Liver Cancer Tumor Markers

Biomarker or molecular testing is well-established in clinical practice for some cancers. The comprehensive list of FDA-approved biomarkers, sometimes called tumor markers, that guide cancer diagnosis and treatment decisions continues to grow, thanks to clinical trials. Some markers, such as PD-L1 expression, help inform immunotherapy use in many cancers, but not in liver cancer. Biomarkers that guide liver cancer treatment decisions, also known as liver tumor markers, are still under investigation.

In oncology, biomarkers play different roles:

• Detecting presence of cancers: To identify cancer at an early stage, when treatment is most effective.
• Monitoring disease progression: To track changes in tumor size, spread, activity and response to treatment.
• Identifying therapeutic targets: To guide the development of targeted therapies.
• Predicting therapeutic responses: To evaluate how a patient may respond to specific treatments.
• Predicting the likelihood of recurrence: To assess the risk of cancer returning after treatment.

Currently, there are a few well-established liver cancer biomarkers used in clinical practice.

Alpha-fetoprotein (AFP)

AFP is the most commonly used liver tumor marker. In fetuses, it is produced by the fetal liver and yolk sac during early pregnancy. As a carrier protein, it transports nutrients like fatty acids, bilirubin, copper and nickel.

In healthy adults, AFP is also produced in the liver, and levels are usually low. High levels of AFP in non-pregnant people may suggest certain liver conditions, including liver cancer. However, AFP levels are not always reliable in diagnosing early-stage cancer. It can also rise due to pregnancy and other liver diseases, such as chronic hepatitis and cirrhosis. To improve the accuracy of cancer diagnosis, doctors combine AFP testing with imaging tools like CT scan, MRI or ultrasound.

As a prognostic marker, AFP levels can indicate how aggressive liver cancer is. Very high AFP levels (>1000 ng/mL) may suggest the cancer has spread to blood vessels and are linked to poorer outcomes.

As a predictive marker, AFP can help doctors decide on treatment options for liver cancer. Ramucirumab is an FDA-approved drug for patients with AFP levels of 400 ng/mL or higher. It can be used when liver cancer does not respond to sorafenib treatment. AFP levels serve as a marker to identify patients who may benefit from this treatment.

AFP is also useful for monitoring treatment response. If AFP levels drop after treatment, it usually means the treatment is working. If levels remain high, the cancer may still be present or have returned.

AFP has different forms based on its structure. Sometimes, doctors also check the levels of AFP variants to improve accuracy. The key variants are AFP-L1, AFP-L2, and AFP-L3. Among these, AFP-L3 is most specific to liver cancer. Measuring the AFP-L3 ratio can help differentiate liver cancer from other liver diseases.

Abnormal prothrombin (APT)

Abnormal prothrombin (APT) or des-γ-carboxy prothrombin (DCP) is another marker for diagnosing liver cancer. It is especially useful for detecting liver cancer in patients with normal AFP levels. For years, it has been widely used in Japan, Europe and the US.

While AFP is the most commonly used marker for liver cancer, researchers are studying other markers that can improve detection and diagnosis.

Cell-free DNA (cfDNA)

cfDNA are fragments of DNA from liver cancer cells that can be found in the bloodstream. Higher levels of cfDNA with liver cancer-related somatic mutations, chemical modifications (e.g., methylation) and fragmentation patterns can be used as tumor markers for early detection and monitoring of post-treatment residual tumor or recurrence. Research is also currently being done on whether these markers can be used to predict treatment success in the future.

Glypican-3 (GPC3)

GPC3 is a protein that is overexpressed in liver cancer cells but not in normal cells. This makes it a promising marker for liver cancer detection and diagnosis. It may serve as a supplementary liver cancer marker where AFP levels are normal. It may also be useful in distinguishing hepatocellular carcinoma (HCC) from other types of liver cancer.

During histopathology assessments, a technique called immunohistochemistry (IHC) stains GPC3 in liver biopsy samples to confirm its presence.

Scientists are also exploring GPC3-targeted treatments, such as CAR T-cell therapy, in a phase I clinical trial.

Golgi 73 (GP73)

GP73 is a protein whose levels increase when liver cells are damaged. While it is not specific to liver cancer, researchers are studying its potential role in cancer detection. High GP73 levels have been found in other cancers, such as stomach, prostate, bladder, and pancreatic cancer.

Plasma microRNA panels

Scientists are also investigating whether microRNA (small genetic fragments) in the blood can serve as liver tumor markers. This research is still in early stages, but microRNA panels could become useful in the future.

Although these markers show promise, none have replaced AFP in routine liver cancer screening. Early and accurate detection can improve treatment options and disease outcomes. This is why doctors continue to rely on AFP along with imaging tests like ultrasound, CT, or MRI to diagnose and monitor liver cancer. Ongoing research will hopefully lead to more reliable markers, further improving patient outcomes in the future.