research about cancer of the liver

Advances in Liver Cancer Research

The hepatitis B virus (shown here) consists of DNA encased in a many-sided protein shell. Chronic infection with the hepatitis B virus can increase the risk of liver cancer. 

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat liver cancer in adults and children. They are also looking for biomarkers that can provide information about liver cancer, such as how aggressive it is or whether it is likely to respond to a particular therapy.

This page highlights some of the latest research in liver cancer, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Prevention of Liver Cancer

There are several types of liver cancer in adults. The two most common types are hepatocellular carcinoma (HCC) and  intrahepatic cholangiocarcinoma  (ICC). ICC is cancer that occurs in parts of the bile ducts within in the liver. It is sometimes considered a type of  bile duct cancer .

HCC is the most common form of liver cancer among adults in the United States. The survival rates of both HCC and ICC are low. Several conditions can increase your chances of developing HCC or ICC. (For a full list of risk factors for HCC and ICC, see our page on Liver and Bile Duct Cancer .) Researchers are testing ways to prevent and treat some of these conditions.

The biggest risk factor for HCC is cirrhosis , a disease that occurs when scar tissue forms in the liver and prevents it from working correctly. Less than 10% of people with cirrhosis will develop HCC. Through NCI’s Phase 0/I/II Cancer Prevention Clinical Trials Program , several studies are testing whether drugs used to treat other diseases can prevent cirrhosis from advancing to liver cancer. Drugs that are being tested include cholesterol-lowering medications (statins), low doses of a cancer drug called erlotinib (Tarceva) , and green tea polyphenols .

Hepatitis Virus Infection

Another common risk factor for HCC is chronic infection with hepatitis B virus or hepatitis C virus . Infection with hepatitis B virus can be prevented by vaccination. There is no vaccine for hepatitis C virus, but researchers are working on developing and testing one .

Chronic infection with hepatitis D virus may also be a risk factor for HCC. NIH's Liver Cancer Program recently completed a study of Mongolian patients that helps explain how infection with the hepatitis D virus might cause liver cancer .

Inflammation

Inflammation of the colon ( colitis ) and inflammation of the bile ducts (primary sclerosing cholangitis) increase the chances of developing ICC. NCI researchers recently found preliminary evidence that these conditions may  make gut bacteria leak into the liver , leading to a buildup of certain immune cells that help ICC grow. Scientists think that blocking these gut bacteria or immune cells might be a way to prevent ICC.

Early Detection of Liver Cancer

Liver cancer that is diagnosed at an early stage has a good chance of being cured with surgery, liver transplantation, or treatments such as radiofrequency ablation . There are no standard screening tests for liver cancer, but several imaging and blood tests are being studied to see if they can detect liver cancer at an early stage, especially among those who are most at risk for liver cancer 

Surveillance

Liver cancer surveillance means closely monitoring someone who has an increased chance of getting HCC. Someone having surveillance may get regular ultrasound exams of the liver, sometimes with a blood test for alpha-fetoprotein .

There are many challenges with these surveillance strategies, and they have not been found to prevent people from dying of liver cancer. For example, doctors cannot always tell which patients are at high risk for HCC and may benefit from surveillance. 

There is also a financial burden associated with surveillance. Sometimes it is hard for patients to get to a clinic for the tests. Plus, the tests for liver cancer surveillance are not always accurate. 

However, scientists are looking at ways to address these problems. For example:

• Researchers from NCI's Translational Liver Cancer (TLC) Consortium  are working to improve surveillance and early detection. In one study, TLC-supported researchers are exploring whether electronic medical records could be used to alert both doctors and patients when a patient is due for a liver ultrasound or alpha-fetoprotein test.
• Another TLC study is exploring how to make HCC surveillance more personalized by matching people with different surveillance tests depending on their level of liver cancer risk.
• A third TLC-supported study aims to find a way to predict which patients with cirrhosis will develop liver cancer. In this study, researchers are using machine learning to combine multiple factors and predict HCC risk in people with cirrhosis .
• In 2020, NCI scientists developed a blood test that, in a small study , correctly pinpointed people with chronic liver disease (including cirrhosis) who later developed HCC. The blood test was able to pick out those who developed HCC even 10 years before their cancer was diagnosed. The scientists are continuing to study how the blood test works.

Small, early-stage liver tumors can be difficult to detect on an ultrasound exam, especially for people have obesity or cirrhosis. Scientists are developing new kinds of imaging tests that may be better at detecting small tumors.

For example, one group of TLC-funded researchers is using small molecules, called peptides , that attach to liver cancer cells. These peptides are linked to dyes that can be seen with a CT scan or MRI .

NCI scientists are also testing a radioactive substance, called a radiotracer, that may help doctors see certain parts of the body. The scientists are learning if the radiotracer may be better able to find HCC than standard imaging . 

A biomarker is a molecule found in blood or other tissues that serves as a sign of a condition or disease. Scientists are working to find biomarkers in blood, urine, or other body fluids that are reliable signs of early-stage liver cancer.

Scientists in NCI’s Early Detection Research Network (EDRN) , a network of institutions researching biomarkers for early-stage cancer, have identified several promising biomarkers of early-stage liver cancer .

These biomarkers are being further studied in NCI’s HCC Early Detection Strategy Study , a long-term study of people with cirrhosis. Investigators are looking to see if these biomarkers are found in blood samples from people who later develop liver cancer.

NCI is also leading a study of Baltimore, MD residents to explore genetic features of liver cancer and to find biomarkers for early detection or prevention. Using data from this study, NCI researchers found several potential biomarkers of HCC .

Liver Cancer Treatment

Liver cancer is often diagnosed at an advanced stage. Treatment options for advanced liver cancer include chemotherapy,  targeted therapy , immunotherapy , radiation, embolization , and ablation . For more information on treatment options, see our page on liver cancer treatment .

Targeted Therapy

Targeted therapies are drugs that attack molecules that help cancer cells grow, divide, and spread.

Targeted Therapy for HCC

For many years, sorafenib (Nexavar) was the only targeted therapy available for people with advanced HCC. But research has led to the discovery of several newer targeted therapies for HCC. 

However, even with these new treatments, most people with HCC don't live for more than 5 years after being diagnosed. So, better treatments are still needed.

Targeted Therapy for ICC

New research has led to FDA approval of several targeted therapies for people with ICC. In addition, ongoing research is testing whether other targeted therapies work for ICC:

• A clinical trial tested the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) on adults with advanced cancer, including ICC, that has a specific mutation in the  BRAF gene . The study helped lead to FDA approval of this drug combination in 2022. Around 5% of people with ICC have the specific BRAF mutation.
• FDA has also approved another targeted therapy for ICC called  futibatinib (Lytgobi) . It is approved for adults with ICC whose cancer cells have a genetic change that fuses the   FGFR2 gene to another gene. Around 15% of people with ICC have such a genetic change. 
• Two ongoing clinical trials are comparing pemigatinib and infigratinib (separately) with standard chemotherapy for people who are newly diagnosed with ICC or cancer of the bile ducts outside of the liver (extrahepatic cholangiocarcinoma). 
• Other clinical trials are testing new targeted therapies for people with ICC who have specific gene changes in their cancer cells. For example, studies are testing targeted therapies such as olaparib (Lynparza)  and LY3410738 in people whose ICC or extrahepatic cholangiocarcinoma cells have changes in the IDH1 gene or IDH2 gene .

Immunotherapy

Immunotherapy for hcc.

Immunotherapy  is now a standard treatment for people with HCC. Several  immune checkpoint inhibitors  are currently approved to treat HCC.

In 2022,  FDA approved a combination of the immunotherapies tremelimumab (Imjudo) and durvalumab (Imfinzi) for people with HCC that can’t be removed by surgery. A clinical trial showed that this combination was more effective than sorafenib alone.

