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.

Cirrhosis

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.

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.

Imaging

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.

Biomarkers

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.

Scientists have developed a new test that can help identify people who are likely to develop hepatocellular carcinoma (HCC), the most common form of liver cancer. The approach uses a simple blood test to check for the patient’s previous exposure to certain viruses.

A study of the new approach was led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. The study also involved researchers from the National Institute of Diabetes and Digestive and Kidney Diseases and several academic centers. The findings were published June 10 in Cell.

“Together with existing screening tests, the new test could play an important role in screening people who are at risk for developing HCC. It could help doctors find and treat HCC early. The method is relatively simple and inexpensive, and it only requires a small blood sample,” said the study’s leader, Xin Wei Wang, Ph.D., co-leader of the NCI Center for Cancer Research (CCR) Liver Cancer Program.

Certain factors increase a person’s chances of developing HCC, such as infection with hepatitis B or hepatitis C virus or cirrhosis of the liver. People who have risk factors are recommended to get screened for HCC every six months with an ultrasound with or without a blood test for alpha-fetoprotein.

But not everyone with risk factors for HCC will develop the disease. Although screening can lead to earlier detection, most patients are diagnosed when the cancer is advanced and often incurable. However, HCC that is caught early has a much better chance of being cured.

“We need a better way to identify people who have the highest risk for HCC and who should get screened more frequently,” said Dr. Wang said, who is also part of NCI’s Translational Liver Cancer Consortium. Better early detection and surveillance approaches are particularly important because rates of HCC are rising in the United States.

“A main focus of the NCI CCR Liver Cancer Program is to develop new methods for early detection, diagnosis, and treatment, with the goal of improving outcomes for patients with HCC,” said Tim Greten, M.D., co-leader of the Liver Cancer Program and a collaborator of the study.

Many screening tests detect features of cancer cells. But those features can change over time, and not all cancer cells in a tumor have the same characteristics. The NCI team took a different approach: detecting features of the cancer’s environment rather than cancer cells themselves.

More research is providing evidence that cancer development is influenced by interactions between viruses and the immune system. The team reasoned that certain interactions between viruses and the immune system may raise the risk of developing HCC.

To explore that possibility, the scientists scanned people’s blood for “footprints” left behind by past viral infections. Because these footprints are left in antibodies, proteins made by the immune system, they also reflect how the immune system reacted to the infection. The mixture of footprints each person has creates a unique pattern, which the researchers called a viral exposure signature.

The team checked for the footprints of more than 1,000 different viruses in blood samples from around 900 people, including 150 who had HCC. They identified a specific viral exposure signature that could accurately distinguish people with HCC from people with chronic liver disease and healthy volunteers. This signature contained footprints from 61 different viruses.

The researchers then tested the signature on blood samples from 173 people with chronic liver disease who were part of a 20-year study. During that time, 44 of the participants developed HCC. Using blood samples taken when the cancer was diagnosed, the signature correctly identified those who developed HCC (area under the curve, AUC=0.98). Importantly, the signature also worked when the researchers used blood samples taken at the beginning of the study, up to 10 years before diagnosis (AUC=0.91).

The signature appeared to be far more accurate than an alpha-fetoprotein test (AUC=0.91 vs. 0.62). An AUC of 0.5 indicates that a test is no better than chance in identifying disease, whereas an AUC of 1.0 represents a test with perfect accuracy.

The scientists are continuing to study their approach and plan to test it in clinical trials. They are collaborating with Katherine McGlynn, Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics to test the approach in a prospective surveillance study of people with risk factors for HCC.

It’s possible that viral infections—even ones that don’t cause cancer—may change the immune system in ways that influence the development of other cancers. For example, certain infections may lessen the immune system’s ability to keep cancer cells in check. NCI scientists are testing the viral exposure signature in a study of prostate cancer, and others are considering applying the approach to a screening study for ovarian, esophageal, liver, and breast cancer in Africa.

Researchers have developed a blood test that, in a preliminary study, accurately detected liver cancer, including in people with early stages of the disease. Unlike most other blood tests in development for cancer detection, this one uses a new type of technology, called fragmentomics, to analyze bits of DNA in the blood.

Liver cancer is the third leading cause of cancer death worldwide. When the disease is caught early, upwards of 70% of people survive more than 5 years. But if it’s found after the cancer has spread, that number drops below 20%.

For that reason, people who have a high risk of liver cancer—such as those with cirrhosis or chronic hepatitis B virus infection—are advised to get regularly monitored for the disease. But current tests for liver cancer don’t work very well, aren’t readily available to all who need them, and are expensive.

The new blood test could potentially address those issues, said study co-leader Amy Kim, Ph.D., of Johns Hopkins University School of Medicine.

