Department of Urology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea.
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Front Immunol. 2023 Dec 8;14:1301510. doi: 10.3389/fimmu.2023.1301510. eCollection 2023.
Predicting the response to Bacillus Calmette-Guérin (BCG) therapy in high-risk patients with non-muscle invasive bladder cancer (NMIBC) is crucial, as failure may necessitate interventions, such as radical cystectomy or salvage therapy. With the recent classification of genetic class 2a (which has HER2 protein abundance as its signature mutation of ), evaluating its prognostic role and relationship with BCG response could yield important results.
This retrospective study included 160 patients with NMIBC who underwent transurethral resection of bladder tumors at Gangneung Asan Hospital between 2000 and 2013 and were stratified based on the European Organization for Research and Treatment of Cancer (EORTC) risk criteria. In addition, we analyzed a subset of 67 patients who had received BCG induction therapy to identify factors predictive of BCG treatment response. Univariate and multivariate analyses were used to assess the impact of clinicopathological factors, HER2 positivity, and EORTC risk on recurrence, progression, survival, and BCG response. Each variable's prognostic significance was determined using the Kaplan-Meier analysis. The tumor microenvironments (TMEs) were evaluated in relation to HER2 and EORTC risk.
Patients with HER2+ had a higher median age, a greater prevalence of high-grade tumors, and more frequent recurrences. The univariate analysis demonstrated that the HER2+, intermediate (. low-risk) high (. low-risk), and EORTC recurrence risk groups were significantly associated with recurrence. In patients treated with BCG, only the HER2+ status predicted recurrence. In the univariate analysis for progression, age, high EORTC progression risk (. low-to-intermediate), HER2+, and programmed death-ligand 1 positive (PD-L1+) were significant factors. In multivariate analyses for progression, age, high EORTC progression risk, and PD-L1+ were significant factors for progression. HER2 expression was associated with the TME, influencing the proportion of PD-L1+ cells, as well as other markers of PD-1, CD8, and Ki67.
The HER2+ status may be related to genetic characteristics that appear more frequently in older age, which suggests a potential for predicting the recurrence and response to BCG treatment. Additionally, analyzing TME trends of aggressive adaptive immune response characterized by HER2 expression provides insight into recurrence and BCG response mechanisms.
预测高危非肌肉浸润性膀胱癌（NMIBC）患者对卡介苗（BCG）治疗的反应至关重要，因为治疗失败可能需要进行干预，如根治性膀胱切除术或挽救性治疗。最近对遗传分类 2a（其特征性突变是 HER2 蛋白丰度）进行了分类，评估其预后作用及其与 BCG 反应的关系可能会产生重要结果。
本回顾性研究纳入了 2000 年至 2013 年间在江陵峨山医院接受经尿道膀胱肿瘤切除术的 160 例 NMIBC 患者，并根据欧洲癌症研究与治疗组织（EORTC）风险标准进行分层。此外，我们分析了接受 BCG 诱导治疗的 67 例患者的亚组，以确定预测 BCG 治疗反应的因素。采用单因素和多因素分析评估临床病理因素、HER2 阳性和 EORTC 风险对复发、进展、生存和 BCG 反应的影响。使用 Kaplan-Meier 分析确定每个变量的预后意义。评估了与 HER2 和 EORTC 风险相关的肿瘤微环境（TME）。
HER2+患者的中位年龄较高，高级别肿瘤更为常见，且复发更为频繁。单因素分析表明，HER2+、中危（低危）高（低危）和 EORTC 复发风险组与复发显著相关。在接受 BCG 治疗的患者中，只有 HER2+状态预测了复发。在进展的单因素分析中，年龄、高 EORTC 进展风险（低至中危）、HER2+和程序性死亡配体 1 阳性（PD-L1+）是显著因素。在进展的多因素分析中，年龄、高 EORTC 进展风险和 PD-L1+是进展的显著因素。HER2 表达与 TME 相关，影响 PD-L1+细胞的比例，以及 PD-1、CD8 和 Ki67 的其他标志物。
HER2+状态可能与遗传特征有关，这些特征在年龄较大时更为常见，这表明有可能预测复发和对 BCG 治疗的反应。此外，分析以 HER2 表达为特征的侵袭性适应性免疫反应的 TME 趋势，为复发和 BCG 反应机制提供了见解。
