University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom.
EORTC Headquarters, Brussels, Belgium.
Eur J Cancer. 2022 Apr;165:97-112. doi: 10.1016/j.ejca.2022.01.017. Epub 2022 Feb 24.
β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial.
Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47-0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS.
Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38-1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80-1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18-0.65) among β-blocker users and 0.59 (95% CI 0.48-0.71) among those not using β-blockers.
This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.
β-肾上腺素能受体在黑色素瘤细胞中上调，并有助于形成免疫抑制、促肿瘤的微环境。本研究通过 EORTC1325/KEYNOTE-054 随机对照试验，探讨了β-阻滞剂对β-肾上腺素能受体阻断的预后和预测价值。
接受区域淋巴结清扫术的 IIIA、IIIB 或 IIIC 期黑色素瘤患者接受 200mg 辅助性 pembrolizumab（n=514）或安慰剂（n=505），每三周一次，持续一年或直至复发或不可接受的毒性。中位随访 3 年后，与安慰剂相比，pembrolizumab 延长了无复发生存期（RFS）（风险比（HR）0.56，95%置信区间（CI）0.47-0.68）。β-阻滞剂的使用定义为随机分组后 30 天内口服任何一种β-阻滞剂。使用多变量 Cox 比例风险模型来估计β-阻滞剂的使用与 RFS 之间的关联的 HR。
在 1019 名随机患者中，有 99 名（10%）患者在基线时使用了β-阻滞剂。β-阻滞剂对 RFS 无独立的预后作用：HR 0.96（95%CI 0.70-1.31）。在 pembrolizumab 组中，与β-阻滞剂使用相关的 RFS 的 HR 为 0.67（95%CI 0.38-1.19），在安慰剂组中为 1.15（95%CI 0.80-1.66）。与安慰剂相比，在使用 pembrolizumab 的患者中，与 RFS 相关的 HR 为 0.34（95%CI 0.18-0.65），在未使用β-阻滞剂的患者中为 0.59（95%CI 0.48-0.71）。
本研究表明β-阻滞剂在切除的高危 III 期黑色素瘤中无预后作用。然而，β-阻滞剂可能预测辅助性 pembrolizumab 治疗的疗效改善。免疫疗法与β-阻滞剂的联合应用值得进一步研究。本研究在 ClinicalTrials.gov 注册，NCT02362594 和 EudraCT，2014-004944-37。
