Margot got the news in her early 20s: "You have liver cancer," her doctors told her. Specifically, Margot had a form of liver cancer known as fibrolamellar carcinoma, a diagnosis with deadly prospects. For patients whose tumors have spread and cannot be removed surgically, average survival is just about a year.
Like many others with fibrolamellar carcinoma, or FLC, Margot—whose name has been changed to protect her privacy—wasn't a candidate for surgery. And after rounds of chemotherapy by oncologists in her home state, the otherwise healthy young woman continued to suffer, with the cancer spreading to her lungs and crippling her entire body with severe pain.
"That's around the time I met her," says Marina Baretti, a medical oncologist and co-director of the Liver and Biliary Cancer Multidisciplinary Clinic at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. "She was one of the first patients to enroll in our clinical trial for a vaccine that, combined with immunotherapy, [employs] the immune system to target and destroy the abnormal protein causing the cancer."
The trial is one of several that Baretti works on with medical oncologist Mark Yarchoan, an associate professor of oncology at Johns Hopkins who runs a federally funded research lab that develops novel immunotherapies for liver cancers and investigates how the immune system fights tumors.
"By month four of [Margot's] treatment, we saw a significant decrease in every one of her target cancer lesions," Baretti recounts. "But even before we saw the scan, little by little she was getting off her pain medications and starting to feel better, so we knew the treatment was working. Eventually she was able to undergo surgery to remove some of the residual disease—and achieve a condition of cancer-free."
Success stories like Margot's don't happen every day, but they're becoming more common, Baretti says, thanks to breakthroughs in liver cancer research and treatments that have occurred over the last five years. The advances are happening as cases of liver cancer (and its various forms) are on the rise across the United States, with experts predicting it will become one of the country's most common and deadly cancers in the next five years.
In the past, liver cancer affected more people in sub-Saharan African and Southeast Asia than in the U.S., given the prevalence in those regions of chronic hepatitis B virus infections and exposure to aflatoxins, a type of fungi in food that can damage the body's ability to suppress tumors. Now, however, the U.S. and other western countries are catching up—but for different reasons. More than three times as many people battle liver cancer in the U.S. today, compared to 1980, and more than twice as many die from it, according to the American Cancer Society.
Baretti points to lifestyle and metabolic factors to explain rising rates of the two most common primary liver cancers: hepatocellular carcinoma (HCC) and cholangiocarcinoma (bile duct cancer). "Many of these cancers develop on the background of advanced fatty liver disease, or metabolic-associated steatohepatitis (MASH), which can quietly progress to cirrhosis," she explains. While sedentary habits, excess alcohol, and metabolic syndrome—which includes Type 2 diabetes, high blood pressure, and obesity—can increase risk, MASH can affect a wide range of patients. "People can develop serious liver disease even if they don't appear overweight or live what we think of as an 'unhealthy' lifestyle," Baretti says. "The liver can accumulate damage silently for years, meaning you can look healthy on the outside but still have significant liver injury on the inside."
Metabolic syndrome can occur when people experience a high body-mass index (including an expanded waistband), high triglycerides, low HDL cholesterol, high blood pressure, and elevated blood sugar. Recent studies estimate that more than one-third of people in the U.S. suffer from metabolic syndrome, which raises their risk for heart attack, stroke, Type 2 diabetes, and liver steatosis. "In large part, the increase in metabolic syndrome is why we're seeing the sharp increase in liver cancer," Baretti says. "It's quickly changing from a rare form of cancer in the U.S. to one much more prevalent."
The American Cancer Society predicts there will be about 42,240 new cases and 30,090 deaths from the condition this year alone. Liver cancer currently ranks as the sixth-deadliest cancer in the country, behind cancers of the lungs, colon and rectum, pancreas, breasts, and prostate, according to the National Cancer Institute.
Progress made through research
Despite the rise in risk factors and cases, Baretti says researchers and biomedical engineers have made progress developing technologies to sequence tumors, pinpoint mutations, and make more accurate diagnoses while also creating new therapies to treat HCC and bile duct cancer. "Until 2020, we only had one approved drug for HCC," she says. "Now we have 10 approved drugs for HCC, and these drugs generally don't come with the harsh side effects of chemotherapy."
Some, she says, involve immunotherapy, a form of treatment that leverages a patient's immune system to attack the "bad-actor" cells and, ultimately, develop lasting immunity against the cancer. Others, she says, involve targeted therapies based on precision medicine, "where we try to dissect the molecular makeup of the cancer and identify a target to exploit for therapeutic interventions."