In the new study, the researchers used machine learning to analyze fragmentomics data and find differences between people with and without liver cancer. When applied to blood samples from hundreds of people—including some known to have liver cancer—the test accurately identified those with liver cancer, including early-stage disease.

They also validated the accuracy of the test using blood samples from another large group of people. The NCI-funded study was published March 1 in Cancer Discovery.

A caveat is the relatively small number of people with liver cancer in the study, Christian Rolfo, M.D., Ph.D., of Tisch Cancer Institute, and Alessandro Russo, M.D., Ph.D., of Papardo Hospital in Messina, Italy, pointed out in a commentary on the study.

Although the results seem promising, the next—and very important—step is to see how the blood test performs in a larger group of people who haven’t yet been diagnosed with liver cancer, noted Tim Greten, M.D., a liver cancer expert in NCI’s Center for Cancer Research, who wasn’t involved in the study.

Study co-leader Victor Velculescu, M.D., Ph.D., of Sidney Kimmel Cancer Center at the Johns Hopkins University School of Medicine, and his colleagues are planning follow-up studies of people at high-risk of liver cancer to see if the approach can catch early-stage disease.

Liquid biopsies and fragmentomics

Scientists have long known that both healthy and cancerous cells shed pieces of their DNA into the bloodstream. More recently, researchers have found that these DNA fragments can act like breadcrumbs, leading straight back to the cancer cells that tossed them out.

That revelation has led to a huge surge in the development of blood tests that detect cancer, said Dr. Greten. Such tests are often called liquid biopsies.

Most liquid biopsy tests developed to date rely on genomics (scanning DNA in blood for cancerous mutations) or epigenomics (analyzing the pattern of chemical tags on DNA in blood). Fragmentomics, in contrast, looks at the pattern of the amount and sizes of DNA fragments in the blood.

In 2019, Dr. Velculescu and his colleagues developed a fragmentomics approach called DELFI that analyzed DNA fragments from throughout the genome.

In a preliminary study, they used DELFI to screen for seven types of cancer, not including liver cancer. DELFI was able to pinpoint whether an individual had cancer and what kind of cancer it was, although its accuracy varied by cancer type.

Given the lack of effective tests for liver cancer, the team decided to see if DELFI could detect liver cancer in the blood. They used DELFI to analyze blood samples from 501 people in the United States and Europe, including 75 people known to have liver cancer and 133 people with liver disease (cirrhosis or hepatitis infection) who were at high risk for liver cancer.

People with liver cancer had DNA fragments that greatly varied in size, whereas people without cancer (including those with liver disease) had DNA fragments that tended to be a consistent size, they found.

Additional experiments revealed that these DNA fragments reflect unique patterns of genetic changes, including changes in chromatin organization, known to occur in liver cancer cells.

“These fragments that we’re picking up in cancer patients are not just random. It’s really reflecting the genome of liver cancer ,” Dr. Kim emphasized.

DELFI differentiates between people with and without liver cancer

The subtle changes in DNA fragmentation in the blood were enough for DELFI to differentiate between people with and without liver cancer, the researchers found.

And it was very accurate. When separating people with liver cancer and those with liver disease, DELFI scored 0.9 on a 0-to-1 performance scale (also called area under the curve, or AUC). It was even better at separating people with liver cancer from people without liver disease (AUC=0.98). A test with perfect accuracy would have an AUC of 1.

The test also picked up on early-stage liver cancer (AUC=0.9 and 0.81 for the two earliest stages), which can be tricky to spot with other tests.

DELFI was good at finding liver cancer when it was present (high sensitivity) and rarely said someone had cancer when they didn’t (high specificity), the researchers noted.

To validate the test in a separate group of people, the team applied it to blood samples of 223 people from Hong Kong. This group included 90 people known to have early-stage liver cancer and 101 people with known liver disease, mainly hepatitis B infection or cirrhosis.

Again, the test correctly distinguished between people with liver cancer and people with liver disease (AUC=0.97).

Participants in the U.S./Europe and Hong Kong groups had different causes of liver cancer and ethnicities, but the test performed well in both groups, Dr. Kim pointed out. That suggests “that this approach could be generalizable across different high-risk populations worldwide,” Drs. Rolfo and Russo wrote.

Finally, the researchers compared DELFI with a blood test that is used to test for liver cancer in people at high risk of the disease. The test looks for a cancer-related protein called alpha-fetoprotein and is typically combined with an ultrasound of the abdomen.

The alpha-fetoprotein test correctly flagged 52% (39 of 75 people) of those with liver cancer in the US/Europe group, while DELFI caught 85% (64 of 75 people). DELFI also identified a greater percentage of people with early-stage liver cancer than the alpha-fetoprotein test.

Fragmentomics for cancer detection

The research team believes fragmentomics has several advantages when it comes to liquid biopsies for cancer detection.