Immunotherapy for ICC

Immunotherapy is a standard treatment for people with ICC. Scientists are also researching new ways to use immunotherapy to treat ICC. For example:

• A clinical trial of people with advanced bile duct cancer, including ICC, compared immunotherapy (durvalumab) plus chemotherapy (gemcitabine and cisplatin) with chemotherapy alone . The immunotherapy-plus-chemotherapy combination helped people live longer and was FDA approved in 2022. It is now a standard treatment for people with ICC.
• In a small clinical trial of people with advanced bile duct cancer, NCI researchers showed that an immunotherapy ( pembrolizumab ) plus two chemotherapy drugs ( capecitabine and oxaliplatin ) shrank or stopped the growth of tumors in more than 80% of patients.
• In a 2021 study of mice with ICC , NCI researchers saw promising results with a combination of two immunotherapy drugs—an immune checkpoint inhibitor and a drug called a  CD40 ligand . The researchers are hoping to launch a clinical trial of the combination for people with ICC.
• NCI researchers have also found that people whose HCC or ICC cells that are molecularly similar to each other are more likely to respond to immunotherapies  than people whose HCC or ICC cells are diverse. A related study by NCI scientists may explain why: Cancer-killing immune cells were less active in tumors with diverse HCC or ICC cells .

Some examples of ongoing immunotherapy research in liver cancer include:

• Studying why immunotherapies only work for some people with liver cancer. NIH's  Liver Cancer Program has recently identified molecular characteristics linked with survival after immunotherapy treatment for HCC or ICC .
• NCI’s Immuno-Oncology Translational Network (IOTN)  is exploring how the immune system interacts with HCC tumors as they develop and what makes some HCCs more sensitive to treatment with immune checkpoint inhibitors .
• An NCI-sponsored clinical trial testing a CAR T-cell therapy for adults with advanced HCC. The therapy involves removing a person’s own immune cells and modifying them in a lab so they can better recognize and attack HCC. The goal of the trial is to see if the new therapy is safe.
• An NCI-sponsored clinical trial testing an investigational immunotherapy drug called M9241 in combination with chemotherapy for adults with ICC. 

Radiation Therapy

NCI’s National Clinical Trials Network (NCTN)  is currently supporting two ongoing clinical trials of radiation therapy for people with HCC that cannot be removed with surgery.

• One trial is comparing proton therapy with standard photon therapy . Proton therapy is a new kind of radiation therapy that may cause less harm to healthy tissues.
• The other trial is testing sorafenib with a type of radiation therapy called stereotactic body radiation therapy . This approach uses special equipment to position the patient and precisely deliver radiation directly to the tumor, which may cause less harm to the rest of the body. Early findings have shown that sorafenib with stereotactic body radiation therapy is more effective than sorafenib alone.

Transarterial Therapy

Some therapies can be put directly into the blood vessels that feed liver tumors. For example, transarterial therapy, also called transarterial embolization , involves placing small beads into blood vessels to cut off blood flow to the tumor.

Researchers are exploring ways to enhance transarterial therapy, such as using radioactive beads that not only block blood flow but also deliver radiation to the tumor. These therapies are also being studied in combination with targeted therapies and with immunotherapies.

For instance, an NCI-led clinical trial is testing a type of transarterial embolization called TACE plus two immunotherapies (tremelimumab and durvalumab) and a targeted therapy (bevacizumab) as a treatment for people with HCC.

Transplantation

Some people with early-stage liver cancer can be cured with a liver transplant. Currently, only patients with a few small tumors in their liver can get a liver transplant. But a 2022 study found that patients who first get treatment to make their tumors smaller can also be cured by a liver transplant .

Precision Medicine

Precision medicine is an approach to patient care that allows doctors to select treatments that are most likely to help patients based on the biology of their tumors.

Biomarkers that are found in tumor tissue (sometimes called tumor markers ) may aid precision medicine approaches for liver cancer treatment.

For instance, investigators in NCI’s Center for Cancer Research are studying liver tumors in finer detail to try to identify molecular features that can help guide treatment decisions or lead to more-precise treatments.

For example, a 2021 study from NCI’s TIGER-LC consortium identified biomarkers in blood that could potentially help doctors determine how aggressive a patient’s HCC is.

Childhood and Adolescent Liver Cancer Treatment

Several types of liver cancer can develop in children and adolescents. The most common types are HCC and  hepatoblastoma . Adolescents are more likely to develop HCC than younger children. Standard treatments for children or adolescents with liver cancer include surgery, chemotherapy, radiation therapy, and ablation therapy.

Because childhood and adolescent liver cancer is fairly rare, randomized clinical trials of new treatments can be a challenge to conduct. The Children’s Oncology Group , part of the NCI–sponsored National Clinical Trials Network , is collaborating with other institutions on the first randomized international trial for children with liver cancer, called the Pediatric Hepatic International Tumor Trial (PHITT). The trial aims to enroll more than 1,000 patients with hepatoblastoma and about 200 patients with hepatocellular carcinoma . This trial will test treatments that are adjusted by risk group and look for biomarkers of prognosis.

Adjusting Treatment by Risk Group in PHITT

PHITT includes several different studies that are using patients’ risk groups  to help guide new treatment approaches. A risk group reflects how likely a patient’s cancer is to come back after treatment. The trial involves multiple studies (or arms) including:

• One study testing whether fewer cycles of cisplatin , which can cause hearing loss at its standard dose, can effectively treat children with low-risk hepatoblastoma who have already had surgery to remove their tumors.
• A study randomly assigning children with intermediate-risk hepatoblastoma to receive cisplatin alone or cisplatin in combination with other chemotherapy drugs. The outcomes and side effects of the regimens will be compared. The hope is that less exposure to toxic drugs will lead to fewer side effects and complications later in life.
• A study randomly assigning children with high-risk hepatoblastoma to receive one of two different combinations of chemotherapy to see if one combination is better than the other.
• A study testing whether adding gemcitabine and oxaliplatin to standard chemotherapy benefits children and adolescents who have HCC that can’t be surgically removed (unresectable) or has spread beyond the liver (metastatic). 

Biomarkers of Prognosis

PHITT also aims to identify biomarkers of prognosis. Trial researchers are collecting samples of participants’ blood, healthy tissue, and cancer tissue to create the world's largest repository of biological samples from children and adolescents with liver cancer.

By studying these samples, scientists have identified several potential biomarkers . These biomarkers could one day be used to guide treatment decisions for patients with hepatoblastoma.

A specific pattern in the tumor tissue of children with hepatoblastoma, called small cell undifferentiated (or SCU) histology, was once thought to be a biomarker of an aggressive cancer. But a 2021 Children’s Oncology Group-led study found that children with SCU hepatoblastomas actually lived just as long as those without SCU .

NCI-Supported Research Programs

Many NCI-funded researchers working at the NIH campus, as well as across the United States and throughout the world, are seeking ways to address liver cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in liver cancer.

The Phase 0/I/II Cancer Prevention Clinical Trials Program conducts early-phase clinical trials of interventions that have the potential to prevent cancer, including liver cancer.

The Liver Cancer Pooling Project (LCPP) is an effort to pool data from different sources to study potential causes of liver cancer. Although there are several known risk factors for liver cancer, not all liver cancers are related to known causes. NCI investigators also use LCPP data to study factors that may protect people from developing liver cancer. For example, a study from LCPP found that people with higher levels of sex hormones (like testosterone) in their blood had a higher risk of developing HCC .

The Thailand Initiative for Genomics and Expression Research in Liver Cancer (TIGER-LC) is a consortium of researchers and clinicians from NCI and Thailand studying genetic differences between HCC and ICC, the most common form of liver cancer in Thailand. The study is designed to address liver cancer prevention, early detection, and treatment.

Early Detection

NCI’s Translational Liver Cancer (TLC) Consortium supports research to improve the early detection of liver cancer. The goals of the consortium are to better define the risks of developing liver cancer, improve surveillance for people who are at high risk of liver cancer, and improve the detection of early-stage liver tumors.

The Liver Cancer Program is a multidisciplinary network of researchers and clinicians from across the NIH who are dedicated to improving the early detection, diagnosis, treatment, and health disparities of liver cancer in adults.

