Alpha-Fetoprotein (AFP)

 Alpha-fetoprotein (AFP) is a fetal serum protein that shares sequence homology with albumin. It is normally synthesized during gestation by the liver, yolk sac, and gastrointestinal tract. Following birth, AFP rapidly clears from the circulation. It may be elevated in patients with cirrhosis, viral hepatitis, drug or alcohol abuse, as well as pregnancy and may be used for screening of fetal spinal cord defects and placental disease.

Serum levels of AFP are elevated in up to 80% of patients with  hepatocellular carcinoma (HCC). Changes in serum AFP levels reflect the course of disease. In patients with cirrhosis, elevation of serum AFP may be increased for up to 18 months before symptoms of HCC manifest and may be used to assist in the diagnosis. An elevation of AFP greater than 400 ng/mL is predictive for HCC with a specificity >95%. In the setting of cirrhosis and a growing liver mass, many centers use a level greater than 1,000 ng/mL as presumptive evidence of HCC and do not require a biopsy.

Beta Subunit of Human Chorionic Gonadotropin (β-hCG)

Beta subunit of human chorionic gonadotropin (β-hCG) is normally produced by the placenta and human fetal tissue. Elevated serum β-hCG is most commonly associated with pregnancy, gestational trophoblastic disease, and germ cell tumors. It can also be found in hypogonadal states and with marijuana use. β-hCG and AFP are elevated in up to 85% of patients with germ cell tumors, but only in about 20% of those with stage I disease. In patients with extragonadal or metastatic disease, highly elevated serum levels of β-hCG or AFP can establish a diagnosis of nonseminomatous germ cell tumor instead of biopsy. Serial measurements of β-hCG every 2–3 months for 1 year following treatment is important as elevation is often the first sign of recurrence, indicating the need to restart treatment. β-hCG is also used to diagnose and monitor response to treatment of gestational trophoblastic disease (Table 1).

Cancer-Associated Antigen 15–3

Elevated cancer-associated antigen 15–3 (CA15-3 levels) may be found in patients with  breast cancers and, with much less specificity and sensitivity, in patients with  ovarian cancer,  lung cancer, or prostate cancer. Increased levels may be associated with pregnancy and lactation, benign breast or ovarian disease, endometriosis, pelvic inflammatory disease, and hepatitis.

Because of a lack of sensitivity for  early detection and lack of specificity, it has not been approved for screening of early breast cancer. However, high preoperative serum levels of CA15-3 are associated with adverse patient outcome. CA15-3, like  carcinoembryonic antigen (CEA) and cancer-associated antigen 27–29 (CA27-29), are most useful for monitoring treatment response in women with breast cancer, especially in advanced disease.

Serial determinations of tumor markers after primary treatment can detect recurrent/metastatic disease with lead times of 2–9 months over clinical symptoms. However, the clinical value of this lead time remains to be determined. The ASCO guidelines do not recommend serial monitoring of CEA, CA27-29, or CA15-3 after primary therapy, except in selected situations, where patients cannot be followed by conventional diagnostic techniques.

Cancer-Associated Antigen 19–9

Cancer-associated antigen 19–9 (CA19-9), an intercellular  adhesion molecule, is an epitope of sialylated Lewis A blood group antigen. Elevated serum levels of CA19-9 are found typically in patients with pancreatic and biliary tract cancers and less often in  gastric cancer, ovarian cancer,  colorectal cancer,  lung cancer,  breast cancer, and  endometrial cancer. Elevated levels of CA19-9 are also found in acute cholangitis, cirrhosis, or other cholestatic diseases. Five percent of the population is genotypically Lewis-null blood type and will never produce CA19-9 antigen, even in the presence of tumoral disease. The sensitivity and specificity for pancreatic cancer has been estimated to be 80–90%. These values correlate with tumor size so that CA19-9 has limited value in identifying patients with small surgically resectable cancers (Table 1).

Cancer-Associated Antigen 27–29

Cancer antigen 27–29 (CA27-29; synonym: BR 27–29) is a normal epithelial cell  mucin-1 (MUC1) apical surface glycoprotein. Elevated serum levels are highly associated with  breast cancer. However they can also be found in  colorectal cancer, stomach cancer, renal cancer,  lung cancer,  ovarian cancer,  pancreatic cancer,  endometrial cancer, and liver cancer and in a number of noncancerous conditions, including first trimester pregnancy, endometriosis, ovarian cyst, and benign kidney, liver, and breast disease. Therefore, it has no role in breast cancer screening. Serum CA27-29 levels are elevated in approximately one third of women with early-stage breast cancer (stages I or II) and in two thirds of women with stages III or IV. There is no agreement regarding the ability of CA27-29 to detect asymptomatic recurrence after curative treatment. Serial monitoring is currently not recommended by the ASCO guidelines (Table 1).

CA125

CA125 is a glycoprotein that is expressed by coelomic epithelium of ovaries, fallopian tubes, the endometrium, and the uterine cervix. Up to 90% of  ovarian cancer is coelomic epithelial ovarian cancer and overexpresses CA125. This glycoprotein can be detected in most cases of endometrioid carcinoma,  ovarian serous carcinoma, and ovarian clear cell carcinoma. Mucinous tumors however express this antigen less frequently. Serum levels of CA125 may also be elevated in cancers of the endometrium, fallopian tubes, pancreas, breast, colon, and lungs. Noncancerous conditions with elevated CA125 levels include menstruation, pregnancy, endometriosis, pelvic inflammatory disease, liver disease, pancreatitis, peritonitis, and inflammation of the pleura. CA125 is an important tumor marker for the diagnosis of epithelial ovarian cancer although it is not perfectly sensitive or specific for ovarian cancer. CA125 can be used clinically to determine response to treatment and predict relapse and survival (Table 1).