A challenge with mutation- and methylation-based liquid biopsies is that these cancer-related changes are scarce in the blood, Dr. Kim said, making them hard to find. But with fragmentomics, the DNA doesn’t have to be scanned as intensively and it keeps the cost of the test down, she explained.

Another advantage of fragmentomics is that it requires much less blood than other liquid biopsy tests, she added.

The fragmentomics approach is also appealing because it requires only a blood draw, Dr. Greten noted, which is typically faster, easier to get, and less expensive than an ultrasound.

Fragmentomics is a next-generation liquid biopsy approach, said Dr. Velculescu. And it can potentially be used to detect other kinds of cancer, in addition to those the team has already studied, he added.

A company founded by Dr. Velculescu, and where he serves as CEO, is working on developing DELFI for commercial use.

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 theFGFR2 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.

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.

June 4, 2020, by NCI Staff

For the first time in nearly 13 years, there is a new treatment available that appears to be better than a standard therapy for people with a type of liver cancer called hepatocellular carcinoma (HCC). On May 29, the Food and Drug Administration (FDA) approved atezolizumab (Tecentriq) and bevacizumab (Avastin) as an initial treatment for people with liver cancer that has spread or that can’t be treated with surgery.

In the study that led to the approval, called IMbrave150, liver cancer patients treated with atezolizumab and bevacizumab lived substantially longer than those treated with sorafenib (Nexavar). They also lived longer without their cancer getting worse. The study findings were published May 14 in the New England Journal of Medicine.

“This is a huge advance for patients,” said one of the study scientists, Richard Finn, M.D., of the University of California, Los Angeles. “This has been something that doctors who treat these patients have wanted for a long time, and this is a significant improvement.”

Atezolizumab is an immune checkpoint inhibitor, a type of treatment that helps the immune system seek out and destroy cancer. Bevacizumab is a targeted therapy that starves tumors by preventing new blood vessels from growing.

Sorafenib is another targeted therapy that blocks the growth of blood vessels and cancer cells. In 2007, sorafenib became the first drug approved by the FDA to treat some patients with HCC.

Until now, the only treatments for HCC that have been approved since 2007 are no more effective than sorafenib, said Tim Greten, M.D., deputy chief of the Thoracic and GI Malignancies Branch of NCI’s Center for Cancer Research.

And not only is the atezolizumab–bevacizumab combination more effective, it also led to “strikingly better patient-reported outcomes,” such as physical abilities, Robin Kelley, M.D., of the UCSF Helen Diller Family Comprehensive Cancer Center, wrote in an editorial.

The combination regimen will likely replace sorafenib as the standard initial treatment for some people with advanced HCC, Dr. Greten said.

Adding on to Immune Checkpoint Inhibitors

Liver cancer is often diagnosed when it has already spread beyond the liver or is intertwined with many blood vessels, preventing it from being treated with surgery.

For people with liver cancer that can’t be treated with surgery (is inoperable), sorafenib and lenvatinib (Lenvima)—another drug that blocks blood vessel growth—are the only options for initial treatment.

A handful of clinical studies have tested immune checkpoint inhibitors as initial treatments for liver cancer but found that they didn’t work well on their own. With some more digging, scientists later found that high levels of a protein called VEGF may prevent immune checkpoint inhibitors from working.

VEGF stimulates the growth of new blood vessels and also changes the number and type of immune system cells in and around tumors, Dr. Finn explained.

Because bevacizumab blocks VEGF, researchers from Genentech and several different medical centers tested atezolizumab with bevacizumab in a small study of people with liver cancer. In 2019, they reported that the combination was more effective than atezolizumab alone and had tolerable side effects. The IMbrave150 trial is a follow-up to that earlier study.

Findings from the IMbrave150 Trial

The IMbrave150 trial, sponsored by F. Hoffman–La Roche/Genentech, involved more than 500 people with HCC. All participants had inoperable tumors and none had received whole-body (systemic) cancer treatment before.

Participants were randomly assigned to receive sorafenib or atezolizumab plus bevacizumab until the treatment stopped working or until the side effects became too harsh.

By all measures, the combination treatment worked better than sorafenib. More people who were treated with the combination than with sorafenib were still alive after 1 year: 67% in the combination group and 55% in the sorafenib group.

The length of time that half of the patients in a treatment group are still alive, called median overall survival, is a key measure of how well a treatment works. The median overall survival was 13 months in the sorafenib group and longer in the combination group.

The exact duration is still being determined for atezolizumab plus bevacizumab because most of the patients in that group are still alive, Dr. Greten noted.

Patients who received the combination treatment also lived 3 months longer without their cancer getting worse or dying (7 months versus 4 months for sorafenib).

