Liver Cancer Risk and Screening in Fatty Liver Disease (NAFLD and NASH)

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• NASH and NAFLD Liver Cancer Risk
• Screening Guidelines and Cirrhosis
• NASH Cancer Immunotherapy Response
• Personalizing Liver Cancer Screening
• Genetic Risk Factors and PNPLA3
• Full Transcript

NASH and NAFLD Liver Cancer Risk

Dr. Scott Friedman, MD, explains that any disease causing advanced liver scarring and cirrhosis is a major risk factor for primary liver cancer. Unlike cancers in other organs, liver cancer very rarely develops in a normal, healthy liver. Patients with more advanced liver disease are at the highest risk for developing cancer. Dr. Scott Friedman, MD, notes that historically, most liver cancers were linked to chronic viral hepatitis infections like Hepatitis B and C. However, with effective antiviral therapies now available, the incidence of these virus-related cancers is declining.

A significant concern with non-alcoholic steatohepatitis (NASH) is that liver cancer can occur even before a patient develops cirrhosis. Dr. Scott Friedman, MD, states that about one-third of liver cancers in NASH patients happen "prematurely," meaning in the absence of cirrhosis. This has critical implications for understanding cancer risk in non-cirrhotic NASH and for determining when to initiate cancer screening protocols.

Screening Guidelines and Cirrhosis

Current liver cancer screening guidelines recommend routine surveillance for patients with advanced liver fibrosis or cirrhosis. Dr. Scott Friedman, MD, emphasizes that when liver fibrosis becomes advanced, patients should undergo imaging tests, such as an ultrasound or MRI, every six months. The goal of this screening is to detect any early-stage liver cancers at a time when they are most likely to be curable through interventions like surgical resection, liver transplantation, or local ablation therapies.

Dr. Anton Titov, MD, the interviewer, engages Dr. Friedman on the topic of personalizing these screening recommendations. The traditional model, based primarily on the presence of cirrhosis, is being re-evaluated for NASH patients. Because cancer can develop earlier in the disease process, physicians must consider a broader set of risk factors to determine the optimal time to begin surveillance for each individual patient.

NASH Cancer Immunotherapy Response

A revolution in cancer therapy has occurred with the development of immunotherapy drugs known as checkpoint inhibitors. These medications work by unleashing the patient's own immune system to attack cancer cells. Dr. Scott Friedman, MD, notes that while these drugs have been highly successful in treating cancers like lung cancer, their effectiveness in liver cancer has been more moderate. Immunotherapy is still more successful than conventional chemotherapy for liver cancer, but response rates vary.

Importantly, Dr. Scott Friedman, MD, highlights a key difference: liver cancers that arise in patients with viral hepatitis appear to be slightly more responsive to these immunologic therapies than cancers that arise in patients with NASH. Researchers are beginning to investigate the immune microenvironment within these tumors to understand why NASH-related cancers might be more resistant to checkpoint inhibitor therapy. This is a rapidly evolving area of research that could lead to more personalized and effective treatment strategies.

Personalizing Liver Cancer Screening

The field of liver cancer screening in NASH is rapidly evolving beyond a one-size-fits-all approach. Dr. Scott Friedman, MD, discusses several factors that help personalize screening strategies. The presence and stage of liver fibrosis remains the most important "tripwire" for indicating the need to start screening. A patient's fibrosis stage is typically determined through non-invasive tests or a liver biopsy.

Another critical factor is a family history of liver cancer. Dr. Scott Friedman, MD, states that if a patient has a first or even second-degree relative who had liver cancer, particularly in the context of NASH, this warrants heightened concern and more aggressive screening. This familial risk suggests there may be inherited genetic factors that predispose individuals to cancer, even if the specific genes are not yet fully identified.

Genetic Risk Factors and PNPLA3

Specific genetic risk factors are emerging as powerful tools for personalizing liver cancer risk assessment. Dr. Scott Friedman, MD, highlights a gene known as PNPLA3. Patients who carry a specific risk polymorphism, or DNA variant, in this gene have an increased risk of developing both NASH and liver cancer. The risk is highest for individuals who have two copies of this risk allele.

Dr. Scott Friedman, MD, explains that genetic testing for PNPLA3 and other risk genes can indicate that a patient should be screened more aggressively for liver cancer, even if their fibrosis stage is not yet advanced. Over time, he anticipates that clinicians will accumulate a panel of genetic risk markers. Combining these genetic risks with clinical factors will allow for the creation of a personalized risk score. This score will more accurately determine an individual's cancer risk and guide decisions on when to start screening and how often it should be repeated.

