| Background & Aims Hepatocellular carcinoma(HCC)ranks as the sixth leading malignancy worldwide and represents the third most frequent cause of cancer-associated death,the incidence and mortality of HCC in China are among the highest in the world.Hepatic resection,ablation and transplantation are effective only in patients diagnosed at early stages.Most patients with advanced HCC are ineligible for curative therapies.Despite the great progress in HCC treatment over the last decade,the outcome of advanced HCC remains far from satisfactory,and optimal therapy options are limited.Moreover,due to frequent recurrence and metastasis,the prognosis of this refractory disease remains dismal,further emphasizing the urgent need to deepen our understanding of the molecular pathogenesis of HCC and to develop novel intervention strategies In 2008,SHARP trial demonstrated a significant improved OS in advanced HCC patients treated with sorafenib.Sorafenib was then approved as the first systemic therapy for advanced HCC.However,it only offers limited survival benefits.As a multi-kinase inhibitor,sorafenib targets serine/threonine kinases(c-Raf and b-Raf)and receptor tyrosine kinases(VEGFR-1/2/3,PDGFR-?,c-Kit,p38,Ret and FLT3,etc.).Increasing efforts have been put into the screening of biomarkers to predict sorafenib response and patient outcome.However,no biomarker has passed clinical validation to date.Furthermore,the expression of sorafenib targets in HCC and their correlation with sorafenib response remain obscure.Therefore,it is necessary to investigate the association between sorafenib targets and sorafenib benefit in HCC and identify novel biomarkers for patient selection to improve therapeutic efficacy.Molecular subtyping based on genetic alterations or aberrant expression of oncogenes has shed new light on oncology research and practice.Substantial progress has been made in treating certain cancers,especially lung and breast cancer,including EGFR-or HER2-based targeted therapy.However,many targeted therapies intended to treat advanced HCC have failed in phase III trials.The successful targeted therapies have largely depended on biomarker-based selection of patients whose tumors were addicted to that biomarker,but this represents an ongoing challenge to the clinical practice of HCC.Most recently,the MET inhibitor tivantinib was tested in a phase III trial to treat patients with MET-overexpressing HCC,but the results were disappointing.Nevertheless,the REACH-2 trial demonstrated a clinically significant benefit of HCC patients treated with ramucirumab(anti-VEGFR2 monoclonal antibody)versus placebo in the subgroup with high baseline AFP levels(?400 ng/m L).Despite its success,this remains the first and only positive trial to treat HCC via biomarker-based patient selection and demonstrates the urgent need for biomarker-guided clinical studies in HCC.Fms like tyrosine kinase 3(FLT-3),is encoded by the FLT3 gene and belongs to the receptor tyrosine kinase family.FLT3 has been reported to be involved in the regulation of normal hematopoietic cell function and hematopoietic malignancy.Being a tyrosine kinase receptor,FLT3 could be also targeted by sorafenib.However,there is no study investigating FLT3 expression in HCC as well as its clinical correlation.In summary,the purpose of this study is to analyze the association between sorafenib targets and patient prognosis in the cohorts of patients treated with sorafenib and investigate whether FLT3 could be a novel predictor for sorafenib benefit in HCC patients.Methods 1.Immunohistochemical staining was used to detect the expression of sorafenib targets in HCC patients received adjuvant sorafenib,then quantitative scoring was performed.2.The correlation between the expression of sorafenib targets in HCC specimens and the prognosis of patient received adjuvant sorafenib was evaluated via univariate and multivariate analysis.3.A cohort(Cohort 1,n=276)comprised of recurrent patients received sorafenib or not matched by Propensity scores(PSs)from multi-centers was employed to validate the value of FLT3 in predicting sorafenib benefit.4.The optimal cutoff point of high FLT3 levels was defined via Cutoff Finder for cohort1.5.Kaplan-meier was used to analyze the prognostic factors of each subgroup of cohort 1.6.The expression of FLT3 in primary HCC patients was detected by Real-time PCR and immunohistochemical staining.7.HCC and para-tumoral normal tissues were used to investigate the expression and CNV of FLT3.8.PDX models were used to confirm the association between FLT3 levels and sorafenib response.Results 1.High FLT3 levels correlated with an improved overall survival of patients received adjuvant sorafenib.2.In the multi-center cohort consisting of patients with recurrence,a remarkably improved post-recurrence survival of patients treated with sorafenib was observed in the subgroup with high FLT3 levels(42% in Cohort 1).3.Copy number losses and decreased expression of FLT3 in HCC were detected in a considerable portion of patients.4.PDX derived from tumors with high FLT3 levels displayed a better response to sorafenib.Conclusion This study found that High FLT3 levels correlate closely with sorafenib benefit in HCC and could be utilized to stratify patients for personalized therapy. |
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