NCI’s Immuno-Oncology Translational Network (IOTN) is a network of researchers who are developing new immunotherapies to treat cancer, including liver cancer. NCI’s Fusion Oncoproteins in Childhood Cancers (FusOnC2) Consortium , part of the Cancer Moonshot, is studying the cause of fibrolamellar hepatocellular carcinoma (FLC/FLHCC) a type of liver cancer in children, adolescents, and young adults.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for liver cancer prevention , screening , and treatment.

Liver Cancer Research Results

The following are some of our latest news articles on liver cancer research:

• Can the New “Omics” on the Block Find Liver Cancer in Blood?
• Seldom-studied immune cells in the liver may be helpful in treating cancer
• Study Tackles Key Questions about Liver Transplants for People with Liver Cancer
• Study Identifies Potential Drug Target to Prevent Some Liver Cancers
• NIH Scientists Develop Blood Test to Help Improve Liver Cancer Screening
• Atezolizumab Plus Bevacizumab Approved to Treat Liver Cancer
• Some Children with Liver Cancer May Need Less Chemotherapy, Study Suggests

View the full list of Liver and Bile Duct Cancer Research Results and Study Updates .

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Liver cancer articles from across Nature Portfolio

Liver cancer, or hepatic cancer, is a malignant tumour that grows on the surface or inside the liver. The leading cause is a viral infection with hepatitis B or C virus. The most frequent liver cancers are hepatocellular carcinoma and hepatoblastoma (formed by immature liver cells).

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Study identifies driver of liver cancer that could be target for treatment.

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Metabolic diseases like obesity can increase the risk of developing liver cancer, research has shown. But how one disease predisposes to the other is unclear. In a new study, Yale researchers uncovered a key role played by a molecule called fatty acid binding protein 5 (FABP5) and found that inhibiting it blocked tumor progression in many cases.

The molecule, said the researchers, could be a target for cancer treatment in the future.

The findings were published April 25 in Nature Metabolism .

Hepatocellular carcinoma is a type of cancer that accounts for 90% of liver tumors and it’s the second-leading cause of cancer-related deaths worldwide.

“ Obesity-related hepatocellular carcinoma is also on the rise in the United States as rates of metabolic disease increase,” said Carlos Fernández-Hernando , the Anthony N. Brady Professor of Comparative Medicine and professor of pathology at Yale School of Medicine (YSM) and senior author of the study.

Obesity can lead to non-alcoholic fatty liver disease, in which excess fat builds up in the liver. In some people, this disease transitions to a more inflammatory condition called non-alcoholic steatohepatitis, Fernández-Hernando explained, and this can lead to liver cancer.

To study what might be driving this disease transition, the researchers fed mice a specific diet that induces fat accumulation in the liver. Previous studies have shown that this diet over time induces non-alcoholic fatty liver disease, followed by non-alcoholic steatohepatitis, and then hepatocellular carcinoma in mice, mimicking the disease transition in humans.

While the mice were on this diet, the researchers looked for any changes in gene expression across various liver cells.

“ One thing that stood out to us was that this molecule FABP5 was highly elevated in liver tumor cells,” said Jonathan Sun, a Ph.D. student in Fernández-Hernando’s lab and lead author of the study. “We also observed that it was expressed in immune cells called macrophages localized in the tumors.”

Depending on the context and the cell type, FABP5 can perform different roles, but ultimately, it’s a molecule that binds to fatty acids and moves them around a cell. Supporting its potential relevance in humans, using data from the Cancer Genome Atlas — a collection of more than 20,000 human cancer samples — the researchers found that FABP5 was overexpressed in human hepatocellular carcinoma cells and patients with high expression of FABP5 had a significantly lower five-year survival rate than patients with low FABP5 expression.

“ Together, these findings told us that inhibiting FABP5 might be a good target for treating tumor progression,” said Yajaira Suárez , the Anthony N. Brady Professor of Comparative Medicine and professor of pathology at YSM and co-senior author of the study.

After treating a subset of mice with a molecule that inhibits FABP5, the researchers found that it blocked tumor progression. While 50% of the mice not treated with inhibitor went on to develop liver tumors, just 25% of the mice treated with the inhibitor did. The tumors they did develop were also fewer in number and smaller than those of their untreated counterparts. These findings were further substantiated in mice genetically deficient in FABP5, which were significantly resistant to obesity-driven hepatocellular carcinoma.

The researchers found two potential explanations for why inhibiting FABP5 had this effect on tumors: Inhibiting FABP5 made the tumor cells more susceptible to a cell death called ferroptosis, and it changed the tumor microenvironment.

“ Inhibiting FABP5 caused macrophages to shift to a more pro-inflammatory state that led them to activate other immune cells,” said Sun. “It rewired the microenvironment to be more aggressive against cancer cells.”

The findings are promising when it comes to potential treatments for liver cancer in humans, said Fernández-Hernando, who is also a member of the Yale Cancer Center and director of the Vascular Biology and Therapeutics Program at YSM. Going forward, he and his lab aim to better understand the link between FABP5 and ferroptosis at the molecular level and test how FABP5 inhibition might affect other cancers and illnesses like cardiovascular disease.

Collaborators of the study include the laboratory of Rachel Perry at YSM, the laboratories of Iwao Ojima and Martin Kaczocha at Stony Brook University, and members of the Liver Center at YSM.

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Monday, March 13, 2023

Scientists reveal a potential new approach to treating liver cancer

Results in cell and mouse studies may have implications for the development of a new class of anticancer drugs.

Scientists at the National Institutes of Health and Massachusetts General Hospital in Boston have uncovered a potential new approach against liver cancer that could lead to the development of a new class of anticancer drugs. In a series of experiments in cells and mice, researchers found that an enzyme produced in liver cancer cells could convert a group of compounds into anticancer drugs, killing cells and reducing disease in animals.

The researchers suggest that this enzyme could become a potential target for the development of new drugs against liver cancers, and perhaps other cancers and diseases as well.   

“We found a molecule that kills cells in a rare liver cancer in a unique way,” said translational scientist Matthew Hall, Ph.D., one of the leaders of the work at NIH’s National Center for Advancing Translational Sciences (NCATS). “It emerged from a screening to find molecules that selectively kill human liver cancer cells. It took a lot of work to figure out that the molecule is converted by an enzyme in these liver cancer cells, creating a toxic, anticancer drug.”

Hall, Nabeel Bardeesy, Ph.D., a liver cancer specialist at Massachusetts General Hospital and their colleagues reported their results March 13 in Nature Cancer .

The finding stems from a collaboration between Massachusetts General Hospital and NCATS researchers. Bardeesy was originally studying cholangiocarcinoma, a type of liver cancer that affects the bile duct. The cancer is characterized by mutations in the IDH1 enzyme. Bardeesy’s team wanted to find compounds and drugs that might be effective against the IDH1 mutation. Through a collaboration with NCATS, Hall and other NCATS scientists rapidly tested thousands of approved drugs and experimental cancer agents for their effectiveness in killing cholangiocarcinoma cells, with IDH1 as a target.

They found several molecules, including one called YC-1, could kill the cancer cells. Yet, when they looked to see how YC-1 was working, they discovered the compound wasn’t affecting the IDH1 mutation.

The Massachusetts researchers showed that the liver cancer cells made an enzyme, SULT1A1. The enzyme activated the YC-1 compound, making it toxic to tumor cells in cancer cell cultures and mouse models of liver cancers. In the animal models treated with YC-1, the liver tumors either had reduced growth or shrank. Conversely, the researchers found no changes in tumors treated with YC-1 in animals with cancer cells lacking the enzyme.

The researchers examined other databases of drug screening results in compound and drug libraries to match drug activity with SULT1A1 activity. They also looked at a large National Cancer Institute database of anticancer compounds for additional possibilities to test for their activity with the enzyme.

They identified several classes of compounds that relied on SULT1A1 for their tumor-killing activity. Using computational methods, they predicted other compounds that also likely were dependent on SULT1A1.

“Once we found SULT1A1 activated YC-1, it led us to ask, ‘What other compounds are active and can kill cells by the same mechanism?’ Hall said. “Can we identify other compounds that were being developed and demonstrate that they were also active because of SULT1A1 activation? The answer was yes. We found other compounds with the same mechanism of action as YC-1.”