The treatment worked—meaning it shrank tumors—for more patients who received the combination than sorafenib (27% versus 12%). That “is the highest reported rate in a phase 3 trial for hepatocellular carcinoma to date,” Dr. Kelley noted.

In addition, far more patients in the combination group had a complete response, meaning all signs of cancer disappeared completely (6% versus 0% in the sorafenib group).

Although complete responses are noteworthy, “the more important point is how long patients actually benefit from the treatment,” Dr. Greten said. The treatment worked for longer than 6 months in 88% of people in the combination group and in 59% of those in the sorafenib group.

Patients in both treatment groups reported that their quality of life got worse during the study period. But people treated with the atezolizumab‒bevacizumab combination reported that their quality of life was preserved for considerably longer, about 7 months more than those treated with sorafenib.

“The goal with incurable cancers is to extend survival and maintain quality of life,” Dr. Finn stressed. In the studies that led to sorafenib’s approval, it didn’t improve quality of life over a placebo treatment, he added.

Safety of Atezolizumab Plus Bevacizumab

Many patients experienced side effects from the combination treatment. But overall, patients appeared to tolerate both drugs, Dr. Greten said.

There were similar rates of side effects and deaths due to side effects in the two groups. But more patients in the combination group had any serious side effects (38% versus 31%).

Fewer patients in the combination group paused or changed the dose of the treatments because of side effects (50% versus 61% in the sorafenib group). And although more patients in the combination group stopped taking one of the drugs (16% versus 10%), only 7% stopped taking both drugs because of side effects.

Bevacizumab can cause bleeding because of its effects on blood vessels, Dr. Greten explained. Liver cancer can also cause changes that heighten the risk of bleeding, such as low numbers of platelets, he added.

“There were a few more bleeding events in the atezolizumab‒bevacizumab arm, but still, as a percentage, it’s very low,” Dr. Finn said. Six percent of patients in both groups had serious bleeding events related to bevacizumab treatment.

“It will be important to identify the right patient population” for the combination treatment, Dr. Greten said. Patients may have to get routine tests to check for bleeding risk factors before taking the treatment, he suggested.

“Alternative therapies should be considered for patients at high risk for bleeding,” Dr. Kelley wrote.

More Combination Treatments Likely to Come

Many ongoing studies of HCC are testing combinations of an immune checkpoint inhibitor and a drug that targets blood vessels, such as pembrolizumab (Keytruda) and lenvatinib, Dr. Finn said. Other studies are testing combinations of immune checkpoint inhibitors, Dr. Kelley noted.

“We’ve made a huge step ,” Dr. Finn said. But he and his colleagues are already thinking about how to continue to improve liver cancer treatment. “The question now is, what do we add on to bevacizumab and atezolizumab?”

Another future goal is to find biological markers (biomarkers), like the level of a blood protein, that doctors can use to figure out which patients are most likely to respond to immune checkpoint inhibitors that are part of a combination treatment. In general, immune checkpoint inhibitors are only effective for a fraction of patients with liver cancer.

“It would be helpful if you could actually identify the patients” who are likely to benefit from the treatment, Dr. Greten said. One of the ongoing goals of NCI’s Liver Cancer Program, of which Dr. Greten is the codirector, is identifying biomarkers for immunotherapy.

For some people with hepatocellular carcinoma (HCC), the most common type of liver cancer, a liver transplant is the only hope for a cure. But the availability of donated organs for transplant is severely limited. So, when a donor liver becomes available, doctors and public health experts must decide who is most likely to benefit.

A new study provides the strongest evidence to date in support of US guidelines for determining which people with liver cancer are eligible for a liver transplant, the study’s investigators said. The US guidelines go beyond the strictest and most well-established criteria for a transplant, which largely focus on the extent of cancer that’s present in the liver (the size and number of tumors) at the time a person is diagnosed.

If treatments can shrink a patient’s tumors so that they fit within these criteria—commonly known as the Milan criteria—the guidelines say, that person may also be a suitable candidate for a transplant.

In the study, 52% of people with HCC whose tumors shrank enough after treatment to meet the Milan criteria for a liver transplant were still alive 10 years after receiving a donated liver. By comparison, people with HCC whose disease met the Milan criteria at the time of their diagnosis fared somewhat better: about 61% were still alive 10 years after liver transplant, the team reported July 20 in JAMA Surgery.

Treating liver cancer to reduce the size and number of tumors before surgery is known as downstaging.

The new findings “provide solid data to examine practice” of giving liver transplants to people with HCC that has been downstaged to meet the Milan criteria, wrote transplant surgeon Yuman Fong, M.D., of City of Hope Medical Center, in an editorial that accompanied the study.

That’s important, several liver cancer experts said, because until now, evidence to support these guidelines has been limited and they have not been adopted worldwide.

