低基线CXCL9可预测阿替利珠单抗联合贝伐单抗治疗不可切除肝癌的早期疾病进展
Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment.
作者信息
Hosoda Shunichi, Suda Goki, Sho Takuya, Ogawa Koji, Kimura Megumi, Yang Zijian, Yoshida Sonoe, Kubo Akinori, Tokuchi Yoshimasa, Kitagataya Takashi, Maehara Osamu, Ohnishi Shunsuke, Nakamura Akihisa, Yamada Ren, Ohara Masatsugu, Kawagishi Naoki, Natsuizaka Mitsuteru, Nakai Masato, Morikawa Kenichi, Furuya Ken, Baba Masaru, Yamamoto Yoshiya, Suzuki Kazuharu, Izumi Takaaki, Meguro Takashi, Terashita Katsumi, Ito Jun, Miyagishima Takuto, Sakamoto Naoya
机构信息
Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
出版信息
Liver Cancer. 2022 Oct 31;12(2):156-170. doi: 10.1159/000527759. eCollection 2023 Jun.
INTRODUCTION
Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial.
METHODS
Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum ( = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort ( = 60) and evaluated in patients treated with lenvatinib.
RESULTS
No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without.
CONCLUSION
Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.
引言
阿替利珠单抗联合贝伐珠单抗治疗不可切除肝细胞癌（HCC）患者具有高效性。然而，在接受阿替利珠单抗联合贝伐珠单抗治疗的HCC患者中，约20%会出现疾病进展（PD），导致预后不良。因此，HCC的预测和早期检测至关重要。
方法
对接受阿替利珠单抗联合贝伐珠单抗治疗且基线血清保存完好（n = 68）的不可切除HCC患者进行筛查，并在治疗开始6周后根据其PD情况进行分类（早期PD；n = 13）。其中，分别选取4例有和没有早期PD的患者进行细胞因子阵列和基因分析。在验证队列（n = 60）中对鉴定出的因素进行验证，并在接受乐伐替尼治疗的患者中进行评估。
结果
循环肿瘤DNA的基因改变未观察到显著差异。细胞因子阵列数据显示，有和没有早期PD的患者之间，基线MIG（CXCL9）、ENA - 78和RANTES存在显著差异。随后在验证队列中的分析显示，早期PD患者的基线CXCL9显著低于无早期PD的患者，预测早期PD的血清CXCL9最佳临界值为333 pg/mL（敏感性：0.600，特异性：0.923，AUC = 0.75）。血清CXCL9较低（<333 pg/mL）的患者中，35.3%（12/34）接受阿替利珠单抗联合贝伐珠单抗治疗时出现早期PD，而无早期PD患者的无进展生存期（PFS）显著更长（中位PFS，126天对227天；HR：2.41，95%CI：1.22 - 4.80，P = 0.0084）。与未对乐伐替尼产生客观反应的患者相比，对乐伐替尼产生客观反应的患者CXCL9水平显著更低。
结论
基线血清CXCL9水平低（<333 pg/mL）可能预测接受阿替利珠单抗联合贝伐珠单抗治疗的不可切除HCC患者的早期PD。
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