Carcinoembryonic Antigen (CEA)

CEA is a normal mucosal cell oncofetal glycoprotein involved in cell adhesion. It is overexpressed in gastric, pulmonary, breast, pancreatic, and predominantly colorectal adenocarcinomas. It may also be elevated in the serum of heavy smokers and patients with ulcerative colitis, pancreatitis, and cirrhosis. Its role as a screening tool remains uncertain because of poor sensitivity and specificity. In patients with established disease, the absolute serum level of CEA correlates with disease burden and has prognostic value. After complete resection, elevated preoperative levels of CEA return to baseline, and persistently elevated levels should warrant a search for residual tumor. CEA serum levels should be checked every 3 months for at least 3 years in patients with stage II or III colon cancer if the patient is a candidate for re-resection because elevated levels give a 1.5–6-month lead time for recurrence detection in comparison to other methods such as imaging. Early detection of asymptomatic recurrence increases the likelihood of a subsequent complete resection (Table 1).

Cytokeratin 19 Fragments

CYFRA 21–1 is a soluble fragment of cytokeratin 19 expressed in normal squamous cells. Elevated serum concentrations are found in tumors of squamous origin, including  lung cancer and are associated with short patient survival. The sensitivity of cytokeratin 19 fragments (CYFRA 21–1) depends on the histological type, being the lowest for  small-cell lung cancer (about 16–40%). It is not used in early detection or monitoring of disease and has not been incorporated in the ASCO guidelines for patients with lung cancer.

Lactate Dehydrogenase (LDH)

Lactate dehydrogenase (LDH) is a ubiquitous enzyme that catalyzes the conversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+. Increased serum levels of LDH have been shown in a number of cancers, including melanoma, lymphoma, germ cell tumors, and  small-cell lung cancer. Elevated levels of LDH can also be caused by a number of noncancerous conditions, including heart failure, hypothyroidism, anemia, as well as lung and liver diseases.

Matrix Metalloproteinase-9 (MMP-9)

Matrix metalloproteinase-9 (MMP-9) is a member of the zinc-dependent homologous proteinase family that degrades extracellular matrix proteins, such as cell adhesion receptors, chemokines, growth factors, and their receptors and protease inhibitors. They are implicated in proliferation of endothelial and hematopoietic stem cells by inducing the release of KIT ligand.

MMP-9 expression is elevated in most tumor tissues, including  ovarian cancer, thyroid carcinoma,  hepatocellular carcinoma, and gastrointestinal carcinoma. Expression of MMP-9 has been detected in both glioma and its endothelial cells. Increasing levels of MMP-9 as measured by in situ hybridization and  immunohistochemistry correlate with higher-grade gliomas. In glioblastoma patients, serum levels of MMP-9 are significantly higher in patients with radiologic evidence of disease compared to patients whose disease is inactive.

Placental Alkaline Phosphatase (PLAP)

Placental isoenzyme of PLAP is increased in 30% of  ovarian cancer (especially serous cystadenocarcinoma), as well as endometrium cancer,  lung cancer,  breast cancer, and 40% of seminoma (75% in metastatic seminoma). Smokers may also have elevated PLAP levels.

Prostate-Specific Antigen (PSA)

 Prostate-specific antigen (PSA) is a glycoprotein that is expressed by normal prostate tissue and is overexpressed in prostate cancer. It is a sensitive and specific marker for this cancer. Levels of PSA depend upon the age and race of the patient. The predictive value for cancer is 20–30% if serum levels are greater than 4 ng/mL and 50% for values exceeding 10 ng/mL. However, 20–30% of patients with prostate cancer have levels within the normal range. The American Urological Association recommends that serial PSA measurements be obtained routinely to detect early recurrence in men who have undergone primary therapy for localized disease. PSA levels should decrease and remain undetectable after radical prostatectomy or at low levels following radiation therapy and cryotherapy. The nadir serum PSA and percent PSA decline at 3 and 6 months predict progression-free survival in men with metastatic prostate cancer treated with  androgen ablation therapy. The degree of PSA decline following second-line treatment of metastatic disease correlates with disease survival (Table 1).

YKL-40

YKL-40 is a member of the mammalian chitinase-like proteins that is highly conserved among different species. It has no enzymatic activity due to amino acid substitutions at the catalytic site. In vitro studies suggest that YKL-40 plays a role in proliferation and differentiation of malignant cells, by decreasing apoptosis of cancer cells, stimulating angiogenesis, and inducing proliferation of fibroblasts surrounding the tumor and remodeling of the extracellular matrix. Elevated serum values of YKL-40 have been reported in a variety of cancers, including breast, colon/rectum, ovary, lung, and kidney cancers, glioblastoma, and melanoma. YKL-40 levels may also be increased in other diseases with an inflammatory component.

YKL-40 is highly overexpressed in a subset of patients with glioblastoma multiforme (GBM) in comparison to low-grade glioma and detected in serum by  ELISA. In a prospective study of 143 patients with high-grade gliomas, serum levels of YKL-40 were increased in patients with active disease compared to those with absence of radiographic disease. Elevated levels of YKL-40 also correlated with shorter survival in GBM patients and anaplastic gliomas in a multivariate analysis. YKL-40 is also a potential predictor of survival for patient with primary central nervous system lymphoma.

In patients with  endometrial cancer or  ovarian cancer, elevated preoperative levels of YKL-40 may identify a subset of high-risk patients with worse clinical outcome. Advances have shown that YKL-40 provokes an immune response and can be used as one of the targets for glioma vaccines.