A 10-year survival rate of more than 50% “is considered a great cure rate for liver cancer,” said Laura Kulik, M.D., of Northwestern Memorial Hospital in Chicago, who was not involved in the new study.

“We’ve always been nervous about the risk of the tumor coming back after transplant in these patients,” said Dr. Kulik, a liver disease specialist who helps evaluate and manage patients before and after a transplant. “This study shows that we’re not wasting donated organs or taking them away from other people” who are more likely to benefit.

The study, which included more than 2,600 patients, “is very solid because it has such a long follow-up time and such a large number of people,” said Tim Greten, M.D., head of the gastrointestinal malignancy section in NCI’s Center for Cancer Research, who also was not involved in the study.

Considering the selection criteria for a liver transplant

The incidence of HCC—the third leading cause of cancer deaths worldwide—has been rising in the United States and elsewhere, increasing the demand for transplants. Most transplanted livers are from organ donors who have recently died.

Other candidates for a liver transplant include people with serious liver diseases other than cancer, such as hepatitis B and C. Unfortunately, people who qualify for a liver transplant are competing for a limited supply of donor organs, Dr. Greten said.

For more than two decades, decisions about which HCC patients are eligible for a liver transplant have been based on a small 1996 study in Italy. That study showed that people with small but inoperable liver tumors did about as well after a liver transplant as people with liver diseases other than cancer, said Parissa Tabrizian, M.D., a surgeon at the Icahn School of Medicine at Mount Sinai and the lead investigator on the new study.

The 1996 study, conducted at a single hospital in Milan, opened the door to liver transplants for people with HCC that is confined to the liver and “had a profound impact on the survival of liver cancer patients,” Dr. Tabrizian said. It allowed the transplant community to establish a simple set of criteria for selecting those most likely to benefit from a transplant.

According to the Milan criteria, transplant recipients must have only a single HCC tumor no bigger than 5 centimeters (about 2 inches) in diameter or two to three tumors of 3 centimeters or less at the time of diagnosis.

Having smaller and fewer tumors indicates that the cancer is less likely to have invaded blood vessels in the liver and, therefore, is less likely to have spread beyond the liver and come back, or recur, after a transplant, Dr. Kulik explained. “Recurrence is the number one cause of death after a transplant,” she said.

However, Dr. Tabrizian said, “the Milan criteria have been repeatedly criticized for being too restrictive.”

So, some experts wondered if people whose tumors could be downstaged to within the Milan criteria might fare as well after a transplant as those who met the Milan criteria from the start, Dr. Greten said.

Based on earlier, smaller studies with shorter follow-up times, some guidelines, including those from the American Association for the Study of Liver Diseases, now suggest that patients whose cancer can be downstaged to meet the Milan criteria be considered for a liver transplant. However, they note that the evidence from these earlier studies is not strong.

10-year survival in transplant recipients

To seek more evidence on how patients who were downstaged fare after a transplant over the long term, Dr. Tabrizian and her colleagues analyzed data from 2,645 adults with HCC who had liver transplants at five US transplant centers from 2001 to 2015.

Of those patients, 2,122 (80%) were within the Milan criteria at diagnosis and stayed within them until the time of transplant (Milan criteria group) and 341 (13%) had HCC that was successfully downstaged to within the Milan criteria (downstaged group) at the time of transplant.

The remaining 182 patients (7%) had HCC that could not be downstaged or had progressed beyond the Milan criteria but ultimately underwent a transplant (beyond Milan criteria group).

More people in the Milan criteria group were still alive 5 and 10 years after a transplant than those in the downstaged group (see the table). People in the beyond Milan criteria group had statistically similar survival rates after transplant to those in the downstaged group. However, the chances that their cancer would come back after transplant was markedly higher.

Although people in the downstaged group had lower survival and higher recurrence rates than those in the Milan criteria group after transplant, they “were nevertheless able to achieve meaningful long-term outcomes after successful downstaging,” the study team wrote.

“These are patients who would not have been considered for a curative treatment and would not have lived as long” with treatment options other than a transplant, Dr. Tabrizian said.

On the other hand, she said, those whose tumors cannot be downstaged should probably not be considered for a transplant.

“We’ve been learning more and more that it’s not just size and number of tumors that matters when predicting how well patients will do,” Dr. Tabrizian continued.

For example, she explained, the ability to shrink tumors to meet the Milan criteria is thought to indicate that the cancer is less aggressive than those tumors that don’t respond well to treatment.

Dr. Tabrizian’s team also identified several patient factors, such as having more than three liver tumors at diagnosis, that were linked with the likelihood that a person’s cancer would not respond well to treatments aimed at downstaging. These factors may “aid in decision-making and risk-benefit assessment,” the study team wrote.

The team also found that transplant patients who received a liver from a living donor—which is an option for some people—fared similarly to those who received a liver from a deceased donor.

