Chinese Hepatocellular Carcinoma Patients Research Articles

Prognostic effect of DNA methylation of BTG2 gene in Chinese hepatocellular carcinoma

BackgroundThis study aims to develop a prognostic model for overall survival based on potential methylation sites within B-cell translocation gene 2 (BTG2) in Chinese patients with hepatocellular carcinoma (HCC). MethodsThis is a retrospective study. The beta values of nine CpG sites and RSEM normalized count values of BTG2 gene were extracted from the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) (TCGA-LIHC) dataset, with the beta value representing the methylation level by indicating the ratio of the intensity of the methylated bead type to the combined locus intensity. Pyrosequencing was performed to determine the range of methylation values surrounding cg01798157 site in BTG2 gene. A weighted linear model was developed to predict the overall survival (OS). ResultsThe beta value of cg01798157 was significantly negatively associated with the mRNA expression of BTG2 in the TCGA-LIHC dataset (Spearman's rho = −0.5306, P = 2.27 × 10−27). The methylation level of cg01798157 was significantly associated with OS in the cohort of 51 Chinese HCC patients (Hazard ratio = 0.597, 95% CI: 0.434–0.820, P = 0.001). Multivariate Cox regression analysis identified methylation level of cg01798157, cirrhosis, and microvascular invasion as independent prognostic factors. The prognostic efficiency of death risk score was superior to that of cirrhosis or microvascular invasion alone. ConclusionsThe methylation level of cg01798157 in BTG2 may be an epigenetic biomarker in Chinese patients with resectable HCC.

Integrated plasma proteomics and N-glycoproteomics reveals alterations in the N-glycosylation in Chinese hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a life-threatening disease that presents diagnostic challenges due to the absence of reliable biomarkers. Recently, plasma proteomics and glycoproteomics have emerged as powerful tools for identifying potential diagnostic biomarkers for various diseases. In this study, we conducted a comprehensive proteomic and glycoproteomic analysis of plasma samples from 11 HCC patients and 11 healthy control (HC) individuals. We identified 20 differentially expressed (DE) proteins and 32 DE intact glycosylated peptides (IGPs) that can effectively differentiate between HCC patients and HC samples. Our findings demonstrate that IGP profiles had better predictive power than protein profiles for screening HCC. Pathways associated with DE proteins and IGPs were identified. It was reported that the protein expression level of galectin 3 binding protein (LGALS3BP) and its N-linked glycosylation at the N398 and N551 sites might serve as valuable candidates for HCC diagnosis. These results highlight the importance of N-glycoproteomics in advancing our understanding of HCC and suggest possible candidates for the future diagnosis of this disease.

Validation of combined AFP, AFP-L3, and PIVKA II for diagnosis and monitoring of hepatocellular carcinoma in Chinese patients

BackgroundIn this study, we aimed to investigate the performance of GALAD, GALAD-C, and GAAP models in Chinese population in comparison to our newly build statistical model. MethodsIn this study, we built the AALP model based on age, α-fetoprotein (AFP), AFP-L3, and prothrombin induced by vitamin K absence-II (PIVKA II) to differentiate between patients with HCC and patients with CLD. We then compared the serum levels of AFP-L3 and PIVKA II in patients with HCC who were defined as remission or progression and showed the prognostic value of combined biomarkers. ResultsThe AUC value of the AALP model for HCC detection was 0.939 and AALP model exhibited a sensitivity of 81 % and a high specificity of 95 %. AALP model also exhibited good performance in the subgroups of patients with CLD. Furthermore, we demonstrated the consistency between imaging results and serum levels of AFP-L3 and PIVKA II. ConclusionsThe AALP model achieved a good diagnostic performance and a high sensitivity for predicting HCC patients. Our research also showed that AFP-L3 and PIVKA II are complementary to each other but irreplaceable in the clinical detection and monitoring of HCC.

Prognostic Performance of the China Liver Cancer Staging System in Hepatocellular Carcinoma Following Transarterial Chemoembolization.

