Lessons Learned May Hold the Key for Improving Outcomes in Fibrolamellar Carcinoma

Fibrolamellar carcinoma is an extremely rare form of liver cancer that affects approximately 1 in 5 million Americans. However, because the disease appears so infrequently, it may be underdiagnosed.

Mark Yarchoan, MD

Mark Yarchoan, MD

Fibrolamellar carcinoma is an extremely rare form of liver cancer that affects approximately 1 in 5 million Americans.1 However, because the disease appears so infrequently, it may be underdiagnosed, said Mark Yarchoan, MD. He added that, with an annual age-adjusted incidence rate of just 0.02 per 100,000 in the United States, fibrolamellar carcinoma is so uncommon that investigators have yet to truly determine the demographics of the disease.2

“We have a clinical trial here at Hopkins specifically for this rare cancer,” said Yarchoan, a liver cancer specialist and assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. “Before we had a trial, this was a cancer that we would see rarely in our practice, although several patients came here with a different diagnosis thinking that they had the more normal type of liver cancer, HCC [hepatocellular carcinoma]. Actually, when we analyzed their tumor, we realized that they had this rare fibrolamellar carcinoma. We believe that many cases of this cancer are missed in clinical practice.”

Fibrolamellar carcinoma may be called by many different terms, including eosinophilic glassy cell hepatoma, fibrolamellar oncocytic hepatoma, and fibrolamellar HCC. The disease generally affects adolescents and adults younger than 40 years old. Unlike most liver cancers, which typically appears in those with liver damage, fibrolamellar carcinoma attacks people with healthy livers.

Currently, there is no systemic therapy available. Most patients undergo surgical resection, which has a median 5-year overall survival (OS) rate of 44% to 68%.1 The 5-year OS rate ranges from 2% to 17% for those who receive treatment other than resection, such as transarterial chemoembolization or liver transplant.1 The use of chemotherapy in this setting is controversial and studies have produced conflicting results.3

Hugh A. Edmondson, MD, first identified fibrolamellar carcinoma as a unique form of primary hepatocellular carcinoma in 1956.4 In 1980, John R. Craig, PhD, and colleagues named the disease and identified its distinctive histologic features: “deeply eosinophilic neoplastic hepatocytes, many of which contain intracytoplasmic hyaline globules and distinct pale bodies and fibrosis arranged in a lamellar fashion around the neoplastic hepatocytes.”5

The biggest breakthrough in fibrolamellar carcinoma came in 2014, when Joshua N. Honeyman, MD, of Brown University, and coinvestigators discovered the presence of the DNAJB1-PRKACA chimeric transcript in 100% of all 15 tumor samples they studied. The transcript appears in fibrolamellar carcinoma tumor cells, but is not expressed in normal liver cells.6

Early-stage fibrolamellar carcinoma is often asymptomatic.1 When symptoms do appear, they are nonspecific—such as abdominal pain, weight loss, malaise, and jaundice—and often ascribed to more common conditions. Yarchoan added that the malignancy can be difficult to

diagnose because physicians typically aren’t looking for liver cancer in patients who are young and otherwise healthy.

Most Research Is in the Early Stage

Yarchoan said that, like all rare diseases, it is a challenge to attract money and attention for fibrolamellar carcinoma research. However, he praised the federal government for recently dedicating more funding toward rare cancers. Furthermore, in September, The University of Texas MD Anderson Cancer Center and the Rare Cancer Research Foundation announced a partnership designed to accelerate the development of new treatments for rare cancers by allowing all patients in the United States to contribute tumor samples directly to MD Anderson for translational research efforts.

“I will say that we have been the beneficiaries of cancer therapy developed for more common diseases,” Yarchoan said. “For example, we have a trial here at Hopkins that is the first of its kind for fibrolamellar carcinoma, but it’s using an approach that has been pioneered and other cancers. What we’re doing is really applying something specifically to fibrolamellar carcinoma and I think that is something that we are likely to see more of where we understand that this is a rare cancer, but we can learn from other similar cancers and use approaches that have been successful elsewhere and apply them to our patients.”

Yarchoan is the principal investigator for a phase 1 trial (NCT04248569) evaluating a DNAJB1-PRKACA peptide vaccine (poly-ICLC; Hiltonol) in combination with nivolumab (Opdivo) and ipilimumab (Yervoy). The hope is that the 2 immune checkpoint inhibitors will active the immune system, and then when used in combination with the vaccine, those agents will cause the immune system to attack tumor cells containing the gene fusion.