The scientists suggest these findings have broader implications for developing new anticancer drugs. “We think these molecules have the potential to be an untapped class of anticancer drugs that depend on SULT1A1 for their activity against tumors,” Bardeesy said.

The researchers see YC-1 and similar molecules as prototypes for developing compounds that could be effective against important proteins on cells. Modifying different parts of these molecules could make them more specific for such proteins. The researchers point to the creation of a “toolkit of SULT1A1-activated molecules” that could affect many different targets.

Such a toolkit is comprised of hundreds of known molecules. In theory, the toolkit covers many types of enzymes, called sulfotransferases, that are active in different tissues in the body. For example, in addition to SULT1A1, the human sulfotransferase SULT4A1 is active in the brain. It can activate a subset of the molecules in the toolkit. This might be useful in developing drugs specific for brain cancers.

“We knew SULT1A1-dependent drugs had already been identified,” Bardeesy said. “Our results suggest there could be other SULT1A1-dependent compounds with ranges of different targets. Identifying such compounds and targets on cells could have potential implications for developing other types of small molecules and drugs, not just limited to these cancers. This might become a new approach for some diseases.”

This work was supported by the MGH Fund for Medical Discovery Award; the Cholangiocarcinoma Foundation Christopher J. Wilke Memorial Research Fellowship; NCI 1K99CA245194-01, the V Foundation for Cancer Research, the Department of Defense Translational Team Science Award W81XWH-17-1-0491; NCI SPORE P50 CA127003; the Gallagher Chair in Gastrointestinal Cancer Research and Target Cancer Foundation; and the MGH Excellence Award.

About the National Center for Advancing Translational Sciences (NCATS):  NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit  https://ncats.nih.gov .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Researchers hope identifying blood proteins may lead to earlier prediction of risk, increase treatment options

Jacqueline Mitchell

BIDMC Communications

A new study suggests that proteins detectable in the blood could improve predictions about risk of liver cancer, which is typically diagnosed at later stages when survival rates are lower.

Led by investigators at Harvard-affiliated Beth Israel Deaconess Medical Center and Mass General Brigham, the team’s results are published in JNCI.

Liver cancer, or hepatocellular carcinoma (HCC), ranks as the third leading cause of cancer worldwide and the second leading cause of cancer-related deaths globally, with its incidence rate steadily increasing. Detection of liver cancers often occurs at advanced stages, when life expectancy typically spans less than 12 months. Currently, there is a notable deficiency in accurate, sensitive, and specific tools for the early detection of liver cancer. Many existing methods are relatively expensive, invasive, or limited in accessibility, primarily confined to major hospitals.

“Liver cancer rates are rapidly increasing, and liver cancer has a high mortality rate, but if we can diagnose it early, therapeutic interventions can be potentially curative.” Xinyuan Zhang, BWH

The team used proteomics, the study and profiling of proteins, to develop a minimally invasive model for diagnosing or screening for liver cancer at an earlier, more treatable stage. Using the SomaScan Assay Kit — a high-throughput proteomics platform that measures protein levels in biological samples, available through BIDMC’s Genomics, Proteomics, Bioinformatics and Systems Biology Center — the investigators detected 1,305 biologically relevant proteins that may be present in the blood at early stage of disease.

“Liver cancer rates are rapidly increasing, and liver cancer has a high mortality rate, but if we can diagnose it early, therapeutic interventions can be potentially curative,” said lead author Xinyuan (Cindy) Zhang of the Channing Division of Network Medicine at Brigham and Women’s Hospital. “We need to have a way to detect this form of cancer early enough to intervene with surgery or liver transplantation to treat the disease before it becomes metastatic.”

The study team used SomaScan to analyze plasma samples from participants in both the Nurses’ Health Study and the Health Professional Follow-Up Study, two longitudinal, ongoing, prospective cohorts in the U.S. Notably, they examined blood samples obtained from patients an average of 12 years before their liver cancer diagnosis to pinpoint protein biomarker signals. After examination, the researchers cross-referenced medical records to confirm whether these patients ultimately developed liver cancer.

From the blood samples, the researchers identified 56 plasma proteins that showed significantly elevated levels in patients with liver cancer compared to matched control samples without HCC. The team selected four of these proteins to create a predictive model, which they tested on the U.K. Biobank Pharma Proteomics dataset, comprised of 50,000 individuals, 45 of whom were diagnosed with liver cancer. Their model had greater accuracy in predicting liver cancer compared to traditional risk factors.

The authors caution that their study included a limited number of liver cancer cases and further validation in larger, more diverse patient populations and in high-risk populations is needed.

“It’s always been challenging to identify highly specific disease biomarkers in the blood using traditional tools, but new technology allows us to detect a broad and dynamic range of both high and low abundant proteins,” said co-senior author Towia A. Libermann of the division of Interdisciplinary Medicine and Biotechnology at BIDMC. “New insights into the biological mechanisms underlying liver cancer development emerge from our data that may lead to identification of novel therapeutic targets. Most importantly, we were able to validate these early detection biomarkers using alternative protein analysis techniques and in an independent population cohort from the U.K.”

The study team aims to extend their methodology to uncover additional plasma protein biomarkers, explore biomarkers linked with different cancer types, and gain deeper insights into the role of HCC risk factors across specific patient populations. With further progress, the protein biomarkers investigated in the study could potentially hold clinical significance as a non-invasive test for assessing liver cancer risk.

 “Even though further investigation in additional populations is needed, our results reveal a robust circulating protein profile associated with liver cancer years before diagnosis, which is truly remarkable,” said co-senior author Xuehong Zhang, who conducted work on this study while at the Channing Division of Network Medicine at the Brigham. Zhang is now at Yale

Additional authors include Long H. Ngo, Simon T. Dillon, Xuesong Gu and Michelle Lai, of BIDMC; Longgang Zhao of BWH; Tracey G. Simon and Andrew T. Chan of MGH; and Edward L. Giovannucci of the Harvard T.H. Chan School of Public Health.

This study was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) through grants R21 CA238651. Andrew T. Chan served as a consultant for Bayer Pharma AG, Pfizer Inc., and Boehringer Ingelheim for work unrelated to this topic. He has also received grant support from Pfizer Inc., Zoe Ltd, and Freenome for work unrelated to this topic.

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Liver Cancer: Latest Research

ON THIS PAGE: You will read about the scientific research being done to learn more about liver cancer and how to treat it. Use the menu to see other pages.

Doctors are working to learn more about liver cancer, ways to prevent it, how to best treat it, and how to provide the best care to people diagnosed with liver cancer. The following areas of research may include new options for patients through clinical trials. Always talk with your doctor about the best diagnostic and treatment options for you.

Cancer vaccines. Cancer vaccines are treatments that may help the immune system recognize and attack hepatocellular carcinoma (HCC) cells. Sometimes the vaccine is given with an immune system stimulant, such as sargramostim (Leukine, Prokine).

Combining systemic cancer medications. Different drugs destroy cancer cells in different ways. Using a combination of drugs can increase the chance that more cancer cells will be destroyed. Many times, 1 drug will help another drug work better.

Combining other therapies. Researchers are looking into whether combining treatments, such as radiofrequency ablation (RFA) and chemoembolization, is more effective than using these treatments separately.

Anti-angiogenesis drugs. In addition to sorafenib and regorafenib, which are discussed in Types of Treatment , several other anti-angiogenic drugs are being studied in clinical trials.

Greater use of liver transplantation. Researchers are investigating the possibility of expanding the criteria for liver transplantation for HCC. This would make more patients eligible for the procedure.

Gene therapy. This new treatment changes a gene to fight cancer. Although gene therapy is in the very early stages of development, some clinical trials are already underway. In one example, the new gene makes chemotherapy work better. In this type of treatment, a gene can be directly injected into the tumor. The doctor then gives the patient an inactive drug, and the new gene helps activate the drug in the tumor. This approach is also being tested in combination with the other treatments listed above.