To validate prognostic performance of the China liver cancer (CNLC) staging system as well as to compare these parameters with those of the Barcelona Clinic Liver Cancer (BCLC) staging system for Chinese hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). This multicenter retrospective study included 1,124 patients with HCC between January 2012 and December 2020 from six Chinese hospitals. Based on overall survival (OS), the prognostic performance outcomes for the CNLC and BCLC staging systems were compared by model discrimination [C statistic and Akaike information criterion (AIC)], monotonicity of the gradient (linear trend chi-square test), homogeneity (likelihood ratio chi-square test), and calibration (calibration plots). A prospective cohort of 44 patients receiving TACE-based therapy included between January 2021 and December 2022 was used to prospectively validate the outcomes. Median OS was 19.1 (18.2-20.0) months, with significant differences in OS between stages defined by the CNLC and BCLC observed (p<0.001). The CNLC performed better than the BCLC regarding model discrimination (C-index: 0.661 vs. 0.644; AIC: 10,583.28 vs. 10,583.72), model monotonicity of the gradient (linear trend chi-square test: 66.107 vs. 57.418; p<0.001), model homogeneity (159.2 vs. 158.7; p<0.001). Both staging systems had good model calibration. Similar results were observed in the prospective cohort. Combining model discrimination, gradient monotonicity, homogeneity, and calibration, the CNLC performed better than the BCLC for Chinese HCC patients receiving TACE.

The predictive value of the modified AFP model for liver transplantation outcomes in multinodular hepatocellular carcinoma patients

BackgroundThere is a lack of studies focusing on the benefit of liver transplantation (LT) in hepatocellular carcinoma (HCC) patients with > 3 tumors. This study aims to establish a model to effectively predict overall survival in Chinese HCC patients with multiple tumors (> 3 tumors) who undergo LT.MethodsThis retrospective study included 434 HCC liver transplant recipients from the China Liver Transplant Registry. All HCC patients had more than 3 tumor nodules. Three selection criteria systems (i.e., AFP, Metroticket 2.0, and Up-to-7) were compared regarding the prediction of HCC recurrence. The modified AFP model was established by univariate and multivariate competing risk analyses.ResultsThe AFP score 2 and the AFP score ≥ 3 groups had 5-year recurrence rates of 19.6% and 40.5% in our cohort. The prediction of HCC recurrence based on the AFP model was associated with a c-statistic of 0.606, which was superior to the Up-to-7 and Metroticket 2.0 models. AFP level > 1000 ng/mL, largest tumor size ≥ 8 cm, vascular invasion, and MELD score ≥ 15 were associated with overall survival. The 5-year survival rate in the modified AFP score 0 group was 71.7%.ConclusionsThe AFP model is superior in predicting tumor recurrence in HCC patients with > 3 tumors prior to LT. With the modified AFP model, patients likely to derive sufficient benefit from LT can be identified.

Small RNA sequencing identified miR-3180 as a potential prognostic biomarker for Chinese hepatocellular carcinoma patients.

MicroRNAs (miRNAs) and their target genes are aberrantly expressed in many cancers and are linked to carcinogenesis and metastasis, especially among hepatocellular carcinoma (HCC) patients. This study sought to identify new biomarkers related to HCC prognosis using small RNA sequencing from the tumor and matched normal adjacent tissue of 32 patients with HCC. Eight miRNAs were downregulated and 61 were upregulated more than twofold. Of these, five miRNAs, hsa-miR-3180, hsa-miR-5589-5p, hsa-miR-490-5p, hsa-miR-137, and hsa-miR-378i, were significantly associated with 5-year overall survival (OS) rates. Differential upregulation of hsa-miR-3180 and downregulation of hsa-miR-378i in tumor samples supported the finding that low and high concentrations of hsa-miR-3180 (p = 0.029) and hsa-miR-378i (p = 0.047), respectively, were associated with higher 5-year OS. Cox regression analyses indicated that hsa-miR-3180 (HR = 0.08; p = 0.013) and hsa-miR-378i (HR = 18.34; p = 0.045) were independent prognostic factors of poor survival. However, high hsa-miR-3180 expression obtained larger AUCs for OS and progression-free survival (PFS) and had better nomogram prediction than hsa-miR-378i. These findings indicate that hsa-miR-3180 may be associated with HCC progression and could serve as a potential biomarker for this disease.

