Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Translational Genomics and Targeted Therapies in Solid Tumors, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain.
Department for Sustainable Food Process-DiSTAS, Università Cattolica del Sacro Cuore, Piacenza, Italy.
Eur J Cancer. 2023 Sep;191:112948. doi: 10.1016/j.ejca.2023.112948. Epub 2023 Jun 20.
Cyclin-dependent kinase (CDK)4/6-inhibitors with endocrine therapy represent the standard of treatment of hormone receptor-positive(HR+)/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Gut microbiota seems to predict treatment response in several tumour types, being directly implied in chemotherapy resistance and development of adverse effects. No evidence is available on gut microbiota impact on efficacy of HR+ breast cancer treatment.
We assessed the potential association among faecal microbiota and therapeutic efficacy of CDK4/6-inhibitors on 14 MBC patients classified as responders (R) and non-responders (NR) according to progression-free survival. A stool sample was collected at baseline and V3-V4 16S targeted sequencing was employed to assess its bacterial composition. Statistical associations with R and NR were studied.
No significant differences were observed between R and NR in terms of α-/β-diversity at the phylum and species level. Machine-learning (ML) algorithms evidenced four bacterial species as a discriminant for R (Bifidobacterium longum, Ruminococcus callidus) and NR (Clostridium innocuum, Schaalia odontolytica), and an area under curve (AUC) of 0.946 after Random Forest modelling. Network analysis evidenced two major clusters of bacterial species, named Species Interacting Groups (SIG)1-2, with SIG1 harbouring 75% of NR-related bacterial species, and SIG2 regrouping 76% of R-related species (p < 0.001). Cross-correlations among several patients' circulating immune cells or biomarkers and bacterial species' relative abundances showed associations with potential prognostic implications.
Our results provide initial insights into the gut microbiota involvement in sensitivity and/or resistance to CDK4/6-inhibitors + endocrine therapy in MBC. If confirmed in larger trials, several microbiota manipulation strategies might be hypothesised to improve response to CDK4/6-inhibitors.
细胞周期蛋白依赖性激酶（CDK）4/6 抑制剂联合内分泌治疗是激素受体阳性（HR+）/人表皮生长因子受体 2（HER2）阴性转移性乳腺癌（MBC）的标准治疗方法。肠道微生物群似乎可以预测多种肿瘤类型的治疗反应，直接参与化疗耐药和不良反应的发展。目前尚无肠道微生物群对 HR+乳腺癌治疗疗效影响的证据。
我们评估了 14 名 MBC 患者粪便微生物群与 CDK4/6 抑制剂治疗效果之间的潜在相关性，这些患者根据无进展生存期分为应答者（R）和无应答者（NR）。在基线时采集粪便样本，并进行 V3-V4 16S 靶向测序以评估其细菌组成。研究了与 R 和 NR 相关的统计关联。
在门和物种水平的 α-/β 多样性方面，R 和 NR 之间没有观察到显著差异。机器学习（ML）算法证实了四种细菌物种可作为 R（长双歧杆菌、迟缓真杆菌）和 NR（脆弱拟杆菌、Schaalia odontolytica）的鉴别特征，随机森林模型的 AUC 为 0.946。网络分析证实了两个主要的细菌物种簇，命名为物种相互作用组（SIG）1-2，其中 SIG1 含有 75%的 NR 相关细菌物种，SIG2 包含 76%的 R 相关物种（p<0.001）。循环免疫细胞或生物标志物与细菌物种相对丰度之间的交叉相关显示与潜在的预后意义相关。
我们的研究结果初步揭示了肠道微生物群在 CDK4/6 抑制剂+内分泌治疗治疗 MBC 中的敏感性和/或耐药性中的作用。如果在更大的试验中得到证实，可能会假设几种微生物群操作策略来提高对 CDK4/6 抑制剂的反应。