Palliative and supportive care. Clinical trials are underway to find better ways of reducing symptoms and side effects of current HCC treatments to improve comfort and quality of life for patients.

Looking for More About the Latest Research?

If you would like more information about the latest areas of research in liver cancer, explore these related items that take you outside of this guide:

To find clinical trials specific to your diagnosis, talk with your doctor or search online clinical trial databases .

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Liver cancer: Molecular signaling pathway of tumor development decoded

Study reveals new starting point for the treatment of hepatocellular carcinoma.

As a malignant disease of the liver cells, hepatocellular carcinoma (HCC) is one of the main causes of cancer-related deaths. While the treatment options for this aggressive type of cancer remain limited, the incidence is increasing. A research team led by Latifa Bakiri and Erwin Wagner from MedUni Vienna’s Clinical Institute for Laboratory Medicine has now described a molecular signalling pathway that plays a key role in the development of liver cancer, thereby identifying a potential new starting point for the development of therapeutic treatments. The results of the study have just been published in the journal Proceedings of the National Academy of Sciences ( PNAS ).

In their research, the international team led by MedUni Vienna, built on earlier study results that had suggested the involvement of certain transcription factors (c-Fos and c-Jun) in the development of hepatocellular carcinomas. Transcription factors are proteins involved in numerous cellular processes, including the control of genes associated with the development of HCC. To advance these findings, the scientists developed a new mouse model.

The experiments carried out with these proteins showed that the combination with previously unexplored (Fra) proteins in this context triggers the cascade of tumour formation. Specifically, this involves the interaction between c-Jun and Fra-2, which the studies showed to be essential in the development of liver cancer. "It is remarkable that we were able to reverse tumour growth by switching off the protein combination of c-Jun and Fra-2," reports the head of the study Erwin Wagner.

The study also showed that tumour growth can be stopped by blocking a specific gene (c-Myc). "Accordingly, our research results suggest that the molecular signalling pathway we have identified represents a promising starting point for further research into HCC and the development of new therapeutic measures," concludes first author Latifa Bakiri.

Hepatocellular carcinoma is an aggressive tumour with rapid progression and limited therapeutic options. Even though the incidence has increased significantly in Western countries in recent decades, this type of cancer is still comparatively rare. However, due to its poor prognosis, HCC is one of the most common causes of cancer-related deaths. HCC occurs in particular in the context of advanced liver disease (cirrhosis, chronic hepatitis B) and is often only diagnosed at a late stage.

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• Latifa Bakiri, Sebastian C. Hasenfuss, Ana Guío-Carrión, Martin K. Thomsen, Peter Hasselblatt, Erwin F. Wagner. Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc . Proceedings of the National Academy of Sciences , 2024; 121 (18) DOI: 10.1073/pnas.2404188121

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Cancer Research Catalyst The Official Blog of the American Association for Cancer Research

Home > Cancer Research Catalyst > Why Is Liver Cancer on the Rise?

Why Is Liver Cancer on the Rise?

Although liver cancer isn’t as prevalent as lung cancer or breast cancer, this cancer is now the fastest-increasing cause of cancer death in the United States. In the Spring 2018 issue of Cancer Today, contributing editor Sue Rochman explored contributing factors for the increased liver cancer incidence since the mid-1970s.

A study published in the December 2018 JAMA Oncology found that incidence of liver cancer increased by 75 percent worldwide between 1990 and 2015. In many countries, liver cancer is among the top four causes of cancer death. Worldwide, hepatitis B—a virus that damages the liver and is spread through contact with infected blood, semen and other body fluids—is the most common cause of liver cancer. In the U.S., fewer than 5 percent of liver cancer cases are caused by hepatitis B, primarily because children in the U.S. have routinely been vaccinated against the virus since 1982.

A study published in the January/February 2018 CA: A Cancer Journal for Clinicians suggests that about 71 percent of liver cancer diagnoses in the U.S. can be attributable to preventable risk factors. One of these risk factors in the U.S. is hepatitis C, a virus that spreads through contact with the infected blood. The study, which was led by Farhad Islami, the strategic director for cancer surveillance research at the American Cancer Society in Atlanta, found that hepatitis C infection was responsible for close to 25 percent of liver cancer cases. Treatments to cure hepatitis C infection are available but can be pricey, the article notes, and other preventable factors are also increasing the incidence and death rates.

The study attributed about 22 percent of liver cancer deaths to cigarette smoking. Obesity is another driving force. Previous research has found that from 2000 to 2003, about 26 percent of liver cancer cases were attributable to excess body weight; from 2008 through 2011, body weight could be linked to about 36 percent of liver cancer cases that occurred. Alcoholism and nonalcoholic steatohepatitis, a type of severe fatty liver disease, are also risk factors.

“Basically, preventing exposure to those risk factors would mean a substantial proportion of liver cancer deaths—about 50 percent—could be prevented,” said Islami.

To learn more information about trends in mortality and liver cancer incidence, patients’ experiences, and treatments for the disease, read the full article on Cancer Today ’s website . Cancer Today is a magazine and website for cancer patients, survivors and caregivers published by the American Association for Cancer Research.

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• What is liver cancer? An expert explains

Learn more from liver surgeon Sean Cleary, M.D.

Mayo Clinic explains liver cancer

Sean P. Cleary, M.D., Hepatobiliary and Pancreatic Surgeon, Mayo Clinic: Hello. I'm Dr. Sean Cleary, a liver surgeon at Mayo Clinic. In this video, we'll cover the basics of liver cancer: What is it? Who gets it? What are the symptoms, diagnosis and treatment? Whether you're looking for answers for yourself or someone you love, we're here to give you the best information available. First, before we get into liver cancer, let's talk about what your liver actually does. Your liver is a football-sized organ that sits under the right portion of your abdomen, beneath your diaphragm and beside your stomach. The liver has over 500 known functions. But the most common way the liver works is by balancing the chemicals in your blood, making bile--which is a crucial part of the digestive process, clearing toxins from the blood and regulating blood clotting. Each year, about 24,500 men and 10,000 women are diagnosed with liver cancer in the United States. Most people who have cancer in the liver have cancer that spreads, or metastasizes, to the liver from another site, such as the colon, breast, stomach or other organs. It is important to differentiate this type of cancer from liver cancer that begins in the liver cells. The treatment of cancer that spreads to the liver, rather than starting in the liver, is determined by the original organ in the body where the cancer started. So for example, if the cancer started in your colon and then spread to the liver, it would be called metastatic colon cancer. Today we'll be focusing on liver cancer that starts in the liver. As with all cancers, liver cancer start when changes or mutations accumulate in the DNA of those liver cells. The cells DNA is the material that provides instructions for every chemical and structural process in your body. DNA mutations cause changes in these instructions. And when enough of these mutations accumulate and affect important genes the cells can begin to grow out of control and eventually form a tumor or a mass of cancerous cells.

Who gets it?

Most liver cancers occur in people with an underlying liver disease. But sometimes liver cancer happens in people with no underlying liver disease and it's not exactly clear why. Liver disease can cause longstanding inflammation in the liver and accumulate mutations that can lead to cancer. One of the big problems is that many people can have liver disease and not be aware of it until their liver is quite damaged or a cancer forms. Here are some things that we know increase your risk of developing liver cancer: If you have chronic infections of hepatitis B or C, cirrhosis, certain inherited liver diseases such as hemochromatosis and Wilson's disease, diabetes, non-alcoholic fatty liver disease, or an exposure to aflatoxins, you have a greater chance of developing liver cancer. Excessive alcohol consumption over many years can also lead to irreversible liver damage and lead to liver cancer.

What are the symptoms?

Most people don't have signs and symptoms in the early stages of primary liver cancer. When signs and symptoms do appear, they may include unintentional weight loss, loss of appetite, upper abdominal pain, nausea and vomiting, general weakness and fatigue, abdominal swelling, jaundice where your eyes and skin turn yellow, and white, chalky stools. Other symptoms can include fever, enlarged veins on the abdomen that can be seen through the skin, and abnormal bruising or bleeding. Screening programs using ultrasound are very effective at finding liver cancer before symptoms develop. And we encourage everyone with known liver problems to talk to their doctor about whether screening is right for you.