In a living donor transplant, one section of a healthy living person’s liver is removed and used to replace the patient’s diseased liver. This approach is possible because the liver can quickly regrow in both the donor and recipient. However, the surgery still has some risk for the donor.

Organ donations offer people with liver cancer a new chance at life

The new study results provide data that can better inform decisions about allocating organs to people with HCC and other liver diseases, Dr. Fong wrote in his editorial.

For people with HCC tumors that are initially beyond the Milan criteria, he wrote, developing a panel of additional tumor markers, like alpha-fetoprotein and others, that might predict which patients will do best with a transplant “could help to optimize organ use.”

“More robust studies are still needed to make this downstaging policy globally acceptable,” Dr. Tabrizian said. “Hopefully, we can continue to show excellent results and make this a standard of care” worldwide.

“And as we improve our understanding of tumor biology and of this disease, we hope we can continue to expand the criteria for transplant eligibility and increase cure rates,” she continued.

Although the shortage of healthy donor organs remains a challenge, she hopes that by increasing awareness and increasing organ donations this problem could be solved.

Finally, Dr. Kulik said, the study highlights the importance that people with liver cancer be seen by experts in liver cancer treatment and transplantation to increase their chances of receiving a potentially lifesaving transplant. This has become easier with the rise of telemedicine and video consultations, she added.

And, she continued, “we see such a difference in people after they undergo a transplant and have a new chance at life.”

Some children with liver cancer may need less chemotherapy than is typically used to treat the disease, according to results from a phase 3 clinical trial.

The study, led by the NCI-supported Children’s Oncology Group, included children and infants with the most common type of childhood liver cancer, hepatoblastoma, whose tumors had been surgically removed when the disease was diagnosed. Such patients subsequently receive chemotherapy to kill any remaining cancer cells.

Liver cancer is rare in children, and only about one-third of these patients have tumors that can be removed surgically at the time of diagnosis.

Approximately 90% of children whose tumors are removed at diagnosis and who receive chemotherapy survive the disease. But some survivors develop lasting side effects of chemotherapy, including hearing loss caused by the drug cisplatin.

Investigators were therefore interested in learning whether a lower dose of chemotherapy could be used to reduce side effects without affecting survival.

In the study, children who received half of the normal amount of chemotherapy survived as long as children who received the full amount in previous trials, researchers reported in The Lancet on April 8.

“We found that four cycles of chemotherapy—the standard amount—were not needed and that two cycles seemed to be enough,” said Howard Katzenstein, M.D., of Nemours Children’s Specialty Care and Wolfson Children’s Hospital in Jacksonville, FL, one of the investigators.

The trial is part of a broader effort by the Children’s Oncology Group and other cancer researchers to evaluate treatment regimens for children with cancer that can reduce the risk of side effects without increasing the chances the disease will return.

Focusing on Patients’ Quality of Life

For children with hepatoblastoma who receive “up-front” surgery, it is common to administer chemotherapy in the hospital. In addition to extending the length of a hospital stay, chemotherapy may cause side effects during treatment, such as nausea, vomiting, risk of infection, and kidney damage, Dr. Katzenstein noted.

“In a group of patients with a 90% cure rate, we need to ensure that these children have the best possible quality of life,” said Dr. Katzenstein. The goal of the trial, which also included other patients whose tumors could not be surgically removed at diagnosis, was to “optimize” the amount of adjuvant chemotherapy needed to cure the patients.

In the study, 49 patients with hepatoblastoma who had surgery at diagnosis received two cycles of a combination of three chemotherapy drugs (cisplatin, fluorouracil, and vincristine) rather than the standard four cycles.

After a median follow-up of 42 months, more than 90% of patients in the trial had no symptoms of liver cancer or a recurrence of the disease (an outcome known as event-free survival), the researchers found. This result compares well with the results of previous trials involving surgery plus four cycles of chemotherapy, they noted.

Only one patient in the trial experienced hearing loss. After a median follow-up of 4 years, 95% of the patients were alive; the 5-year overall survival rate was 91%.

“The results of this trial will inform decisions about how the disease is treated in the future,” said Nita Seibel, M.D., head of Pediatric Solid Tumor Therapeutics in NCI’s Cancer Therapy Evaluation Program, who was not involved in the study.

She cautioned, however, that the study was small and that the findings apply only to the care of patients with tumors that surgeons can safely remove at diagnosis. Patients are not candidates for the reduced amount of chemotherapy if their tumors are advanced or have spread to other parts of the body.

“The trial builds on the work of a previous study that reduced the number of cycles of chemotherapy for some patients with hepatoblastoma from six to four,” Dr. Seibel continued. “The ultimate goal of this research is to reduce the amount of chemotherapy a patient needs without compromising outcomes.”