Gene-based cancer-testis antigens as prognostic indicators in hepatocellular carcinoma

Cancer/testis antigens (CTAs) are reproductive tissue-restricted genes, frequently ectopic expressed in tumors. CTA genes associate with a poor prognosis in some solid tumors, due to their potential roles in the tumorigenesis and progression. However, whether CTAs relate with hepatocellular carcinoma (HCC) remains unclear. In this study, the prognostic signatures based on CTA genes were investigated and validated in three cohorts including Chinese HCC patients with hepatitis B virus infection (CHCC-HBV), International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) cohorts. Univariate, LASSO, and multivariate Cox regression analyses were used to screen prognostic genes and develop the prognostic gene signature. A prognosis model was established with six CTA genes (SSX1, CTCFL, OIP5, CEP55, NOL4, and TPPP2) in CHCC-HBV cohort, and further validated in the ICGC and TCGA cohorts. The CTA signature was an essential prognostic predictor independent of other clinical pathological factors. High-risk group exhibited up-regulated cell cycle-related and tumor-related pathways and more M0 macrophage, activated mast cell, activated memory CD4+ T cell, and memory B cell infiltration. Furthermore, CTA signature correlated with the sensitivity to multiple chemotherapy drugs. Our results highlighted that the CTA gene profiling was a prognostic assessment tool for HCC patients.

Effectiveness and tolerability of camrelizumab combined with molecular targeted therapy for patients with unresectable or advanced HCC

There is a lack of effective programmed cell death protein 1 (PD-1)‐targeted immunotherapy with good tolerability in patients with advanced hepatocellular carcinoma (HCC) and severely compromised liver function. We assessed patient outcomes after combined camrelizumab and molecular targeted therapy in a multicenter cohort study in China. The study included 99 patients with advanced HCC (58 Child-Pugh A and 41 Child-Pugh B), 84 of them received camrelizumab combined with molecular targeted therapy from January 10, 2019, to March 31, 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were assessed. The median follow-up was 12.1 months. For patients with Child-Pugh B, the OS probability at 12-months, ORR and DCR were 49.7%, 31.7% and 65.9%, respectively, and the median PFS was 5.1 months [95% confidence interval (CI) 3.0–7.1], which were comparable with Child-Pugh A patients, although median OS was shorter in Child‐Pugh B patients (20.5 vs.13.4 months, P = 0.12). In multivariate analysis, macrovascular infiltration (MVI), but not sex, age, hepatitis B virus etiology, extrahepatic metastasis, Child-Pugh B, or AFP > 400 ng/ml, was associated with 12-months OS [hazard ratio (HR) 2.970, 95% CI 1.276–6.917, P = 0.012] and ORR (HR 2.906, 95% CI 1.18–7.16, P = 0.020). Grade 3/4 immune-related AEs occurred in 26.8% of Child-Pugh B patients, including one potentially treatment-related death. In both groups, the most common AEs were immune thrombocytopenia and hepatotoxicity. Camrelizumab combined with targeted therapy showed favorable effectiveness and tolerability with manageable toxicities in Chinese HCC patients, regardless of Child-Pugh A/B liver function. MVI was associated with suboptimal immunotherapy response and poor prognosis.Graphical abstract

An open-label, multi-center phase IIIb study of durvalumab and tremelimumab as first-line treatment in patients with unresectable hepatocellular carcinoma (TREMENDOUS study).

TPS628 Background: Hepatocellular carcinoma (HCC) is of high incidence and mortality rate in China, with nearly half of them are diagnosed as advanced or metastatic stage at the initial diagnosis. First-line treatment options for patients with advanced disease previously included tyrosine kinase inhibitors and immune checkpoint inhibitors in combination with vascular endothelial growth factor. Recently, the phase III HIMALAYA trial investigated the STRIDE regimen, tremelimumab 300mg × 1 dose and durvalumab 1500mg every 4 weeks, compared to sorafenib in previously untreated locally advanced or metastatic HCC patients, and resulted in significantly improved overall survival (OS) (16.4 mos vs 13.8mos, HR=0.78) and a well-tolerated safety profile (≥grade 3 treatment-related adverse events 25.8% vs 36.9% ). Notably, the HIMALAYA trial did not enroll subject from mainland China and excluded patients with class Child-Pugh B liver dysfunction or ECOG performance status (PS) 2. We hypothesize the STRIDE regimen will be safe and well tolerated in Chinese patients with locally advanced or metastatic HCC with Child-Pugh class A or B liver dysfunction or ECOG PS 0-2. In addition, the study will also assess efficacy and explore biomarkers. Methods: This will be an open label, multi-center phase IIIb study investigating the safety and efficacy of the STRIDE regimen in Chinese unresectable HCC patients without prior systemic therapy. Patients with Child-Pugh A liver dysfunction and ECOG PS 0-1 will be enrolled in cohort 1, while patients with Child-Pugh B liver dysfunction or ECOG PS 2 will be enrolled in cohort 2. Patients with main portal vein tumor thrombosis (Vp4), clinically significant ascites or hepatic encephalopathy, or active or prior documented gastrointestinal bleeding within 12 months will be excluded. We plan to enroll 300 patients with the primary endpoint of grade 3-5 adverse event (AE) rate by CTCAE v5.0 and adverse events of special interest (AESI). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), OS, OS rate at 6 months and 12 months. Patients of both cohorts will receive a single dose of tremelimumab 300 mg and durvalumab 1500 mg at Cycle 1 (Week 0), followed by durvalumab 1500 mg monotherapy every 4 weeks until confirmed disease progression or unacceptable toxicity. Archival or fresh tumor biopsy will be required at baseline. The trial is currently screening eligible subjects. Clinical trial information: CTR20222433 .

