Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers?

Sorafenib has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma(HCC) since 2007 and numerous studieshave investigated the role of markers involved in the angiogenesis process at both the expression and genetic level and clinical aspect. What results have ten years of research produced? Several clinical and biological markers are associated with prognosis. The most interesting clinical parameters are adverse events, Barcelona Clinic Liver Cancer stage, and macroscopic vascular invasion, while several single nucleotide polymorphisms and plasma angiopoietin-2 levels represent the most promising biological biomarkers. A recent pooled analysis of two phase III randomized trials showed that the neutrophil-to-lymphocyte ratio, etiology and extra-hepatic spread are predictive factors of response to sorafenib, but did not identify any predictive biological markers. After 10 years of research into sorafenib there are still no validated prognostic or predictive factors of response to the drug in HCC. The aim of the present review was to summarize 10 years of research into sorafenib, looking in particular at the potential of associated clinical and biological markers to predict its efficacy in patients with advanced HCC.

Molecular classifications of gastric cancers: Novel insights and possible future applications

Despite some notable advances in the systemic management of gastric cancer(GC), the prognosis of patients with advanced disease remains overall poor and their chance of cure is anecdotic. In a molecularly selected population, a median overall survival of 13.8 mo has been reached with the use of human epidermal growth factor 2(HER2) inhibitors in combination with chemotherapy, which has soon after become the standard of care for patients with HER2-overexpressing GC. Moreover, oncologists have recognized the clinical utility of conceiving cancers as a collection of different molecularlydriven entities rather than a single disease. Several molecular drivers have been identified as having crucial roles in other tumors and new molecular classifications have been recently proposed for gastric cancer as well. Not only these classifications allow the identification of different tumor subtypes with unique features, but also they serve as springboard for the development of different therapeutic strategies. Hopefully, the application of standard systemic chemotherapy, specifictargeted agents, immunotherapy or even surgery in specific cancer subgroups will help maximizing treatment outcomes and will avoid treating patients with minimal chance to respond, therefore diluting the average benefit. In this review, we aim at elucidating the aspects of GC molecular subtypes, and the possible future applications of such molecular analyses.

Hepatocellular carcinoma and microbiota:Implications for clinical management and treatment

Gut microbiota plays an essential role in host homeostasis.It is involved in several physiological processes such as nutrients digestion and absorption,maintenance of intestinal epithelial barrier integrity and immune system self-tolerance.Especially the gut microbiota is assumed to play a crucial role in many gastrointestinal,pancreatic and liver disorders.Its role in hepatic carcinogenesis is also gaining increasing interest,especially regarding the development of therapeutic strategies.Different studies are highlighting a link between some bacterial strains and liver disease,including hepatocellular carcinoma(HCC).Indeed,HCC represents an interesting field of research in this perspective,due to the gut-liver axis,to the implication of microbiota in the immune system and to the increasing number of immunotherapy agents investigated in this tumour.Thus,the assessment of the role of microbiota in influencing clinical outcome for patients treated with these drugs is becoming of increasing importance.Our review aims to give an overview on the relationship between microbiota and HCC development/progression and treatment.We focus on potential implications on the available treatment strategies and those under study in the various stages of disease.We highlight the pathogenic mechanisms and investigate the underlying molecular pathways involved.Moreover,we investigate the potential prognostic and/or predictive role of microbiota for target therapies,immune checkpoint inhibitors and loco-regional treatment.Finally,given the limitation of current treatments,we analyze the gut microbiota-mediated therapies and its potential options for HCC treatment focusing on fecal microbiota transplantation.

Circulating tumour DNA in gastrointestinal cancer in clinical practice:Just a dream or maybe not?