“When you have this fusion, that creates an event where 2 different pieces of protein that normally are not together, come together,” Yarchoan said. “It’s been challenging to target this driver gene with traditional targeted therapy, so our approach has been trying to target this event using the immune system.”

Yarchoan is currently recruiting patients and hopes to release results in 2022. “We’re excited about the work that we’re doing.”

Earlier this year, investigators at Rush University published findings from a retrospective study of patients who received 5-fluorouracil, interferon, and nivolumab (Opdivo) for the treatment of patients with relapsed/refractory, metastatic, or unresectable fibrolamellar carcinoma from May 2018 to June 2020 (N = 22). Patients received a median of 18 cycles (range, 8-44) of treatment.7

At the time of analysis, the median progression-free survival (PFS) was 9 months (range, 4.5-26), 29% longer than prior to treatment with the triplet. The overall response rate (ORR) was 50% and the disease control rate was 93%.

“We know that those sorts of retrospective reports can be different than prospective reports,” Yarchoan said. “The group at MD Anderson is formally studying this triplet in a prospective trial, and I think that will be informative.”

MD Anderson is conducting a phase 1/2 trial (NCT04380545) studying this triplet in 15 patients with unresectable fibrolamellar carcinoma. The primary end point is safety; secondary end points are ORR, conversion rate to surgery, and PFS. The expected study completion date is July 2023.

The University of Texas MD Anderson Cancer Center is investigating the combination of sapanisertib and ziv-aflibercept for fibrolamellar carcinoma as part of a multiarm, phase 1 trial in metastatic or nonresectable recurrent solid tumors (NCT02159989). The primary objective is to evaluate safety and tolerability, and to determine the maximum-tolerated dose and recommended phase 2 dose for the combination.

Sanford M. Simon, PhD, who was senior author on the research that led to the discovery of DNAJB1-PRKACA and who is now head of the Laboratory of Cellular Biophysics at Rockefeller, tested more than 5000 compounds to determine whether any of them could be repurposed to treat patients with fibrolamellar carcinoma. In data published in October 2021, investigators concluded that TOPO1 inhibitors, HDAC inhibitors, and napabucasin (BBI608), a newly developed STAT3 inhibitor, displayed efficacy in mouse models and patient-derived xenografts.8

There are several FDA-approved TOPO1 inhibitors including irinotecan, topotecan, and rubitecan. At present, there are 4 FDA-approved HADAC inhibitors: vorinostat (Zolinza), romidepsin (Istodax), Panobinostat (Farydak), and belinostat (Beleodaq).

“Dr Simon’s group has done great work for this cancer, first of all, identifying the signature genetic events that drives this cancer and then most recently, screening an enormous number of different drugs, in an animal model of fibrolamellar cancer, to really try to see which drugs might be hits,” Yarchoan said. “I would just caution...that many cancers have been cured in mice, then many things don’t pan out when we try them in people.

“I can’t say that these drugs will work in people, but they look promising. I think this work has given us some new targets that we need to explore in human trials.”


  1. National Cancer Institute. Fibrolamellar carcinoma (FLC/FLHCC). February 27, 2019. Accessed October 19, 2021. https://bit.ly/3BYOmMv
  2. Choti, MA. Fibrolamellar carcinoma—epidemiology. Medscape Reference. January 8, 2020. Accessed October 20, 2021. https://emedicine.medscape.com/article/278354-overview#a6
  3. Choti, MA. Fibrolamellar carcinoma treatment & management. Medscape Reference. January 8, 2020. Accessed October 19, 2021. https://emedicine.medscape.com/article/278354-treatment
  4. Edmondson HA. Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. AMA Am J Dis Child. 1956;91(2):168-186. doi:10.1001/archpedi.1956.02060020170015
  5. Craig JR, Peters RL, Edmondson HA, Omata M. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer. 1980;46(2):372-379. doi:10.1002/1097-0142(19800715)46:2<372:aid-cncr2820460227>3.0.co;2-s
  6. Honeyman JN, Simon EP, Robine N, et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343(6174):1010-1014. doi:10.1126/science.1249484
  7. Gottlieb S, O'Grady C, Gliksberg A, Kent P. Early experiences with triple immunochemotherapy in adolescents and young adults with high-risk fibrolamellar carcinoma. Oncology. 2021;99(5):310-317. doi:10.1159/000513358
  8. Lalazar G, Requena D, Ramos-Espiritu L, et al. Identification of novel therapeutic targets for fibrolamellar carcinoma using patient-derived xenografts and direct-from-patient screening. Cancer Discov. 2021;11(10):2544-2563. doi:10.1158/2159-8290.CD-20-0872
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