Genomic landscape of Chinese patients with hepatocellular carcinoma using next-generation sequencing and its association with the prognosis

Introduction and ObjectivesThe occurrence of hepatocellular carcinoma (HCC) is not entirely clear at present. This study comprehensively described the landscape of genetic aberrations in Chinese HCC patients using next-generation sequencing (NGS) and investigated the association of genetic aberrations with clinicopathological characteristics and prognosis. Materials and MethodsThe clinicopathological data of 78 HCC patients undergoing surgery were retrospectively analyzed. The genomic DNA extracted from tumor samples was detected using a NGS-based gene panel. ResultsMutations in TP53 (55%), TERT (37%), MUC16 (29%) and CTNNB1 (27%) were most common in HCC. The co-occurrences between frequently mutated genes occurring ≥10% were relatively common in HCC. Forty-eight (61.5%) cases harbored DNA damage repair gene mutations, mainly including PRKDC (11.5%), SLX4 (9.0%), ATM (7.7%), MSH6 (7.7%), and PTEN (6.4%), and 39 (50.0%) patients had at least one actionable mutation. FH amplification (odds ratio: 3.752, 95% confidence interval: 1.170-12.028, p=0.026) and RB1 mutations (odds ratio: 13.185, 95% confidence interval: 1.214-143.198, p=0.034) were identified as the independent risk factors for early postoperative recurrence in HCC. ConclusionsOur study provides a novel insight into the genomic profiling of Chinese HCC patients. FH amplification and RB1 mutations may be associated with an increased risk of early postoperative recurrence in HCC.

Evaluation of transcriptomic molecular classification, biological behavior, and clinicopathological features in hepatocellular carcinoma

ABSTRACT Background Studies in France, Korea, and Singapore found that G1-G6 transcriptomes are involved in hepatocellular carcinoma (HCC) carcinogenesis. However, the suitability of this method in Chinese HCC patients has remained unknown. Methods The correlation between the G1–G6 molecular classification and clinicopathological features were analyzed in 107 Chinese HCC patients through the retrospective cohort study. RNA sequencing and bioinformatics analysis were performed to screen related targets and molecular signaling pathways. Results We found that the G1–G3 subgroups were associated with high serum alpha-fetoprotein (AFP) level, high copy number of hepatitis B virus (HBV) DNA, complex histopathological structure, macrovascular invasion. The G1 subgroup was mainly related to liver cancer stemness, and G3 subgroup showed the worst prognosis. The G5 and G6 subgroups were associated with activation of the Wnt/β-catenin pathway. Compared with the G4–G6 group, the G1–G3 group showed significantly higher expression levels of regenerating family member 1 beta (REG1B), regenerating family member 3 gamma (REG3G), and inositol 1,4,5-trisphosphate receptor type 1 (ITPR1), and enriched calcium signaling pathway. Conclusions This study enhances our understanding of the heterogenicity of China HCC and indicates that the G1–G6 signatures can be used to identify predictive biomarkers against HCC patients in China.

Immunohistochemical Analysis of P53 Gene Expression and other Protein Indicators in Chinese Hepatocellular Carcinoma Patients

Immunohistochemical Analysis of P53 Gene Expression and other Protein Indicators in Chinese Hepatocellular Carcinoma Patients

Whole-exome sequencing identifies a set of genes as markers of hepatocellular carcinomaearly recurrence.

