Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA.
BMC Cancer. 2020 May 6;20(1):383. doi: 10.1186/s12885-020-06882-6.
The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs.
We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culture-based antibiotic susceptibilities.
Of the medications assessed, only antibiotics and corticosteroids significantly associated with shorter OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, β-lactams showed the strongest association with OS across all tested cancers.
The timing and strength of the correlations with antibiotics and corticosteroids after controlling for confounding factors are consistent with the microbiome involvement with the response to ICIs across several cancers.
微生物组已被证明会影响少数癌症和临床前模型中免疫检查点抑制剂（ICI）的反应。在这里，我们试图广泛调查癌症，以确定那些可能通过对接受 ICI 治疗的晚期癌症患者进行回顾性分析来发挥预后作用的癌症。
我们对 690 名接受 ICI 治疗晚期癌症的患者进行了回顾性分析。我们使用文献综述来定义药物、微生物组和 ICI 反应之间关系的因果模型，以指导电子病历的摘要。有微生物组变化先例的药物包括抗生素、皮质类固醇、质子泵抑制剂、组胺受体阻滞剂、非甾体抗炎药和他汀类药物。我们测试了药物时机对总生存期（OS）的影响，并评估了每种癌症中药物作用的稳健性。最后，我们比较了不同类别的抗生素对 OS 的影响大小与通过基于培养的抗生素药敏性文献综述与 ICI 反应相关的分类群。
在所评估的药物中，只有抗生素和皮质类固醇与较短的 OS 显著相关。抗生素和皮质类固醇的危险比（HRs）在 ICI 治疗开始时最高，但在 ICI 之前使用时仍具有统计学意义。即使在控制 ECOG 表现状态、Charlson 合并症指数评分和分期等多个因素后，抗生素和皮质类固醇仍与 OS 显著相关。当按类别对抗生素进行分组时，β-内酰胺类抗生素在所有测试的癌症中与 OS 的相关性最强。
在控制混杂因素后，抗生素和皮质类固醇与 OS 的相关性的时间和强度与微生物组参与几种癌症对 ICI 的反应一致。