How is it diagnosed?

Tests and procedures used to diagnose liver cancer include blood tests. These may reveal liver function abnormalities. Imaging tests such as an ultrasound, CT, and MRI. And if you are diagnosed, the next step is determining the extent of liver cancer or stage. Your doctor will then ask for staging tests to help determine the size and location of cancer and whether it has spread. Imaging tests used to stage liver cancer include CT scans, MRI, and bone scans. There are different methods of staging liver cancer. For example, one method uses Roman numerals one through four, and another uses letters A through D. Your doctor evaluates your cancer stage to determine your treatment options and your prognosis.

How is it treated?

There are a number of ways your doctor can help you develop a strategy to combat liver cancer. Surgery may be scheduled to remove the tumor or remove the entire liver to perform a liver transplant. Your treatment may include radiation therapy, which uses high-powered energy from sources such as X-rays and protons, to destroy cancer cells and shrink tumors. Doctors carefully direct the energy to liver while sparing the healthy surrounding tissue. Chemotherapy is a common treatment and is the use of powerful chemicals to combat and hopefully kill the cancer. Targeted drug therapy focuses on specific abnormalities present within cancer cells. By blocking these abnormalities, targeted drug treatments can cause cancer cells to die.

Liver cancer is a frightening diagnosis, but finding a team of experts to work together can help you sort out your best options for treatment using the latest technology, most advanced research and specialized care techniques. With new therapies worked on every day. We have lots of hope for positive outcomes. If you'd like to learn even more about liver cancer, here are related videos, or visit mayoclinic.org. We wish you well.

Liver cancer begins in the liver cells. The most common type of liver cancer starts in cells called hepatocytes and is called hepatocellular carcinoma.

Liver cancer is cancer that begins in the cells of your liver. Your liver is a football-sized organ that sits in the upper right portion of your abdomen, beneath your diaphragm and above your stomach.

Several types of cancer can form in the liver. The most common type of liver cancer is hepatocellular carcinoma, which begins in the main type of liver cell (hepatocyte). Other types of liver cancer, such as intrahepatic cholangiocarcinoma and hepatoblastoma, are much less common.

Cancer that spreads to the liver is more common than cancer that begins in the liver cells. Cancer that begins in another area of the body — such as the colon, lung or breast — and then spreads to the liver is called metastatic cancer rather than liver cancer. This type of cancer is named after the organ in which it began — such as metastatic colon cancer to describe cancer that begins in the colon and spreads to the liver.

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The liver is the largest internal organ in the body. It's about the size of a football. It sits mainly in the upper right portion of the stomach area, above the stomach.

Most people don't have signs and symptoms in the early stages of primary liver cancer. When signs and symptoms do appear, they may include:

• Losing weight without trying
• Loss of appetite
• Upper abdominal pain
• Nausea and vomiting
• General weakness and fatigue
• Abdominal swelling
• Yellow discoloration of your skin and the whites of your eyes (jaundice)
• White, chalky stools

When to see a doctor

Make an appointment with your doctor if you experience any signs or symptoms that worry you.

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Liver cancer happens when liver cells develop changes (mutations) in their DNA. A cell's DNA is the material that provides instructions for every chemical process in your body. DNA mutations cause changes in these instructions. One result is that cells may begin to grow out of control and eventually form a tumor — a mass of cancerous cells.

Sometimes the cause of liver cancer is known, such as with chronic hepatitis infections. But sometimes liver cancer happens in people with no underlying diseases and it's not clear what causes it.

Risk factors

Factors that increase the risk of primary liver cancer include:

• Chronic infection with HBV or HCV. Chronic infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV) increases your risk of liver cancer.
• Cirrhosis. This progressive and irreversible condition causes scar tissue to form in your liver and increases your chances of developing liver cancer.
• Certain inherited liver diseases. Liver diseases that can increase the risk of liver cancer include hemochromatosis and Wilson's disease.
• Diabetes. People with this blood sugar disorder have a greater risk of liver cancer than those who don't have diabetes.
• Nonalcoholic fatty liver disease. An accumulation of fat in the liver increases the risk of liver cancer.
• Exposure to aflatoxins. Aflatoxins are poisons produced by molds that grow on crops that are stored poorly. Crops, such as grains and nuts, can become contaminated with aflatoxins, which can end up in foods made of these products.
• Excessive alcohol consumption. Consuming more than a moderate amount of alcohol daily over many years can lead to irreversible liver damage and increase your risk of liver cancer.

Reduce your risk of cirrhosis

Cirrhosis is scarring of the liver, and it increases the risk of liver cancer. You can reduce your risk of cirrhosis if you:

• Drink alcohol in moderation, if at all. If you choose to drink alcohol, limit the amount you drink. For women, this means no more than one drink a day. For men, this means no more than two drinks a day.
• Maintain a healthy weight. If your current weight is healthy, work to maintain it by choosing a healthy diet and exercising most days of the week. If you need to lose weight, reduce the number of calories you eat each day and increase the amount of exercise you do. Aim to lose weight slowly — 1 or 2 pounds (0.5 to 1 kilograms) each week.

Get vaccinated against hepatitis B

You can reduce your risk of hepatitis B by receiving the hepatitis B vaccine. The vaccine can be given to almost anyone, including infants, older adults and those with compromised immune systems.

Take measures to prevent hepatitis C

No vaccine for hepatitis C exists, but you can reduce your risk of infection.

• Know the health status of any sexual partner. Don't engage in unprotected sex unless you're certain your partner isn't infected with HBV , HCV or any other sexually transmitted infection. If you don't know the health status of your partner, use a condom every time you have sexual intercourse.
• Don't use intravenous (IV) drugs, but if you do, use a clean needle. Reduce your risk of HCV by not injecting illegal drugs. But if that isn't an option for you, make sure any needle you use is sterile, and don't share it. Contaminated drug paraphernalia is a common cause of hepatitis C infection. Take advantage of needle-exchange programs in your community and consider seeking help for your drug use.
• Seek safe, clean shops when getting a piercing or tattoo. Needles that may not be properly sterilized can spread the hepatitis C virus. Before getting a piercing or tattoo, check out the shops in your area and ask staff members about their safety practices. If employees at a shop refuse to answer your questions or don't take your questions seriously, take that as a sign that the facility isn't right for you.

Seek treatment for hepatitis B or C infection

Treatments are available for hepatitis B and hepatitis C infections. Research shows that treatment can reduce the risk of liver cancer.

Ask your doctor about liver cancer screening

For the general population, screening for liver cancer hasn't been proved to reduce the risk of dying of liver cancer, and it isn't generally recommended. People with conditions that increase the risk of liver cancer might consider screening, such as people who have:

• Hepatitis B infection
• Hepatitis C infection
• Liver cirrhosis

Discuss the pros and cons of screening with your doctor. Together you can decide whether screening is right for you based on your risk. Screening typically involves a blood test and an abdominal ultrasound exam every six months.

Liver cancer care at Mayo Clinic

• AskMayoExpert. Hepatocellular carcinoma (adult). Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2018.
• Feldman M, et al. Hepatic tumors and cysts. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 10th ed. Philadelphia, Pa.: Saunders Elsevier; 2016. https://www.clinicalkey.com. Accessed Feb. 21, 2019.
• Marrero JA, et al. Diagnosis, staging and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68:723.
• Adult liver cancer symptoms, tests, prognosis and stages (PDQ) – Patient version. National Cancer Institute. https://www.cancer.gov/types/liver/patient/about-adult-liver-cancer-pdq. Accessed March 1, 2019.
• Hepatobiliary cancers. Plymouth Meeting, Pa.: National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed Feb. 21, 2019.
• Heimbach JK, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358.
• Hepatitis B questions and answers for the public. Centers for Disease Control and Prevention. https://www.cdc.gov/hepatitis/hbv/bfaq.htm. Accessed March 4, 2019.
• Hepatitis C questions and answers for the public. Centers for Disease Control and Prevention. https://www.cdc.gov/hepatitis/hcv/cfaq.htm. Accessed March 4, 2019.
• Cirrhosis. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/liver-disease/cirrhosis/all-content. Accessed Feb. 21, 2019.
• Palliative care. Plymouth Meeting, Pa.: National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed Feb. 21, 2019.
• Adult cancer pain. Plymouth Meeting, Pa.: National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed Feb. 21, 2019.
• Warner KJ. Allscripts EPSi. Mayo Clinic, Rochester, Minn. Aug. 15, 2018.
• Kulik L, et al. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156:477.
• Liver cancer FAQs

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Researchers identify biomarkers in blood to predict liver cancer

by Mass General Brigham

Early detection has the potential to transform treatment and outcomes in cancer care, especially for cancers like liver cancer, which is typically diagnosed at a late stage with limited options for cure. A new study led by investigators from Mass General Brigham and Beth Israel Deaconess Medical Center suggests that proteins detectable in the blood could improve predictions about risk of liver cancer years before typical diagnosis.

