Association of <i>NOS3</i> and <i>ANGPT2</i> Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study

Casadei-Gardini, Andrea; Marisi, Giorgia; Dadduzio, Vincenzo; Gramantieri, Laura; Faloppi, Luca; Ulivi, Paola; Foschi, Francesco Giuseppe; Tamburini, Emiliano; Vivaldi, Caterina; Rizzato, Mario Domenico; Ielasi, Luca; Canale, Matteo; Conti, Fabio; Rudnas, Britt; Fornaro, Lorenzo; Silvestris, Nicola; Silletta, Marianna; Cardellino, Giovanni Gerardo; Fornari, Francesca; Orsi, Giulia; Rovesti, Giulia; Zagonel, Vittorina; Cascinu, Stefano; Scartozzi, Mario

doi:10.1158/1078-0432.ccr-19-3897

Cited by 14 publications

(12 citation statements)

References 25 publications

(27 reference statements)

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“…This cohort included a Western population from Italy, and those derived from prospectively collected data in the same setting as the lenvatinib cohort, enrolled in our previous studies. 8,[17][18][19] Then, the classification based on the five variables identified in the lenvatinib cohort was applied to this cohort. Finally, outcomes of the two therapies were compared in the three risk classes, and an interaction test was carried out.…”

Section: Methodsmentioning

confidence: 99%

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma

et al. 2021

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Background: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. Patients and methods: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. Results: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n ¼ 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n ¼ 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n ¼ 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. Conclusions: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

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Section: Methodsmentioning

confidence: 99%

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma

et al. 2021

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“…The NOS3 rs2070744 TC/CC genotypes may reduce the promoter activity of the NOS3 gene compared to the TT genotype, resulting in reduced NO production [25][26][27] . As is the case with the portal hemodynamic study 14,15 , the effects of NO with the NOS3 rs2070744 when treated with lenvatinib may differ from the results of a previous study 12 . Therefore, we presumed that the NOS3 rs2070744 and FGFR4 rs351855 genotypes could be useful predictors of the clinical response to lenvatinib treatment.…”

Section: Discussionmentioning

confidence: 81%

“…To the best of our knowledge, this is the first study to report a correlation between the NOS3 rs2070744 genotypes and the clinical response to lenvatinib in patients with unresectable HCC. In a study investigating the utility of NOS3 SNPs, the NOS3 rs2070744 TT genotype was strongly associated with worse prognoses in patients with advanced HCC treated with sorafenib 12 . However, the NOS3 rs2070744 TC/CC genotypes tended to correspond to a worse prognosis after the administration of lenvatinib, although there were no statistically significant differences.…”

Section: Discussionmentioning

confidence: 99%

“…A point mutation of thymine to cytosine at the NOS3 T-786C polymorphism (rs2070744) results in the altered NOS protein levels and enzymatic activity 10 , 11 . The previous study has reported a correlation between the NOS3 rs2070744 genotypes and the clinical response to sorafenib, which exerts antitumor effects by inhibiting vascular endothelial growth factor receptor (VEGFR), in patients with HCC 12 .…”

Section: Introductionmentioning

confidence: 99%

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Influence of NOS3 rs2070744 genotypes on hepatocellular carcinoma patients treated with lenvatinib

Azuma

Uojima

Chuma

et al. 2020

Sci Rep

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We investigated whether or not nitric oxide synthase 3 (NOS3) rs2070744 genotypes can affect the response for lenvatinib treatment in patients with hepatocellular carcinoma (HCC). We evaluated the relation of the NOS3 rs2070744 genotypes to the tumor response, progression-free survival (PFS), and overall survival (OS) as the response for lenvatinib. We also examined the association between fibroblast growth factor receptor (FGFR) gene polymorphisms, a potential feature of lenvatinib, and the response. There were no significant differences between the studies for either PFS or OS, even though patients with the TT genotype had a longer mean PFS (hazard ratio [HR] 0.60; p = 0.069) and mean OS (HR 0.46; p = 0.075) than those with the TC/CC genotypes. However, patients with a single-nucleotide polymorphism (SNP) combination pattern of the NOS3 rs2070744 TC/CC and FGFR4 rs351855 CT/TT genotypes had a significantly shorter mean PFS (HR 2.56; p = 0.006) and mean OS (HR 3.36; p = 0.013) than those with the other genotypes. The NOS3 rs2070744 genotypes did not influence the clinical response. However, the SNP combination pattern of the NOS3 rs2070744 and FGFR4 rs351855 genotypes may be helpful as treatment effect predictors and prognostic factors for HCC patients treated with lenvatinib.

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“…Hypoxia can, in turn, stimulate the angiogenic process, the tumor growth (71,73,75,76), and may recruit immunosuppressive cells (77). Indeed, there is a complex bidirectional relationship between angiogenesis and immunity (78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88).…”

Section: Immune Checkpoint Inhibitors + Tyrosine-kinase Inhibitors (Tki)mentioning

confidence: 99%

Immune Checkpoint Inhibitors in the Treatment of HCC

et al. 2021

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Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.

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Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study

Cited by 14 publications

References 25 publications

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma

Influence of NOS3 rs2070744 genotypes on hepatocellular carcinoma patients treated with lenvatinib

Immune Checkpoint Inhibitors in the Treatment of HCC

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