But progress in reaching this goal has been “gradual,” she added, in part because pediatric liver cancer is so rare. Only about 100 to 125 cases of hepatoblastoma are diagnosed in North America each year.

“Hopefully we will get to a point when some of these children may be treated with surgery alone and not receive chemotherapy, but we’re not there yet,” she said.

Guidelines for Selecting Patients for Surgery

As the new results demonstrate, liver cancer “is a very treatable” disease for children with hepatoblastoma that can be surgically removed at diagnosis, said Greg Tiao, M.D., a pediatric surgeon at Cincinnati Children’s Hospital and an investigator on the trial.

To help doctors identify children with hepatoblastoma who can safely undergo surgery at diagnosis, Rebecka Meyers, M.D., of the University of Utah Hospital and an investigator on the trial, led a team that developed guidelines for identifying tumors that can be removed safely based on imaging studies.

For example, patients with tumors that affect part of the liver, rather than the entire liver, may be candidates for surgery.

These guidelines were incorporated into the clinical trial. Until now, surgeons have relied primarily on their own knowledge and experience to decide which patients were candidates to have their tumors removed.

“But even surgeons at large medical centers who see children with cancer might only see one or two patients with hepatoblastoma each year,” said Dr. Tiao.

Follow-up and larger studies will be needed to determine how the use of the guidelines may influence the selection of patients and patient outcomes, the researchers noted.

An International Trial for Children with Liver Cancer

The approach of using fewer cycles of chemotherapy following surgery for children newly diagnosed with hepatoblastoma is being evaluated further in a large international clinical trial that is under way in North America, Europe, Japan, and Australia.

This study will assess various treatment approaches in approximately 1,200 children.

For example, some patients whose tumors cannot be removed surgically at diagnosis will initially receive chemotherapy to reduce the size of their tumors, potentially making it possible for the tumors to be removed by surgery.

The trial is expected to provide the evidence that will help to establish standard treatments for all patients with hepatoblastoma in the future.

“This is the first trial in hepatoblastoma that’s truly been organized internationally,” said Dr. Katzenstein. “The results will provide the evidence base from a large international study to know when we can safely give patients less chemotherapy and thereby avoid the problems associated with it.”

While new cases of most cancer types have dropped over the past decade, cases of the most common type of liver cancer, hepatocellular carcinoma (HCC), are on the rise. Until recently, the main cause of HCC was hepatitis C virus infection. Although hepatitis C infection still causes many cases of HCC, the biggest contributor to the recent rise in cases is a condition called nonalcoholic steatohepatitis (NASH), which can progress to HCC.

In a new NCI-funded study, researchers have now identified a protein that could potentially be targeted to prevent both NASH and liver cancer: β2-spectrin.

Mice genetically modified to have no β2-spectrin in their livers did not develop NASH. And when the same mice were injected with chemicals that cause liver cancer, they developed fewer tumors than normal mice, Shuyun Rao, Ph.D., of George Washington University, and her colleagues reported December 15, 2021, in Science Translational Medicine.

The researchers also showed that they could treat normal mice with RNA molecules to reduce the amount of β2-spectrin in their livers. The RNA treatment prevented NASH in mice with healthy livers and reversed it in mice that had already developed the disease.

NASH arises from a milder liver condition, nonalcoholic fatty liver disease (NAFLD).

It's estimated that approximately 25% of adults worldwide have NAFLD, with rates varying by country. So if a safe β2-spectrin–blocking drug could be developed for use in humans, Dr. Rao said, “it could impact a lot of people.”

Nonalcoholic fatty liver disease and liver cancer

NAFLD is characterized by a buildup of fat in the liver. While people with NAFLD are at higher risk for other health problems, like cardiovascular disease, they don’t usually have severe liver problems.

“Initially, is simply accumulation of fat granules” in liver cells, explained Konstantin Salnikow, Ph.D., of NCI’s Division of Cancer Biology, who was not involved in the study. The condition can be controlled, or even reversed, with exercise and changes in a person's diet.

People with obesity are at higher risk for developing NAFLD. “Obesity is very common; a third of the world’s population has it,” said Lopa Mishra, M.D., the study’s senior investigator. And up to 90% of people with severe obesity are thought to have NAFLD.

In some cases, NAFLD progresses to a more severe condition called nonalcoholic steatohepatitis, or NASH. In people with NASH, a buildup of fat causes liver inflammation and fibrosis, where scar tissue builds up in the liver. In some cases, NASH can result in liver cirrhosis, a more severe form of fibrosis.

And people with NASH often develop HCC. While it’s unclear what causes the transition, “up to 12% of people with NASH go on to develop cancer,” said Dr. Mishra.

Previous research, however, has suggested that a protein called TGF-β may be involved in this progression.

