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

ABSTRACT: 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.

SUBMITTER: Azuma S

PROVIDER: S-EPMC7553969 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Azuma Shintaro S Uojima Haruki H Chuma Makoto M Shao Xue X Hidaka Hisashi H Nakazawa Takahide T Kondo Masaaki M Numata Kazushi K Iwabuchi Shogo S Kako Makoto M Maeda Shin S Koizumi Wasaburo W Atsuda Koichiro K

Scientific reports 20201013 1

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 res ...[more]

PMID: 33051476

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Project description:BackgroundImmune checkpoint inhibitor (ICI)-based combination therapy has opened a new avenue for the treatment of multiple malignancies including hepatocellular carcinoma (HCC). However, considering the unsatisfactory efficacy, biomarkers are urgently needed to identify the patients most likely to benefit from ICI-based combination therapy.MethodsA total of 194 patients undergoing ICI-based combination therapy for unresectable HCC were retrospectively enrolled and divided into a training cohort (n = 129) and a validation cohort (n = 65) randomly. A novel circulating immune index (CII) defined as the ratio of white blood cell count (×109/L) to lymphocyte proportion (%) was constructed and its prognostic value was determined and validated.ResultsPatients with CII ≤ 43.1 reported prolonged overall survival (OS) compared to those with CII > 43.1 (median OS: 24.7 vs 15.1 months; 6-, 12-, 18-month OS: 94.2%, 76.7%, 66.1% vs 86.4%, 68.2%, 22.8%, P = 0.019), and CII was identified as an independent prognostic factor for OS (hazard ratio, 2.24; 95% confidence interval, 1.17-4.31; P = 0.015). These results were subsequently verified in the validation cohort. Additionally, patients with low CII levels had improved best radiological tumor response (complete response, partial response, stable disease, progressive disease: 3%, 36%, 50%, 11% vs 0%, 27%, 46%, 27%; P = 0.037) and disease control rate (89% vs 73%; P = 0.031) in the pooled cohort and better pathologic response (pathologic complete response, major pathologic response, partial pathologic response, no pathologic response: 20%, 44%, 28%, 8% vs 0%, 0%, 40%, 60%; P = 0.005) in the neoadjuvant cohort. Detection of lymphocyte subsets revealed that an elevated proportion of CD4+ T cells was related to better OS, while the proportion of CD8+ T cells was not.ConclusionsWe constructed a novel circulating immune biomarker that was capable of predicting OS and therapeutic efficacy for HCC patients undergoing ICI and lenvatinib combination therapy.

Project description:BackgroundThere is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy.MethodsWe retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions.ResultsOverall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively.ConclusionSorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.

Dataset Information

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

Publications

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

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