Without basic science and biomedical research, though, none of that would be possible. "Research has been instrumental in these gains, with new understandings about the biology and molecular makeup of cancer being rapidly translated from the bench to the bedside to develop more effective therapies and help patients," Baretti says. "As a result, even when patients present with a more advanced state of the disease, these new drugs can sometimes transform the cancer into something manageable over the long-term—patients can be cured, or their cancer can be downgraded so they become eligible for surgery or a transplant."
Baretti, a physician-scientist, sees the progress firsthand while treating patients in the clinic and conducting research in the lab, with the two perspectives influencing her work in both spaces in positive ways. "There's a continuous interplay between the clinic and lab," she says. "As a team of researchers who also treat patients, we're focused on translational research—meaning research that translates quickly and directly into better medical treatment and care."
Much of this happens through her partnership with Yarchoan and hematology oncologist Elizabeth Jaffee, deputy director of the Kimmel Cancer Center and a professor of oncology at Johns Hopkins. Their work together, Baretti explains, "can involve starting from an observation in the clinic that raises questions, before going back to the lab to understand why some phenomena are happening or figuring out the underlying mechanism and how to target certain pathways to improve the efficacy of our treatments," Baretti explains. "Once we see interesting results in the lab, then it's my job to figure out how we can translate those into clinical opportunities—and, potentially, into clinical trials."
Personalized vaccines
Currently, Yarchoan, Baretti, and their teams have eight clinical trials underway, including some for personalized anti-tumor vaccines. These tailored vaccines, Yarchoan says, "hold the remarkable potential over the next decade for breakthroughs that could transform therapeutic cancer vaccines from a promising aspiration into a cornerstone of oncology care."
Generally, the process involves:
- Taking a biopsy of a patient's tumor cells to determine the specific cancer-associated genetic mutations
- Using a computer algorithm to identify which mutated genes produce abnormal proteins recognized by the immune system
- Manufacturing a vaccine with the DNA for the selected gene mutations
- Administering the vaccine (often as an add-on to other treatments), designed to help the immune system recognize the abnormal proteins encoded in the genes and destroy the cells that produce them
So far, the results look promising—and are starting to change and save lives. Last year, for instance, in a preliminary clinical trial for patients with advanced HCC, a personalized vaccine administered in tandem with immunotherapy shrunk patient tumors twice as much as immunotherapy alone. Similarly, in a trial for the kind of liver cancer Margot developed, FLC, a vaccine given alongside immunotherapy led to "incredibly remarkable responses overall, with 75% of patients benefitting in terms of disease control," Baretti says. "Some patients like [Margot] had very profound responses in which most of the tumor melted away, so much so that they were able to undergo surgery and are now cancer-free.
"Importantly," she added, "we demonstrated an ability to induce an immunological response—meaning we induced the tumor-killing T cells to specifically target the cancer cells, and we think this is a mechanism we can continue developing and using to see sustained, positive responses."
The breakthrough is huge, says Baretti, who works closely in the clinic with patients with FLC, a form of HCC that affects children and young adults "who are otherwise totally healthy and then end up with this aggressive form of liver cancer," she explains. Unlike bile duct cancer and HCCs, FLC isn't a lifestyle disease. It stems instead from the fusion of two genes, DNAJB1 and PRKACA, which causes an overproduction of the protein kinase A enzyme, a key driver of the condition. "Even after surgery, the recurrence rate is unacceptably very high, and when patients present with metastatic FLC disease, the median survival rate is around one year. There is an enormous unmet need."
Baretti worries, however, that the federal government's pauses and cuts in NIH funding could stymie the advancements "right as we're on the cusp of a major revolution in treatment—and right as liver cancer rates are rapidly rising and affecting people everywhere," she says. Yarchoan's lab, for example, is fully supported by funding from the National Cancer Institute, a branch of NIH. And although his funding streams are still flowing, stories abound of other delayed and cancelled research grants from NIH, making many scientists and physicians anxious they could be next.
"It's not just about the science—it's about taking care of patients and families, which is a bipartisan issue," says Baretti, who grew up and earned her medical degree in Italy before relocating to the U.S. because of the unique collaboration between the federal government and research institutions.
"The moment you slow the pace, you risk losing the momentum."