Hepatocellular carcinoma (HCC) is characterized by a high recurrence rate and poor prognosis. In recent years, the therapeutic regimen of programmed cell death protein 1 (PD-1) antibody combined with multi-targeted tyrosine kinase inhibitors (mTKIs) has achieved better results in the clinical application of hepatocellular carcinoma. Whole-exome sequencing can reflect the mutational characteristics of patients' exons and guide the clinical selection of molecular targeting drugs more accurately, which is in line with the concept of precision medicine. We performed exome sequencing on 63 patients with HCC treated with radical surgery at our hospital and collected their clinical indexes and postoperative follow-up data. Using machine learning, a prediction model for recurrence within 1year was constructed and the model was presented in a nomogram. Patients treated with PD-1 antibodies in combination with mTKIs after relapse were grouped by prognosis, and the valuable mutated genes were screened according to whole-exome sequencing data. The tumor tissue immune cells were analyzed using the UCSC Xena database. The expressions of target proteins were verified by Polymerase Chain Reaction (PCR) and Immunohistochemistry (IHC), respectively, on commercial HCC cell lines and pathological specimens of hepatocellular carcinoma collected clinically. The proportion of patients who relapsed within a year was 41% and the prognosis of those patients was poor. The characteristic exon mutation profile with a high frequency of variants in multiple mucin genes was present in Chinese HCC patients. Multiple nidi and 30 exon variants were brought into the prediction model with an area under the curve (AUC) = 0.94. MUC6 gene mutation was obvious in patients with an early recurrence, and MUC3A and MUC4 gene mutations were evident in patients with poorer responses to PD-1 antibodies combined with mTKIs. Those three mucins were negatively correlated with immune infiltrating cells. We depicted the exon characteristics of hepatocellular carcinoma in the Chinese population and established a predictive model for recurrence within 1year after radical surgical treatment. Moreover, we found that mucins were worthy targets of hepatocellular carcinoma.

The Combination of AFP and "Up-To-Seven" Criteria May Be a Better Strategy for Liver Transplantation in Chinese Cirrhotic HCC Patients.

BackgroundOrthotopic liver transplantation (OLT) is a life-saving option for patients with hepatocellular carcinoma (HCC), but the expanded OLT criteria remain controversial.ObjectiveThe study aimed to explore whether expanded OLT criteria can be applied to Chinese cirrhotic patients with HCC.MethodsThis retrospective study analyzed risk factors for HCC recurrence and death and compared patients’ tumor characteristics and outcomes in groups of Milan, “Up-to-seven,” and Hangzhou criteria, and groups between met and unmet the combinative criteria of “Up-to-seven” and AFP of < 1000 ng/mL.ResultsAmong 153 patients who underwent OLT for HCC from January 2015 to February 2019 in 4 years of follow-up, 20 (13.1%) patients had HCC recurrence, and 11 (7.2%) had HCC-related death. Multivariate Cox regression analysis showed that preoperative alpha-fetoprotein (AFP) of > 1000 ng/mL (hazard ratio [HR]: 10.05, 95% confidence interval [CI]: 2.45–41.13, P = 0.001) was an independent risk factor for HCC recurrence and HCC-related death (HR: 6.63, 95%CI: 1.31–33.52, P = 0.022). Patients who did not meet Milan criteria but satisfied the “Up-to-seven” criteria had no differences in overall survival (OS) (P = 0.69) and disease-free survival (DFS) (P = 0.35) than patients who met the Milan criteria. The combination of “Up-to-seven” criteria and AFP of < 1000 ng/mL differed significantly (HR: 18.9; 95% CI: 4.0–89.2; P < 0.001). Patients with HCC who met the “Up-to-seven” criteria and AFP of < 1000 ng/mL (n = 121) had excellent survival with 4-year OS of 91.6% (P < 0.001) and DFS of 90.8% (P < 0.001), which is significantly better compared to the other group (n = 32) (OS of 67.5% and DFS of 46.5%) and patients who met the Milan criteria (n = 108, OS of 89.8%, DFS of 89.6%), allowing 28.9% (13/45) of patients who did not meet the Milan criteria to benefit from OLT.ConclusionChinese cirrhotic patients with HCC who met the combinative criteria of “Up-to-seven” and AFP of < 1000 ng/mL had better survival than those who met the Milan criteria, and these combinative criteria benefited more patients and may become a better option for OLT.