Dr. Anton Titov, MD, facilitates this deep dive into the future of personalized medicine. The ultimate goal is to tailor not only cancer risk prediction but also therapy selection based on the unique genetic makeup of a patient's tumor, moving towards truly individualized patient care.

Full Transcript

Dr. Anton Titov, MD: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are risk factors for liver cancer. Why do some patients progress to liver cancer, and what is the context of cancer in the liver on the background of NASH and NAFLD?

Dr. Scott Friedman, MD: Let me make some general points. First, any disease that leads to advanced scarring and cirrhosis in the liver is a risk factor for cancer. In fact, primary liver cancer very rarely occurs in a normal liver, unlike some other organ cancers.

We know that patients with more advanced disease are at risk for developing cancer. When the liver fibrosis gets advanced enough, those patients should be routinely screened every six months with an imaging test to detect any early cancers at a time when they might be curable.

For most of the cancers that have occurred in the last 25 years, almost all of them occurred in patients who had chronic liver disease from viral hepatitis—Hepatitis B, particularly in Asia, as well as hepatitis C worldwide. We have good therapies for those viral infections, and so we are beginning to see the risk of HCC or the numbers of HCC go down as we get better at treating the underlying viral disease.

An important feature of the cancers that occur in those patients with viral hepatitis is that patients typically already have cirrhosis when they develop cancer. We know that we need to start screening when they're close to developing cirrhosis.

What's of some concern about the cancers we're beginning to see in patients with NASH is that there's a slightly higher possibility that liver cancer may occur even before the patient is cirrhotic or has advanced NASH. About a third of the cancers that occur in patients with NASH are occurring, we would almost say, prematurely. It means when they don't even have cirrhosis yet.

That has important implications for risk in non-cirrhotic NASH and also when we should start screening. Screening guidelines don't necessarily recommend screening for cancer unless patients with NASH have fibrosis or advanced fibrosis.

We know that the liver cancers occur earlier in NASH than in viral hepatitis-related cancers. We also know that they may have different responsiveness to the leading therapies for cancer.

As you and your viewers may know, there's been a revolution in cancer therapy with the development of checkpoint blockade that effectively unleashes the immune system in a patient to attack cancer internally. Those drugs have been successful in many cancers, particularly lung cancer. They have been slightly less successful in liver cancer.

Immunotherapy still is more successful than conventional chemotherapy. But it looks like the cancers that arise in patients with viral hepatitis are slightly more responsive to those immunologic therapies than the cancers when they arise in NASH patients.

We are beginning to understand what's different about the immune microenvironment in the cancers in NASH. What makes them a little bit more resistant to these exciting checkpoint inhibitor therapies? Early days, as with so many elements of NASH, but we're beginning to separate out the drivers of cancer in patients with NASH that are different from those drivers of cancer in patients with viral hepatitis B and C.

Dr. Anton Titov, MD: Professor Friedman, you mentioned the liver cancer screening according to guidelines. But also you wrote in one of the reviews about personalizing screening for hepatocellular carcinoma in NASH patients. What are the factors that help to personalize liver cancer screening in NASH? What should patients and their physicians pay attention to?

Dr. Scott Friedman, MD: This is still a very rapidly evolving field. Certainly, the presence and stage of liver fibrosis by itself is an important tripwire to indicate the need for screening. A family history of liver cancer is also very compelling, even though we don't know what it is about that family history.

When we hear that a patient had a loved one, first or even second-degree relative who had NASH with cancer, we also have a heightened concern and a heightened screening. In addition, some of those genetic risks that I mentioned, in particular in a gene known as PNPLA3.

It's known that patients who have a risk polymorphism, or risk DNA base pair change in PNPLA3 that increases the risk of NASH, it also increases the risk that NASH patient will develop cancer. So if you have a patient that has two copies of the risk allele, or the risk DNA sequence, in PNPLA3, that indicates that the patient should be screened a bit more aggressively.

Although the exact frequency with which they should be screened has not been firmly established. Probably over time, we're going to accumulate more and more genetic risks, which, when you add them up, will confer either a low, medium, or a high risk of cancer in patients who have NASH.

We're still in the early days and trying to define a real risk score that indicates in a very personalized or individualized way when and how patients should be screened or how their cancer should be treated.

As you know, there's a whole revolution underway in characterizing the expression of specific genes in tumors throughout the body to indicate which of the immunologic therapies are likely to be most effective. Those approaches are now increasingly being tried in liver cancer patients as well.

We are trying to personalize not only the risk but also the therapy based on the kinds of genes that are expressed by their tumor.