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Genetic Marker Linked to Drug-Resistant Liver Cancer

An illustration of a human liver.
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A genetic marker discovered by UT Southwestern Medical Center researchers could help physicians predict which patients with hepatocellular carcinoma are most likely to develop resistance to the drug lenvatinib. The finding, published in the journal Gastroenterology, may lead to alternative treatments for the most common form of liver cancer.


“Drug resistance in hepatocellular carcinomas is common but has not been well understood,” said David Hsieh, M.D., Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and the study’s lead author. Dr. Hsieh is also a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “These findings can potentially guide future clinical trials on how to prevent and treat lenvatinib resistance in hepatocellular carcinoma as well as other cancers.”

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Mir Lim, M.D., a UTSW resident in Internal Medicine, was the study’s first author.


According to the Centers for Disease Control and Prevention, more than 35,000 people in the U.S. are diagnosed with liver cancer each year; most of those cases involve hepatocellular carcinoma. For about one-fourth of hepatocellular carcinoma patients whose cancers cannot be treated with surgery or liver transplantation, lenvatinib is effective in stopping tumor growth.


In this retrospective study, Dr. Hsieh and colleagues analyzed the genetic profiles of circulating tumor DNA (ctDNA), shed from cancer cells and disseminated into the bloodstream, for 46 patients who underwent treatment for hepatocellular carcinoma at UTSW and Parkland Memorial Hospital. Sixteen patients were treated with lenvatinib, and 30 received immunotherapy drugs. By examining ctDNA collected before treatment and after cancers had progressed with treatment, the research team could identify differences in the genetic profiles of cancers once they were resistant to treatment.


In samples from patients who received lenvatinib, the number of mutations in the genes EGFR and ERBB2, as well as the number of copies of the genes present in cancer cells, tended to increase. Those gains were not seen in patients treated with other drugs, suggesting that the change was a response to lenvatinib. EGFR and ERBB2 are known to play a role in cell growth and are mutated in many cancer types, but they have not been well recognized in hepatocellular carcinoma.


Dr. Hsieh’s group next carried out an additional analysis of 227 patients treated for hepatocellular carcinoma at cancer centers around the country. About 62.5% of patients without EGFR or ERBB2 mutations before treatment showed tumor shrinkage or stability after starting lenvatinib compared with 20% of those who had EGFR or ERBB2 mutations. On average, patients whose tumors had EGFR or ERBB2 mutations had a shorter survival time than those whose tumors lacked the mutations.


Using a national cohort of 1,616 patients, researchers then calculated that about 11% of hepatocellular carcinoma patients have mutations in EGFR or ERBB2. The results suggest these patients are less likely to respond to lenvatinib. In the future, these patients could be offered alternative or combination treatments, Dr. Hsieh said.


“This research may define a new marker to select patients for specific treatments,” he said. “It also suggests that drugs targeting EGFR and ERBB2 combined with lenvatinib may be a very effective treatment in select patients.”


In part based on the results, UTSW now routinely analyzes for genetic mutations present in hepatocellular carcinomas – something not done for liver cancers at most hospitals. However, the institution is awaiting the results of larger validation studies before recommending changes to treatment based on this sequencing. 


Reference: Lim M, Franses JW, Imperial R, Majeed U, Tsai J, Hsiehchen D. EGFR/ERBB2 amplifications and alterations associated with resistance to lenvatinib in hepatocellular carcinoma. Gastroenterology. 2023;164(6):1006-1008.e3. doi: 10.1053/j.gastro.2023.01.023



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