NGS analysis of germline mutation profile of patients with hepatocellular carcinoma in China.

10585 Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide with very poor prognosis. Many studies have focused on oncogene characteristics, however, the germline landscape of Chinese HCC patients has not been fully clarified. The purpose of this study is to assess the inherited genetic factors regarding germline mutations in Chinese HCC patients. Methods: Genetic mutations were reviewed in 1670 Chinese HCC patients who underwent hybridization capture based next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of 1670 patients with HCC, 110 (6.7%) patients were identified to carry 111 pathogenic variants(P) or likely pathogenic variants(LP) in 112-cancer predisposition gene panel, and there was no age difference between P/LP group and non-P/LP group (average age: 57 vs 56, p = 0.64). The most frequently germline mutated genes were BRCA1/2 (11.7%), followed by ATM(4.5%), BLM(4.5%), ERCC2(4.5%), ERCC3(4.5%) and BRIP1(3.6%), ERCC4(3.6%), FANCD2(3.6%), MUTYH(3.6%), RAD50(3.6%). Of all the 111 germline mutations, 47% (n = 52) lay in the Homologous Recombination Repair (HRR) pathways. Both in P/LP group and non-P/LP group, the most frequently somatic mutated genes were TP53, TERT and MUC16. 7/110(6.4%)of patients in P/LP group were high TMB(≥10 mutations/megabase) and 131/1560(8.5%) in non-P/LP group. There was no statistical difference in TMB between P/LP and non-P/LP group. Conclusions: Taken together, we have presented the spectrum of pathogenic germline mutations in Chinese HCC patients. P/LP germline variants in cancer predisposition genes were detected in 6.7% of those patients, and predisposition genes associated with HCC risk needs further investigation. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.

Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first line sorafenib: Pooled efficacy and safety in Chinese patients across two global randomized phase 3 studies (REACH-2 and REACH).

e16081 Background: REACH-2 and REACH were two global, randomized, double-blind, placebo (PL)-controlled phase 3 studies of Ramucirumab (RAM) versus PL in patients with HCC after prior sorafenib. REACH-2 confirmed the RAM treatment benefit for patients with baseline AFP ≥ 400 ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥ 400 ng/mL. A pooled analysis was performed to evaluate the efficacy and safety of RAM in Chinese patients (including patients from mainland China, Hong Kong, and Taiwan) from REACH-2 and REACH with baseline AFP ≥400 ng/mL. Methods: Except for AFP level requirement, REACH-2 and REACH were similar in study design and included patients who had advanced HCC (BCLC stage C or B disease refractory or not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior sorafenib. Patients were randomized to RAM (8 mg/kg) I.V. or PL Q2W, plus best supportive care, until disease progression or unacceptable toxicity. Individual patient data were pooled from REACH-2 and REACH (AFP ≥400 mg/mL). Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR), and safety were reported. Efficacy analyses were stratified by study to account for any potential difference in the two studies. Results: Data from 155 Chinese patients were pooled from REACH (51) and REACH-2 (104) (N = 98 RAM vs N = 57 PL). Baseline characteristics were generally balanced between arms in pooled data set; however, lower median level of AFP was noted in the RAM arm. In the pooled population, RAM treatment numerically improved OS over PL (median OS 7.1 months vs 4.7 months; HR = 0.735 [95% CI: 0.512, 1.055]). Improvements in PFS (median PFS 2.6 months vs 1.5 months; HR = 0.666 [95% CI: 0.459, 0.967]), ORR (3.1% vs 0%), and DCR (44.9% vs 29.8%) were also observed. Hypertension (6.1% vs 1.8%), pneumonia (5.1% vs 1.8%), and hyponatremia (5.1% vs 1.8%) were the Grade ≥3 treatment-emergent adverse events (TEAEs) among ≥ 5% patients that was more frequently observed in the RAM arm compared with the PL arm. Conclusions: Pooled analysis of two phase 3 trials of RAM as second-line treatment in patients with HCC following sorafenib demonstrated a clinically meaningful benefit with a manageable safety profile in Chinese HCC patients with baseline AFP ≥ 400 ng/mL. Treatment benefits in OS observed in the pooled Chinese population were consistent with the entire population from REACH/REACH-2 (AFP ≥ 400 ng/mL). Clinical trial information: NCT01140347, NCT02435433.