Results are published in JNCI: Journal of the National Cancer Institute .

"Liver cancer rates are rapidly increasing, and liver cancer has a high mortality rate , but if we can diagnose it early, therapeutic interventions can be potentially curative," said lead author Xinyuan (Cindy) Zhang, Ph.D., of the Channing Division of Network Medicine at Brigham and Women's Hospital. "We need to have a way to detect this form of cancer early enough to intervene with surgery or liver transplantation to treat the disease before it becomes metastatic."

Liver cancer, or hepatocellular carcinoma (HCC), ranks as the third leading cause of cancer worldwide and the second leading cause of cancer-related deaths globally, with its incidence rate nearly tripled since the 1980s in the US. Detection of liver cancers often occurs at advanced stages, where life expectancy typically spans less than 12 months.

Certain high-risk populations, such as individuals with cirrhosis and hepatitis, stand to benefit from early detection tests significantly. Currently, there is a notable deficiency in accurate, sensitive, and specific tools for the early detection of liver cancer. Many existing methods are relatively expensive, invasive, or limited in accessibility, primarily confined to major hospitals.

The research team included investigators from Mass General Brigham's founding members, Brigham and Women's Hospital and Massachusetts General Hospital, Harvard T.H. Chan School of Public Health, Beth Israel Deaconess Medical Center, and Yale University. The team utilized proteomics (profiling of proteins) to develop a prediction model aimed at diagnosing or screening for liver cancer at an earlier stage.

They used the SomaScan Assay Kit, a high-throughput proteomics platform that measures protein levels in biological samples , available through the Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center. The SomaScan platform allowed them to detect minute levels of circulating proteins that may be present at an early stage of the disease, measuring 1,305 proteins simultaneously in the blood.

"It's always been challenging to identify highly specific disease biomarkers in the blood using traditional tools, but this new technology allows us to detect a broad and dynamic range of both high and low abundant proteins," said co-senior author Towia A. Libermann, Ph.D., of the Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center.

"New insights into the biological mechanisms underlying liver cancer development emerge from our data that may lead to the identification of novel therapeutic targets. Most importantly, we were able to validate these early detection biomarkers using alternative protein analysis techniques and in an independent population cohort from the UK."

The study team used SomaScan to analyze plasma samples from participants in both the Nurses' Health Study and the Health Professional Follow-Up Study, two longitudinal, ongoing, prospective cohorts in the U.S. Notably; they examined blood samples obtained from individuals an average of 12 years before their liver cancer diagnosis to pinpoint protein biomarker signals.

After examination, the researchers cross-referenced medical records to confirm whether these patients ultimately developed liver cancer.

From the blood samples, the researchers identified 56 plasma proteins that showed significantly elevated levels in individuals with liver cancer compared to matched control individuals without hepatocellular cancer. The team selected four of these proteins to create a predictive model, which they tested on the UK Biobank Pharma Proteomics dataset, comprised of 50,000 individuals, 45 of whom were diagnosed with liver cancer.

Their model had greater accuracy in predicting liver cancer compared to traditional risk factors.

The authors caution that their study included a limited number of liver cancer cases, and further validation in larger, more diverse patient populations and in high-risk populations is needed.

"Even though further investigation in additional populations is absolutely needed, our results reveal a robust circulating protein profile associated with liver cancer years before diagnosis, which is remarkable," said co-senior author Xuehong Zhang, MBBS, ScD, who conducted work on this study while at the Channing Division of Network Medicine at the Brigham. Zhang is now at Yale.

The study team also aims to extend their methodology to uncover additional plasma protein biomarkers utilizing the more expanded SomaScan assay measuring 11,000 proteins, explore biomarkers linked with different cancer types, and gain deeper insights into the role of hepatocellular cancer risk factors across specific patient populations.

With further progress, the protein biomarkers investigated in the study could potentially hold clinical significance as a non-invasive test for assessing liver cancer risk.

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Combined therapy makes headway for liver cancer

Adding another drug to immunotherapy increased response rate for hepatocellular carcinoma patients in phase 2 trial, utsw reports.

David Hsieh, M.D., is Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Experimental Therapeutics Research Program of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

DALLAS – May 02, 2024 – A drug that targets a protein known as phosphatidylserine boosted the response rate for hepatocellular carcinoma (HCC) patients receiving immunotherapy without compromising their safety, according to results of a phase two clinical trial conducted by UT Southwestern Medical Center. The findings, published in Nature Communications , show the potential benefits of augmenting immunotherapy for this and other forms of cancer.

“This study shows the promise of improving the success of cancer immunotherapies by targeting other immunomodulating proteins simultaneously,” said study leader David Hsieh, M.D. , Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Experimental Therapeutics Research Program of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

HCC is the most common form of liver cancer and the fourth most frequent cause of cancer-related deaths worldwide. For many years, the only existing treatment for tumors of this kind that can’t be surgically removed was a drug called sorafenib. It works by slowing the growth of tumor-feeding blood vessels. Although this targeted therapy drug was groundbreaking when it was approved by the U.S. Food and Drug Administration in 2007, it extends survival by only a few months.

More recently, immunotherapies – treatments that spur the immune system to fight tumors – have emerged as the most effective treatments for HCC patients. However, only a fraction of patients responded to these drugs when delivered alone, and combining multiple immunotherapies increased the likelihood of serious and occasionally deadly side effects.

Several years ago, researchers discovered that phosphatidylserine, a fatty substance called a phospholipid sometimes present on the surface of cancer cells, appeared to interact with immune cells to prevent them from attacking tumors. An antibody drug called bavituximab that neutralizes phosphatidylserine showed no effect on tumor response, progression, or survival when administered alone across multiple cancer types or when combined with sorafenib in HCC. But bavituximab had never been tested in combination with immunotherapy agents.

Toward that end, Dr. Hsieh and his colleagues recruited 28 patients with HCC receiving care at UT Southwestern and Parkland Health. These patients, whose cancers couldn’t be surgically removed, received imaging of their tumors at the start of the study. They then received a combination of bavituximab and pembrolizumab, an immunotherapy drug approved in 2016 to treat various cancers. While receiving both therapies, these patients had periodic imaging to determine whether their tumors shrank, stopped growing, or continued to grow and multiply. The researchers followed these patients for an average of 28.5 months.

Although previous clinical trials had shown that only about 16% of HCC patients responded to pembrolizumab alone, nine patients, or 32%, responded to the combined therapy. Two of them had a complete response, with no evidence of disease on imaging at the end of the trial. The combined therapy halted progression in another 32% of patients. For responders, the two drugs continued to shrink their tumors for a median time of 13.3 months, and four patients were still responding to the combination therapy when the study ended.

Researchers noted that adding bavituximab did not appear to increase side effects over those taking pembrolizumab alone based on data from prior trials – an important point showcasing this combination’s safety.

These results suggest that adding agents that target phosphatidylserine to immunotherapy regimens could increase the likelihood of response in HCC and potentially other cancers in which this protein might affect anti-cancer immunity.

