CTNNB1 Alterations Affect Outcomes in Patients With HCC

CTNNB1 alterations affect outcomes in patients with hepatocellular carcinoma (HCC).

In hepatocellular carcinoma (HCC), CTNNB1 mRNA expression, but not CTNNB1 mutation status, is associated with survival, researchers report. “Patients whose tumors had lower CTNNB1 expression appeared to derive more benefit from immune checkpoint inhibitors and TKI therapy in first line,” Jonathan Pai, MD, and coauthors wrote in an abstract presented at the 2024 ASCO Annual Meeting and in Journal of Clinical Oncology.

Between 2001 and 2020, almost 470,000 patients in the US received a diagnosis of HCC. And between 2000 and 2020, nearly 330,000 deaths were attributed to HCC, with incidence and mortality increasing in men and women, according to the CDC’s United States Cancer Statistics database.

In adults under 55 years of various races, incidence decreased during this period in men but not women. Among those who died, mortality improved more in men than in women, especially among non-Hispanic American Indians and Alaska Natives.

The WNT/beta-catenin pathway plays an integral role in developing HCC, and CTNNB1 (Catenin Beta-1) has been implicated in HCC progression, metastasis, and drug resistance, the researchers explained in their poster. Yet the impact of CTNNB1 alterations on the prognosis and efficacy of immunotherapy and tyrosine kinase inhibitors in HCC is unclear.

Associations Tested In Real-World Cohort

In their investigation of the associations between CTNNB1 mutations, mRNA expression, and clinical outcomes in a real-world cohort of patients with HCC, Dr. Pai and his colleagues tested 1,652 HCC tumors at Caris Life Sciences in Phoenix, Arizona. They analyzed the samples using whole transcriptome sequencing (WTS, Illumina Novaseq), whole exome sequencing (WES, NovaSeq), and NextGen DNA sequencing (592 genes, NextSeq). The researchers then stratified mRNA expression (transcripts per million) into top (Q4) and bottom quartiles (Q1). Kaplan Meier estimates were calculated for overall survival in the molecularly defined cohorts and were estimated from the time of tissue collection to the last contact. χ² and Mann-Whitney tests determined molecular differences between subgroups and adjusted for multiple comparisons.

The research team found pathogenic CTNNB1 mutations present in 32% of HCC, and mutation status was not associated with CTNNB1 expression level.

• Patients whose tumors had lower CTNNB1 expression had significantly improved overall survival: 17.9 versus 12.4 months, Q1 versus Q4 (HR, 0.72; 95% CI, 0.58-0.89; P=0.002). This association remained significant in those who received first-line interventional oncology, with Q1 versus Q4 overall survival 16.7 versus10.6 months (HR 0.54; 95% CI, 0.32-0.94; P=0.025) or tyrosine kinase inhibitors, with Q1 versus Q4 overall survival 27.1 vs. 17.6 months (HR, 0.60; 95% CI, 0.38-0.94; P=0.025).
• Low CTNNB1-expressing tumors (Q1) had more frequent ARID1A mutations (15% vs 8%); less frequent TP53 mutations (31% vs 42%); lower VEGFA, EPHB4, EPHA2, HIF1A, TGFB1/2/3 expression, lower MAPK activation, and lower T-cell inflamed scores than did Q4 tumors (all q<0.05).
• All tumors were microsatellite stable. CTNNB1 mutation status did not impact overall survival in patients treated with interventional oncology or tyrosine kinase inhibitors.

“CTNNB1 expression is associated with DNA repair, immune, neuronal, and angiogenic pathways, which may pave the way for potential therapeutic opportunities,” the authors concluded. “Further studies are needed to prospectively evaluate CTNNB1 as a biomarker for treatment selection in HCC.”