A real-world study of Chinese hepatocellular carcinoma patients treated with TACE.

The aim of the study was to explore the real situation of transcatheter arterial chemoembolization (TACE) treatment mode and clinical benefits for hepatocellular carcinoma (HCC) patients, as well as to potentially provide data support and clinical basis for the decision-making of HCC patients. We collect the diagnosis and treatment information of patients who were clinically diagnosed with primary liver cancer (PLC) and received the first treatment in the medical center since January 1st, 2012 from the Chinese Liver Cancer Survey (CLCS) database. Then, we entered the formatted data into the real-world study (RWS) database. TACE-related data were collected prospectively. From December 2018 to January 2020, HCC patients who were eligible for CLCS and received TACE were treated at three time points (admission day/before TACE, before discharge/after TACE, follow-up/first follow-up after discharge) to collect and analyze the quality of life of patients and the use of medical resources. Patients with clinical diagnosis of HCC who received TACE treatment at least once were screened based on CLCS locking data. Demographic and TACE treatment related studies were conducted on the selected HCC patients. The data of the whole group of 5436 HCC patients who received TACE treatment in 48 medical centers showed that the first department of patients was surgery (65.89%), followed by internal medicine (22.42%) (p>0.05). The proportion of patients treated with TACE was 51.85%; the proportion of patients treated with 2 TACE was 23.64%; the proportion of patients with more than 3 times was 20.60% (p>0.05). In the CLCS database, the TACE-first group, there were 1758 patients who received only one treatment in total, and 3069 patients who received ≥ 2 treatments (p<0.05). The common complications related to TACE treatment were nausea (25.77%), fever (31.53%), vomiting (20.99%), liver pain (40.67%) and other uncomfortable symptoms (p<0.05). A more comprehensive understanding of the clinical impact and benefits of TACE in Chinese HCC patients is needed.

Somatic Mutation Profiles Revealed by Next Generation Sequencing (NGS) in 39 Chinese Hepatocellular Carcinoma Patients.

The features and significance of somatic mutation profiles in hepatocellular carcinoma (HCC) have not been completely elucidated to date. In this study, 39 tumor specimens from HCC patients were collected for gene variation analysis by next-generation sequencing (NGS), and a correlation analysis between mutated genes and clinical characteristics was also conducted. The results were compared with genome data from cBioPortal database. Our study found that T > G/A > C transversions (Tv) and C > T/G > A transitions (Ti) were dominant. The sequence variations of TP53, MUC16, MUC12, MUC4 and others, and the copy number variations (CNVs) of FGF3, TERT, and SOX2 were found to be more frequent in our cohort than in cBioPortal datasets, and they were highly enriched in pathways in cancer and participated in complex biological regulatory processes. The TP53 mutation was the key mutation (76.9%, 30/39), and the most common amino acid alteration and mutation types were p.R249S (23.5%) and missense mutation (82.3%) in the TP53 variation. Furthermore, TP53 had more co-mutations with MUC17, NBPF10, and AHNAK2. However, there were no significant differences in clinical characteristics between HCC patients with mutant TP53 and wild-type TP53, and the overall survival rate between treatment via precision medication guided by NGS and that via empirical medication (logrank p = 0.181). Therefore, the role of NGS in the guidance of personalized targeted therapy, solely based on NGS, may be limited. Multi-center, large sample, prospective studies are needed to further verify these results.

Abstract 1457: Discovery of biomarkers assocaited with treatment responses to sorafenib and transarterial chemoembolisation (TACE) in Chinese hepatocellular carcinoma patients

