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A Single Nucleotide Polymorphism rs1010816 Predicts Sorafenib Therapeutic Outcomes in Advanced Hepatocellular Carcinoma.

ABSTRACT: Sorafenib is currently a targeted agent widely used in the treatment of advanced hepatocellular carcinoma (aHCC). However, to date there is still a lack of a reliable marker capable of predicting sorafenib therapeutic responses. Here, we conducted a genome-wide association study (GWAS) to identify candidate single-nucleotide polymorphism outcome predictors in aHCC patients. A total of 74 real-world sorafenib-treated aHCC patients were enrolled for GWAS and outcome analysis. GWAS showed that rs1010816 (p = 2.2 × 10^-7) was associated with sorafenib therapeutic response in aHCC patients. Kaplan-Meier analysis indicated that the "TT" genotype was significantly associated with a favorable therapeutic response but not significantly associated with overall survival (OS). Univariate followed by multivariate Cox proportional hazard analysis showed that ascites, main portal vein thrombosis, lower platelet count, lower total sorafenib doses, higher PALBI score in model A and higher ALBI grade in model B were significantly associated with a shorter OS. Subgroup analysis showed that only in alcoholic aHCC patients treated by sorafenib, rs1010816 "TT" genotype was significantly associated with longer OS (p = 0.021). Sorafenib had a favorable therapeutic outcome in alcoholic aHCC patients carrying rs1010816 "TT" genotype.

SUBMITTER: Lin CL

PROVIDER: S-EPMC9862766 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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A Single Nucleotide Polymorphism rs1010816 Predicts Sorafenib Therapeutic Outcomes in Advanced Hepatocellular Carcinoma.

Lin Chih-Lang CL Liang Kung-Hao KH Hu Ching-Chih CC Chien Cheng-Hung CH Chen Li-Wei LW Chien Rong-Nan RN Lin Yang-Hsiang YH Yeh Chau-Ting CT

International journal of molecular sciences 20230114 2

Sorafenib is currently a targeted agent widely used in the treatment of advanced hepatocellular carcinoma (aHCC). However, to date there is still a lack of a reliable marker capable of predicting sorafenib therapeutic responses. Here, we conducted a genome-wide association study (GWAS) to identify candidate single-nucleotide polymorphism outcome predictors in aHCC patients. A total of 74 real-world sorafenib-treated aHCC patients were enrolled for GWAS and outcome analysis. GWAS showed that rs10 ...[more]

PMID: 36675198

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Project description:BackgroundPhase III trials show sorafenib improves survival in advanced hepatocellular carcinoma (HCC). Because of narrow trial eligibility, results may not be generalizable to a broader HCC population. We sought to evaluate the effectiveness of initial sorafenib versus no treatment among Medicare beneficiaries with advanced HCC.Materials and methodsPatients with advanced HCC diagnosed from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Eligible patients received initial sorafenib or no therapy and were covered by Medicare parts A, B, and D. Sorafenib use and outcomes were described in this population. Using a propensity score (PS)-matched sample, we compared the effectiveness of sorafenib versus no treatment by Cox proportional hazards and binomial regression, using a landmark requiring all patients to survive ≥60 days after diagnosis.ResultsOf 1,532 patients, 27% received initial sorafenib. Median duration of sorafenib use was 60 days (interquartile range [IQR], 30-107 days), and median survival from first prescription was 3 months (IQR, 1-8 months). In the PS-matched cohort, median survival was 3 months from the 60-day landmark in sorafenib-treated (n = 223) and 2 months in untreated (n = 223) patients (adjusted hazard ratio, 0.95 [95% confidence interval (CI), 0.78-1.16]). Sorafenib was associated with a nonsignificant reduction in mortality at 3 months (44% versus 51%; adjusted risk ratio, 0.88 [95% CI, 0.72-1.07]), but no reduction thereafter.ConclusionSurvival after sorafenib initiation in newly diagnosed Medicare beneficiaries with HCC is exceptionally short, suggesting trial results are not generalizable to all HCC patients. The downsides of sorafenib use-high drug-related symptom burden and high drug cost-must be considered in light of this minimal benefit.Implications for practiceThe findings of a median survival of only 3 months in Medicare beneficiaries with HCC prescribed sorafenib as first-line therapy highlight the questionable value of sorafenib in this population. Patients should be cautioned that outside of the narrow confines of randomized trials, their life expectancy may be very short, and any benefit of sorafenib is likely to be quite small. Given that sorafenib causes considerable adverse effects and offers no symptom palliation, supportive care should be discussed as a reasonable alternative to sorafenib, particularly for patients who have a poor performance status or advanced cirrhosis.

