EGFR and ERBB2 Mutations May Be Associated With Lenvatinib-Resistant Hepatocellular Carcinoma

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A genetic marker involving the EGFR and ERBB2 genes may be predictive of which patients with hepatocellular carcinoma are most likely to develop resistance to lenvatinib, according to a study published by Lim et al in Gastroenterology. The new findings could help researchers develop alternative therapeutics for this patient population.


There are over 35,000 new diagnoses of hepatic cancer in the United States per year—most of which involve hepatocellular carcinoma—according to the U.S. Centers for Disease Control and Prevention. For about 25% of patients with hepatocellular carcinoma whose cancer cannot be treated with surgery or liver transplantation, lenvatinib has proven effective at preventing tumor progression.

The EGFR and ERBB2 genes are known to play a role in cell growth and are mutated in many cancer types. However, they have not been well recognized in hepatocellular carcinoma.

“Drug resistance in hepatocellular carcinoma is common but has not been well understood,” explained senior study author David Hsieh, MD, Assistant Professor of Internal Medicine in the Division of Hematology and Oncology at the University of Texas Southwestern Medical Center. “These findings can potentially guide future clinical trials on how to prevent and treat lenvatinib resistance in hepatocellular carcinoma as well as other cancers,” he added.

Study Methods and Results

In the new retrospective study, investigators analyzed the genetic profiles of circulating tumor DNA (ctDNA) for 46 patients with hepatocellular carcinoma—16 of whom were treated with lenvatinib and 30 of whom were treated with immunotherapy. By examining the ctDNA collected prior to treatment and following cancer progression after treatment, the investigators were able to identify differences in the genetic profiles of hepatocellular carcinoma tumors once they were resistant to treatment.

In the samples from patients who were treated with lenvatinib, the investigators discovered that the number of mutations in the EGFR and ERBB2 genes—as well as the number of copies of the genes present in the cancer cells—tended to increase. This increase was not observed in the patients treated with other drugs, suggesting that the change was a response to lenvatinib.

The investigators next carried out an additional analysis of 227 patients treated for hepatocellular carcinoma at cancer centers across the country. About 62.5% of the patients without EGFR or ERBB2 mutations prior to treatment demonstrated tumor shrinkage or stability after starting lenvatinib compared with 20% of those who had EGFR or ERBB2 mutations. Further, those whose tumors had EGFR or ERBB2 mutations had shorter survival times than those whose tumors lacked the mutations.

Using a national cohort of 1,616 patients, the investigators were able to estimate that 11% of patients with hepatocellular carcinoma might have EGFR or ERBB2 mutations. The investigators suggested that these patients may be less likely to respond to lenvatinib.


The investigators hope that patients with EGFR or ERBB2 mutations could soon be offered alternative or combination treatments.

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

In part based on the new findings, the investigators concluded that the University of Texas Southwestern Medical Center now routinely analyzes for genetic mutations present in patients with hepatocellular carcinomas—a practice not conducted for hepatic cancers at most hospitals. However, the institution is awaiting the results of larger validation studies before recommending changes to the standard treatment approach based on this sequencing. 

Disclosure: The research in this study was funded in part by the Cancer Prevention and Research Institute of Texas. For full disclosures of the study authors, visit

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