The evaluation of circulating tumor DNA(ctDNA)is increasingly integrated into the management of diagnosis and treatment of gastrointestinal cancer as it represents an innovative and minimally invasive biomarker that could allow us to reach clinical needs not met yet in randomized clinical trials.Recent research provided an interesting overview of the role of circulating tumor DNA in gastric,biliary,liver,pancreatic,and colorectal cancer.Data regarding upper gastrointestinal tumors are currently not practice changing.Tumor detection rates are low in the early stages,while in advanced stages ctDNA is useful for molecular tracking evaluation.Most of the evidence comes from colorectal cancer studies,where ctDNA was evaluated both in the early and advanced stages with the postsurgery minimal residual disease assessment and the response assessment,respectively.ctDNA qualifies as a promising tool in the era of precision medicine,with potential applications in the entire management of gastrointestinal cancer patients.Further evidence is needed to establish which setting may be influenced greatly by liquid biopsy in clinical practice.

How to improve metastatic pancreatic ductal adenocarcinoma patients’selection:Between clinical trials and the real-world

As underlined in the minireview by Blomstrand et al,given the poor prognosis and the paucity of data on a therapeutic sequence in pancreatic ductal adenocarcinoma(PDAC),additional randomized controlled trials and real-world evidence studies addressing current and novel regimens are needed.The real-world outcomes of first-line chemotherapy regimens such as FOLFIRINOX and gemcitabine/nab-paclitaxel are thoroughly reviewed and seem to be largely generalizable in a real-world context.Regarding second-line chemotherapy,the key question about the optimal sequence of regimens remains uncertain.Precisely in this setting,it is therefore useful to encourage the implementation of clinical studies that may contribute to the scarcity of data available up to now.We report our experience with a small group of patients treated with second-line liposomal irinotecan(nal-IRI)plus 5-fluorouracil and leucovorin.To improve the treatment of patients affected by PDAC,it is useful to identify subgroups of patients who may benefit from target treatments(e.g.,BRCA mutant)and it is also important to focus on any prognostic factors that may affect the survival and treatment of these patients.

Polymorphism AGT2(rs4762)is involved in the development of dermatologic events:Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib

BACKGROUND Dermatologic adverse events(DAEs)are associated with a better outcome in patients with hepatocellular carcinoma(HCC)irrespective of the therapeutic agent received.The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors(TKIs)to the skin or an immune-mediated reaction triggered by the oncologic treatment.As is the case in other conditions,individual genetic variants may partially explain a higher risk of DAEs.AIM To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs.METHODS We first analyzed 27 single-nucleotide polymorphisms(SNPs)from 12 genes selected as potential predictors of adverse event(AE)development in HCC patients treated with sorafenib[Barcelona Clinic Liver Cancer 1(BCLC1)cohort].Three additional cohorts were analyzed for AGT1(rs699)and AGT2(rs4762)polymorphisms-initially identified as predictors of DAEs:BCLC2(n=79),Northern Italy(n=221)and Naples(n=69)cohorts,respectively.The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models,and presented with hazard ratios and their 95%confidence intervals(95%CI).RESULTS The BCLC1 cohort showed that patients with arterial hypertension(AHT)(HR=1.61;P value=0.007)and/or AGT SNPs had an increased risk of DAEs.Thereafter,AGT2(rs4762)AA genotype was found to be linked to a statistically significant increased probability of DAEs(HR=5.97;P value=0.0201,AA vs GG)in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage,ECOG-PS,diabetes and AHT.The value of this genetic marker was externally validated in the cohort combining the BCLC1,BCLC2 and Naples cohorts[HR=3.12(95%CI:1.2-8.14),P value=0.0199,AGT2(rs4762)AA vs AG genotype and HR=2.73(95%CI:1.18-6.32)P value=0.0188,AGT2(rs4762)AA vs GG genotype].None of the other gene variants tested were found to be associated with the risk of DAE development.CONCLUSION DAE development in HCC patients receiving TKIs could be explained by the AGT2(rs4762)gene variant.If validated in other anti-oncogenic treatments,it might be considered a good prognosis marker.