Abstract Background: Liver cancer is one of the most deadly tumors. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers. Sorafenib, a multi-target kinase inhibitor, is one the main systemic therapy drug of HCC. It increased the median overall survival time from 7.9 mo to 10.7 mo for patients with advanced stage HCC. However, about 60% of HCC patients done't respond well to sorafenib, and most of them develop progression in below 6 mo. Similarly, TACE is also an effective treatment of HCC but only with partial response rate. Therefore, finding new strategies to screen the best matched patients is key to improve the efficacy of sorafenib and TACE treatment. Methods: We evaluated the efficacy of sorafenib starting with 98 HCC patients but only 73 patients completed the study because 24 dropped out due to death (n=2), drug violation (n=4), adverse reactions (n=3), and failure of outcome evaluation (n=15). Forty-five patients were treated by TACE. We divided the patients to a progressive disease (PD) group (46.6%, 34 patients) and a Non-PD group (53.4%, including 2 with partial response and 37 with stable disease) based on their CT and MRI evaluations. At the same time, we performed Whole-exome sequencing (WES) on the tumor samples and patient-matched blood samples. Results: We found the PD group, comparing with the Non-PD group, had a higher proportion of patients with MSI (P = 0.028) and mutations in WNT/ß-catenin signaling and chromatin modification pathways, as well as cytoband deletions at 21q11, 1p21.1, 8q24.3, 11p11.12, 5p15.33, and 17q25.3. On contrast, cytoband amplifications at 12p13, 21q22.3, and 8q21 only appeared in the Non-PD group. We also observed a prominent decrease in the PD group COSMIC mutational signature 10 which is believed to associate with POLE mutation. We found MUC16 and FLG2 genes were related to a better survival time. Mutation of NANOGNB, and cytoband deletions at 3q11.2, 4q13.2,11q11,11q22.2 and 17q25.3 were related to a shorter survival time. (p&amp;lt;0.05 for all above except otherwise specified). Conclusions: We found several genes and chromosome variation were associated with sorafenib efficacy and overall survival in HCC patients. These findings indicated that mutations and chromosomal fragment deletions can lead to sorafenib resistance. Mutations of MUC16 and FLG2 may be potential drug targets in HCC. Citation Format: Zhiqiang Wu, Xiaoyu Zhou, Shengzhou Wang, Jinhuai Li, Jun Liu, Wenbo Guo. Discovery of biomarkers assocaited with treatment responses to sorafenib and transarterial chemoembolisation (TACE) in Chinese hepatocellular carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1457.

Analysis of DNA damage repair pathway genes as a predictive biomarker for HAIC in hepatocellular carcinoma.

e16159 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide.Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil, and leucovorin (FOLFOX) is one of the effective treatment for advanced HCC patients. DNA damage repaired (DDR) pathway has been widely researched in many cancers recent years, which was a promising predictive biomarker for the response to platinum-based chemotherapy and Immunotherapy. But the DDR characteristics of different subset pathways in HCC, and its correlation with HAIC efficacy were unknown. Methods: Whole exome sequencing (WES) data of 366 HCC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS, panel on 381/733-gene) was performed on FFPE tumor samples from 2092 Chinese HCC patients (Chinese cohort). Germ-line or somatic mutations of 32 DDR pathway genes (including Mismatch Repair and Homologous Recombination) were classified as DDR gene mutations. TMB was defined as total number of somatic non-synonymous mutations in coding region. Whole exome sequencing (WES) data and clinical data of 21 HCC advanced patients treated with HAIC were obtained to survival analysis. Results: In total, 59.84% (219/366) of HCC patients in TCGA harboring DDR mutation and 67.38% (1316/2092) in Chinese cohort. In Chinese HCC cohort, the mean TMB level of DDR mutant group was significant higher than wild-type group (mean TMB, mutation vs wild-type = 8.12 vs 6.42 Muts/Mb, P &lt; 0.0001). The top three mutation frequency DDR genes were BRCA2 (17%), ATM (13%) and BARD1 (12%), respectively. The highest mutation frequency DDR subset pathways were Fanconi anemia (FA, 44.14%, 862/2092), homologous recombination repair (HRR, 38.71%, 756/2092) and check point factors (CHP, 17.31%, 338/2092) come in second and third, respectively. Next we compared the TMB level between different DDR subset pathways, the mutant of nucleotide excision repair (NER) pathway harbored the highest medium TMB level (7.26 Muts/Mb). The survival analysis was performed on HCC patients treated with HAIC with FOLFOX. There was no difference in clinical baseline information between DDR mutation group (n = 6) and wild-type group (n = 15). The progression-free survival (PFS) of DDR mutation group were significantly longer than wild-type group (median PFS, mutation vs. wild-type = 8.9 vs. 4.5 months; HR 0.34[95% CI 0.13-0.85]; P = 0.0349), and an extending trend on overall survival (OS) without significant difference (median OS, 15.7 vs 8.9 months; HR 0.37[95% CI 0.13-1.00]; P = 0.0921). Conclusions: The DDR pathways was associated with higher TMB level. Preliminary data from clinical cohorts suggested better treatment outcomes of HAIC with FOLFOX in DDR mutation HCC patients.