Project description:IntroductionSorafenib was the first therapy used for systemic treatment of unresectable hepatocellular carcinoma (HCC). Multiple prognosis factors associated with sorafenib therapy have been described.ObjectivesThe aim of this work was to evaluate survival and time to progression (TTP) on HCC patients treated with sorafenib, and check for predictive factors of sorafenib benefit.Materials and methodsRetrospectively, data from all HCC patients treated with sorafenib in a Liver Unit from 2008 to 2018 were collected and analyzed.ResultsSixty-eight patients were included; 80.9% were male, the median age was 64.5 years, 57.4% had Child-Pugh A cirrhosis and 77.9% were BCLC stage C. Macrovascular invasion (MVI) was present in 25% of the patients and 25% of the subjects had other extrahepatic metastasis. The median survival was 10 months (IQR 6.0-14.8) and median TTP was 5 months (IQR 2.0-7.0). Survival and TTP were similar between Child-Pugh A and B patients: 11.0 months (IQR 6.0-18.0) for Child-Pugh A and 9.0 months (IQR 5.0-14.0) for Child-Pugh B (p = 0.336). In univariate analysis, larger lesion size (LS >5 cm), higher alpha-fetoprotein (AFP >50 ng/mL), and no history of locoregional therapy were statistically associated with mortality (HR 2.17, 95% CI 1.24-3.81; HR 3.49, 95% CI 1.90-6.42; HR 0.54, 95% CI 0.32-0.93, respectively), but only LS and AFP were independent predictive factors, as shown in multivariate analysis (LS: HR 2.08, 95% CI 1.10-3.96; AFP: HR 3.13, 95% CI 1.59-6.16). MVI and LS >5 cm were associated with TTP shorter than 5 months in univariate analysis (MVI: HR 2.80, 95% CI 1.47-5.35; LS: HR 2.1, 95% CI 1.08-4.11), but only MVI was an independent predictive factor of TTP shorter than 5 months (HR 3.42, 95% CI 1.72-6.81). Regarding safety data, 76.5% of patients reported at least one side effect (any grade), and 19.1% presented grade III-IV adverse effects leading to treatment discontinuation.ConclusionsWe observed no significant difference in survival or TTP in Child-Pugh A or Child-Pugh B patients treated with sorafenib, as compared to more recent real-life studies. Lower primary LS and AFP were associated with a better outcome, and lower AFP was the main predictor of survival. The reality of systemic treatment for advanced HCC has recently changed and continues to evolve, but sorafenib remains a viable therapeutic option.

Project description:Targeted therapy is currently the standard treatment for advanced hepatocellular carcinoma (HCC), but an effective treatment after the discontinuation of sorafenib therapy remains uncertain. We aim to investigate the survival benefits of transcatheter arterial chemoembolization (TACE) after stopping sorafenib therapy. We retrospectively analyzed all patients with advanced HCC, who had received palliative TACE after terminating sorafenib therapy, from January 2008 to June 2016. Patients who were in the terminal stage (Child-Pugh class C or performance status 3-4), who received a liver transplantation, or who had received any HCC treatment other than TACE, were excluded. Finally, 28 patients were recruited as the TACE group, and were randomly matched 1:1 by age, gender, Child-Pugh class, extrahepatic metastasis, and portal vein thrombosis with 28 controls who only received supportive care. For avoiding any immortal time bias, the index date of outcome follow-up was also matched. Cumulative incidences of, and hazard ratios (HRs) for, patient mortality were analyzed. The baseline demographic data between the TACE group and the control group were similar, but the 1-year overall survival rate in the TACE group was significantly higher than that of the control group (41.2%, 95% confidence interval [CI]: 19.4-63.0% vs. 24.5%, 95% CI: 6.3-42.7%; p < 0.01). In multivariate analysis, after adjusting for alpha-fetoprotein > 400ng/mL, Child-Pugh class B, and tumor extension > 50% of liver volume, TACE was independently associated with a decreased mortality risk(HR 0.19, 95% CI: 0.08-0.42). In addition, tumor extension > 50% of the liver was another independent prognostic factor associated with an increased mortality risk (HR 2.99, 95% CI: 1.31-6.82). Multivariate stratified analyses verified the association of TACE with a decreased mortality rate in each patient subgroup (all HR < 1.0). By controlling intrahepatic tumor growth, TACE may be a treatment option for use in improving patient survival in advanced HCC, after the termination of sorafenib therapy.

Dataset Information

A Single Nucleotide Polymorphism rs1010816 Predicts Sorafenib Therapeutic Outcomes in Advanced Hepatocellular Carcinoma.

Publications

A Single Nucleotide Polymorphism rs1010816 Predicts Sorafenib Therapeutic Outcomes in Advanced Hepatocellular Carcinoma.

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