Studies have shown that TGF-β can suppress or promote the growth of many types of tumors, depending on the context, Dr. Salnikow said. For example, TGF-β prevents normal cells from becoming cancerous, but it promotes metastasis in cancer cells.

And TGF-β is known to promote fibrosis specifically. “It’s really the fibrosis that predicts whether people with NASH will get cancer, and TGF-β plays a big role in fibrosis,” Dr. Mishra explained.

Dr. Mishra’s team decided to take a closer look at β2-spectrin because it organizes other proteins in the cellular communication pathway orchestrated by TGF-β. Indeed, an earlier study had found that cancer cells did not react to TGF-β activity as expected when β2-spectrin was absent.

Preventing fatty liver disease and liver cancer in mice

To investigate whether β2-spectrin promotes NAFLD or NASH, Dr. Rao and her team compared the livers of mice genetically engineered to lack the protein in their liver cells with those of normal mice.

The genetically modified mice did not seem to have impaired liver function despite the lack of β2-spectrin. “It was a big surprise,” said Dr. Mishra. Because β2-spectrin is found in almost all cells, researchers expected that it was crucial to cellular function.

The researchers went on to feed the mice one of two diets known to cause NAFLD and NASH: either a high-fat diet or a “western diet.” The western diet “has really been shown to reproduce human NASH” in mice, Dr. Mishra explained, and has “a different fat content, a different carbohydrate content” than the high-fat diet. While the western diet has a lower fat content than the high-fat diet, it has still been shown to cause NASH.

When fed either of these disease-causing diets, mice that lacked β2-spectrin in their livers did not develop NASH, whereas normal mice did. The genetically modified mice also gained less weight and had less body fat.

Losing β2-spectrin from their livers prevented NASH—but did it prevent liver cancer as well? To find out, the researchers needed to change their methods. Even in normal mice, HCC does not occur often enough to test whether removing β2-spectrin might prevent the cancer, explained Dr. Mishra.

To speed up the appearance of cancer in the mice, the researchers induced HCC with a chemical called DEN. Normal mice treated with DEN developed liver tumors, even when fed a standard diet.

Compared with normal mice, when mice lacking β2-spectrin in their livers were treated with DEN, they had far fewer liver tumors, and the tumors that did form were smaller on average.

The team was also able to prevent and treat NASH in normal mice by targeting β2-spectrin. To do so, they designed RNA molecules, known as small interfering RNAs (siRNA), that could reduce the amount of β2-spectrin produced in cells.

Mice treated with siRNA and then fed a high-fat diet gained less weight and had less body fat than mice that were untreated.

Furthermore, when mice that had already developed NASH after being fed a western diet were treated with the siRNA, their disease improved, as measured by lower fat and sugar levels in their blood.

To better assess whether their findings in mice might apply to humans, the researchers then turned to a different NASH model—a mix of human liver cells, immune cells, and support cells in a 3-D structure. This 3-D culture model, Dr. Salnikow explained, more closely mimics a human liver than just liver cells in culture.

The 3-D cultures treated with β2-spectrin siRNA had fewer of the characteristics typically seen in the liver of a person with NASH, including the activity of several genes, than 3-D cultures treated with a control treatment. It wasn’t possible for the researchers to tell whether cancer was prevented in this model, since the 3-D cultures don’t form tumors.

Bringing β2-spectrintargeted drugs to the clinic

A big question now is whether siRNA therapy for NASH could potentially be useful in humans. An siRNA drug is already approved by the Food and Drug Administration to treat another form of liver disease called hepatic porphyria, Dr. Mishra noted.

“So, siRNA treatment strategies for the liver have been shown to work,” she said.

But there are still many steps to take before an siRNA drug like the one used in this study could be used to treat people with NAFLD or NASH, Dr. Mishra acknowledged. Although the mice used in their study “are looking absolutely fine,” she continued, further safety studies are needed before human studies can be launched.

And while targeting β2-spectrin with siRNA protected mice from chemically induced cancer, and also prevented and treated NAFLD in mice, it remains to be seen whether such a drug would prevent HCC in people with NASH, Dr. Rao and her colleagues wrote.

There are also open questions regarding the precise way that β2-spectrin promotes NAFLD. While Dr. Mishra’s team did identify some molecular mechanisms by which the protein drives fat accumulation in the liver, the question remains: “How does actually turn on fatty liver disease?” asked Dr. Mishra.

The research team is also interested in identifying the specific parts of the β2-spectrin protein that are responsible for promoting NAFLD. This information could potentially be used to develop a small-molecule drug to block this activity of β2-spectrin.

This study may also have an impact on scientists’ understanding of NAFLD and liver cancer as a whole, according to Dr. Salnikow.

“This is the starting point of understanding the role of the TGF-β pathway” in the transition from NASH to liver cancer, he said. “This is only the tip of the iceberg.”