Department of Medical Oncology, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey.
Department of Pathology, Necmettin Erbakan University School of Medicine, Konya, Turkey.
J Cancer Res Clin Oncol. 2023 Aug;149(10):6849-6856. doi: 10.1007/s00432-023-04628-y. Epub 2023 Feb 20.
Not all RAS wild-type metastatic colorectal cancer (mCRC) patients experience the same benefit from anti-epidermal growth factor receptor (EGFR) treatments. Studies have shown that nuclear factor-κB (NF-κB), hypoxia-inducible factor-1α (HIF-1α), interleukin 8 (IL-8) and transforming growth factor β (TGF-β) may be therapeutic targets for mCRC. The aim of this study was to clarify the prognostic value of NF-κB, HIF-1α, IL-8, and TGF-β expression in patients with left-sided mCRC receiving EGFR inhibitors.
Patients with RAS wild-type, left-sided mCRC treated with anti-EGFR on the first line between September 2013 and April 2022 were included. Immunohistochemical staining for NF-κB, HIF-1α, IL-8 and TGF-β was performed from tumor tissues of 88 patients. Patients were divided into NF-κB, HIF-1α, IL-8 and TGF-β expression positive and negative group, moreover, expression positive group were also divided into two group as expression intensity low and high group. The median follow-up was 25.2 months.
Median progression-free survival (PFS) was 8.1 (6-10.2) months in the cetuximab group, 11.3 (8.5-14) months in the panitumumab group (p = 0.09). Median overall survival (OS) was 23.9 (4.3-43.4) months in the cetuximab group, 26.9 (15.9-31.9) months in the panitumumab group (p = 0.8). Cytoplasmic NF-κB expression was present in all patients. The mOS was 19.8 (11-28.6) months in NF-κB expression intensity low group and 36.5 (20.1-52.8) months in high group (p = 0.03). The mOS of the HIF-1α expression negative group was significantly longer compared with expression positive group (p = 0.014). There was no significant difference in IL-8 and TGF-β expression status on mOS and mPFS (for all, p > 0.05). Positive expression of HIF-1α was poor prognostic for mOS in the univariate analysis (HR:2.7, 95% CI 1.18-6.52, p = 0.02) and in multivariate analysis (HR 3.69, 95% CI 1.41-9.6, p = 0.008). High cytoplasmic expression intensity of NF-κB was found to have a good prognostic value for mOS (HR 0.47, 95% CI 0.26-0.85, p = 0.01).
High cytoplasmic expression intensity of NF-κB and negative expression of HIF-1α could be a good prognostic marker for mOS in RAS wild-type left-sided mCRC.
并非所有 RAS 野生型转移性结直肠癌（mCRC）患者都能从抗表皮生长因子受体（EGFR）治疗中获得相同的获益。研究表明，核因子-κB（NF-κB）、缺氧诱导因子-1α（HIF-1α）、白细胞介素 8（IL-8）和转化生长因子-β（TGF-β）可能是 mCRC 的治疗靶点。本研究旨在阐明 NF-κB、HIF-1α、IL-8 和 TGF-β在接受 EGFR 抑制剂治疗的左侧 mCRC 患者中的表达对预后的影响。
纳入了 2013 年 9 月至 2022 年 4 月接受一线抗 EGFR 治疗的 RAS 野生型、左侧 mCRC 患者。对 88 例患者的肿瘤组织进行 NF-κB、HIF-1α、IL-8 和 TGF-β的免疫组织化学染色。根据 NF-κB、HIF-1α、IL-8 和 TGF-β的表达情况将患者分为阳性和阴性组，此外，表达阳性组还根据表达强度分为低和高组。中位随访时间为 25.2 个月。
西妥昔单抗组的中位无进展生存期（PFS）为 8.1 个月（6-10.2），帕尼单抗组为 11.3 个月（8.5-14）（p=0.09）。西妥昔单抗组的中位总生存期（OS）为 23.9 个月（4.3-43.4），帕尼单抗组为 26.9 个月（15.9-31.9）（p=0.8）。所有患者均有细胞质 NF-κB 表达。NF-κB 表达强度低组的 mOS 为 19.8 个月（11-28.6），高组为 36.5 个月（20.1-52.8）（p=0.03）。HIF-1α 阴性表达组的 mOS 明显长于阳性表达组（p=0.014）。HIF-1α、IL-8 和 TGF-β 的表达状态对 mOS 和 mPFS 均无显著影响（均 p>0.05）。单因素分析中，HIF-1α 的阳性表达是 mOS 的不良预后因素（HR：2.7，95%CI 1.18-6.52，p=0.02），多因素分析中（HR 3.69，95%CI 1.41-9.6，p=0.008）也是如此。细胞质中 NF-κB 的高表达强度被发现对 mOS 有良好的预后价值（HR 0.47，95%CI 0.26-0.85，p=0.01）。
RAS 野生型左侧 mCRC 中，细胞质中 NF-κB 的高表达强度和 HIF-1α 的阴性表达可能是 mOS 的良好预后标志物。
