carcinoma
CA 19-9	Pancreatic carcinoma

Questions and answers:

• Please see tumor markers parts 1, 2, and 4.

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