Other UTSW researchers who contributed to this study include co-first author Muhammad S. Beg, M.D., Adjunct Associate Professor of Internal Medicine; Radhika Kainthla, M.D., Assistant Professor of Internal Medicine; Jay Lohrey, M.D., Assistant Professor of Internal Medicine and Medical Director of the Simmons Cancer Center located at the Moncrief Cancer Institute in Fort Worth; Syed M. Kazmi, M.D., Associate Professor of Internal Medicine; Anil K. Pillai, M.D., Professor of Radiology and Chief of Vascular Interventional Radiology ; Rolf Brekken, Ph.D. , Professor of Surgery and Pharmacology and in the Hamon Center for Therapeutic Oncology Research ; Chul Ahn, Ph.D., Professor in the Peter O’Donnell Jr. School of Public Health and Director of the Biostatistics Shared Resource in the Simmons Cancer Center; Amit G. Singal, M.D., M.S., Professor of Internal Medicine and in the O’Donnell School of Public Health, Medical Director of the Liver Tumor Program, and Chief of Hepatology; Hao Zhu, M.D., Professor in the Children’s Medical Center Research Institute at UT Southwestern (CRI) as well as in Internal Medicine and Pediatrics , co-leader of the Development and Cancer Research Program in the Simmons Cancer Center, and Director of the CRI Tissue Regeneration Program; Yujin Hoshida, M.D., Ph.D., Professor of Internal Medicine and Director of Liver Tumor Translational Research; Adam C. Yopp, M.D., Professor of Surgery, Chief of the Division of Surgical Oncology, and Surgical Director of the Liver Tumor Program; Leticia Khosama, M.S.N., Advanced Practice Registered Nurse; Mary Claire Maxwell, M.S.N., Advanced Practice Registered Nurse; Heather Kline, M.S., Advanced Practice Registered Nurse; Courtney Katz, M.S., Research Associate; and Ellen Siglinsky, B.S., Clinical Research Manager.

Dr. Brekken is an Effie Marie Cain Research Scholar. Dr. Hoshida holds the H. Ray and Paula Calvert Chair in Gastroenterology Oncology in Honor of Udit Verma, M.D. Dr. Kazmi is a Eugene P. Frenkel, M.D. Scholar in Clinical Medicine. Dr. Singal is a Dedman Family Scholar in Clinical Care and holds the Willis C. Maddrey, M.D. Distinguished Chair in Liver Disease. Dr. Yopp holds The Occidental Chemical Chair in Cancer Research. Dr. Zhu holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research.

Drs. Ahn, Brekken, Hoshida, Hsieh, Kazmi, Singal, Yopp, and Zhu are all members of the Simmons Cancer Center.

For this study, Merck provided funding along with pembrolizumab while OncXerna Therapeutics supplied bavituximab. Dr. Hoshida is supported by grants from the National Cancer Institute (CA233794, CA255621), the European Commission (ERC-AdG-2020-101021417), and the Cancer Prevention and Research Institute of Texas (RR180016). This study was also supported by the National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).

Author financial disclosures can be found in the manuscript.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

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Survival for primary liver cancer

Survival depends on different factors. So no one can tell you exactly how long you will live.

Doctors usually work out the outlook for a certain disease by looking at large groups of people. Primary liver cancer is less common. So survival is harder to estimate than for other, more common cancers.

Some of the statistics have to be based on a small number of people. Remember, they can't tell you what will happen in your individual case.

Your doctor can give you more information about your own outlook (prognosis).

You can also talk about this to the Cancer Research UK nurses on freephone 0808 800 4040, from 9am to 5pm, Monday to Friday.

About these statistics

The terms 1 year, 4 year or 5 year survival don't mean that you will only live for 1 or 4 or 5 years.

Organisations such as NHS Digital and researchers collect information. They watch what happens to people with cancer in the years after their diagnosis. So for example, 5 years is a common time point to measure survival. But some people live much longer than this.

5 year survival is the number of people who have not died from their cancer within 5 years after diagnosis.

These figures include people with different types of primary liver cancer including: 

• hepatocellular carcinoma
• intrahepatic bile duct carcinoma
• angiosarcoma

Survival by stage

There are no UK-wide statistics available for liver cancer by stage. Survival statistics are available for each stage of primary liver cancer in England. These figures are for adults diagnosed between 2015 and 2019. 

These are 4 year survival statistics, as 5 year survival statistics are not available. 

More than 45 out of 100 people (more than 45%) with stage 1 liver cancer will survive their cancer for 4 years or more after they're diagnosed. 

Around 35 out of 100 people (around 35%) with stage 2 liver cancer will survive their cancer for 4 years or more after they're diagnosed. 

More than 10 out of 100 people (more than 10%) with stage 3 liver cancer will survive their cancer for 4 years or more after they're diagnosed. 

Almost 5 out of 100 people (almost 5%) with stage 4 liver cancer will survive their cancer for 4 years or more after they're diagnosed.

• Go to more information about primary liver cancer stages

Cancer survival by stage at diagnosis for England, 2022 NHS Digital

These statistics are for net survival. Net survival estimates the number of people who survive their cancer rather than calculating the number of people diagnosed with cancer who are still alive. In other words, it is the survival of cancer patients after taking into account that some people would have died from other causes if they had not had cancer.

Survival for all stages of liver cancer

There are no UK-wide statistics available for the survival for all stages of liver cancer. Survival statistics are available for people with primary liver cancer in England. These figures are for adults diagnosed in England between 2016 and 2020.

For adults diagnosed with liver cancer in England:

• 40 out of 100 people (40%) will survive their cancer for 1 year or more after diagnosis
• almost 15 out of 100 people (almost 15%) will survive their cancer for 5 years or more after they are diagnosed

Cancer survival in England, cancers diagnosed 2016 to 2020, followed up to 2021 NHS England These figures are for people diagnosed with liver cancer in England between 2016 and 2020

Survival for liver cancer by age

There are no UK-wide statistics available for the survival of liver cancer by age. Survival statistics are available for people with primary liver cancer in England. These figures are for adults diagnosed in England between 2015 and 2019. 

5 year survival for liver cancer is generally higher in younger people compared to older people. 

In men diagnosed with liver cancer in England aged:    

• 15 to 44, around 35 out of 100 (around 35%) survive their liver cancer for 5 years or more
• 75 to 99, around 5 out of 100 (around 5%) survive their liver cancer for 5 years or more

In women diagnosed with liver cancer in England aged:

• 15 to 44, 40 out of 100 (40%) survive their liver cancer for 5 years or more
• 75 to 99, 5 out of 100 (5%) survive their liver cancer for 5 years or more  

Cancer survival by age at diagnosis for England, 2022 NHS Digital

These statistics are for net survival. Net survival estimates the number of people who survive their cancer rather than calculating the number of people diagnosed with cancer who are still alive. In other words, it is the survival of cancer patients after taking into account that some people would have died from other causes if they had not had cancer.

What affects survival?

Your outlook is affected by the treatment you have.

Treatment decisions depend on the size of the cancer and whether it has spread. It also depends on the health of your liver tissue that is not affected by the cancer, for example if you have liver cirrhosis. 

Your general health and fitness also affect survival.

• Find out more about treatment options

More statistics

For more in-depth information about survival and liver cancer, go to our Cancer Statistics section .

Related links

Getting diagnosed.

You usually start by seeing your GP. They might refer you for tests or to a specialist if you have symptoms that could be caused by liver cancer.

Risks and causes

Liver cancer is quite rare in the UK, but is increasing. We don’t know what causes most liver cancers. But there are some factors that might increase your risk of developing it.

Treatments include surgery, chemoembolisation (TACE), radiofrequency ablation (RFA), and targeted cancer drugs. 

About liver cancer

Find out about the liver, what primary liver cancer is and how common it is in the UK.

Secondary liver cancer

Secondary liver cancer is when a cancer that started somewhere else in the body has spread to the liver. It is also called liver metastases.

Main primary liver cancer page

Your guide to primary liver cancer, including information about getting diagnosed, the different types and stages of liver cancer, and treatments for the most common type of liver cancer (hepatocellular carcinoma).  If you have cancer that started in another part of your body and has spread to your liver you need to go to our information about secondary liver cancer. 

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