Antibiotic use and survival of patients receiving pembrolizumab for chemotherapy-resistant metastatic urothelial carcinoma

Ishiyama, Yudai; Kondo, Tsunenori; Nemoto, Yasuhiro; Kobari, Yuki; Ishihara, Hiroki; Tachibana, Hidekazu; Yoshida, Kazuhiko; Hashimoto, Yuichi; Takagi, Toshio; Iizuka, Junpei; Tanabe, Kazunari

doi:10.1016/j.urolonc.2021.05.033

Cited by 15 publications

(6 citation statements)

References 27 publications

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“…Antibiotics, [4][5][6][7][8][9][10][11][12][13][14][15][16][17] proton pump inhibitors (PPIs), 4-15 18 and corticosteroids [4][5][6][7][8][9][10][11][12] are drugs with possible detrimental effects on the efficacy of ICIs in several cancer types. Using these three drug types, a "drug score" has been developed to predict survival in patients with advanced cancer treated with ICIs.…”

Section: Open Accessmentioning

confidence: 99%

Associations of concomitant medications with immune-related adverse events and survival in advanced cancers treated with immune checkpoint inhibitors: a comprehensive pan-cancer analysis

Nara,

Taguchi,

Buti

et al. 2024

J Immunother Cancer

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BackgroundWhile concomitant medications can affect the efficacy of immune checkpoint inhibitors (ICIs), few studies have assessed associations of concomitant medications with the occurrence and profile of immune-related adverse events (irAEs).MethodsThis study assessed associations of concomitant medication (antibiotics/proton pump inhibitors (PPIs)/corticosteroids)-based risk model termed the “drug score” with survival and the occurrence and profile of irAEs in 851 patients with advanced cancer treated with ICIs (with or without other agents). The study also assessed the survival impact of the occurrence of irAEs, using a landmark analysis to minimize immortal time bias. Multivariable Cox proportional hazard analyses were conducted for progression-free survival (PFS) and overall survival (OS).ResultsThe drug score classified patients into three risk groups, with significantly different PFS and OS. Notably, the score’s predictive capability was better in patients treated with ICIs only than in those treated with ICIs plus other agents. The landmark analysis showed that patients who developed irAEs had significantly longer PFS and OS than those without irAEs. Generally, concomitant medications were negatively associated with the occurrence of irAEs, especially endocrine irAEs, whereas PPI use was positively associated with gastrointestinal irAEs, as an exception.ConclusionsUsing a large pan-cancer cohort, the prognostic ability of the drug score was validated, as well as that of the occurrence of irAEs. The negative association between concomitant medications and irAE occurrence could be an indirect measure of the detrimental effect on the immune system induced by one or more concomitant drugs.

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Section: Open Accessmentioning

confidence: 99%

Associations of concomitant medications with immune-related adverse events and survival in advanced cancers treated with immune checkpoint inhibitors: a comprehensive pan-cancer analysis

Nara,

Taguchi,

Buti

et al. 2024

J Immunother Cancer

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“…The relatively small number of patients analyzed in the present study, the definition of the timing, and the duration of antibiotic exposure may be the reasons why no correlation between antibiotic exposure and prognosis was found. In this study, we defined antibiotic exposure as antibiotic use for at least 1 week within 1 month before or after starting ICI treatment with reference to previous reports [40][41][42][43]. Reports on the association between the duration of antibiotic exposure and changes in gut microbiome are mixed.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Factors of Platinum-Refractory Advanced Urothelial Carcinoma Treated with Pembrolizumab

Akashi,

Yamamoto,

Hashimoto

et al. 2023

Cancers

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Introduction: Immune checkpoint inhibitor (ICI) therapy has significantly improved the prognosis of some patients with advanced urothelial carcinoma (UC), but it does not provide high therapeutic efficacy in all patients. Therefore, identifying predictive biomarkers is crucial in determining which patients are candidates for ICI treatment. This study aimed to identify the predictors of ICI treatment response in patients with platinum-refractory advanced UC treated with pembrolizumab. Methods: Patients with platinum-refractory advanced UC who had received pembrolizumab at two hospitals in Japan were included. Univariate and multivariate analyses were performed to identify biomarkers for progression-free survival (PFS) and overall survival (OS). Results: Forty-one patients were evaluable for this analysis. Their median age was 75 years, and the vast majority of the patients were male (85.4%). The objective response rate was 29.3%, with a median overall survival (OS) of 17.8 months. On multivariate analysis, an Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥ 2 (HR = 6.33, p = 0.03) and a baseline neutrophil-to-lymphocyte ratio (NLR) > 3 (HR = 2.79, p = 0.04) were significantly associated with poor OS. Antibiotic exposure did not have a significant impact on either PFS or OS. Conclusions: ECOG-PS ≥ 2 and baseline NLR > 3 were independent risk factors for OS in patients with platinum-refractory advanced UC treated with pembrolizumab. Antibiotic exposure was not a predictor of ICI treatment response.

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“…Chen et al demonstrated a significant relationship between the amount of Leptotrichia , Roseomonas , Propionibacterium , Prevotella and Massilia genera in the microbiome of BC tissue and the PD-L1 expression of tumor cells [ 18 ]. Based on the experience of retrospective studies, it was found that the effectiveness of various checkpoint inhibitors was significantly reduced by different antibiotics when used in parallel; this effect may also be explained by distinct changes in microbial composition that are detrimental to therapeutic effectiveness of these anticancer medications [ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Bladder Tissue Microbiome Composition in Patients of Bladder Cancer or Benign Prostatic Hyperplasia and Related Human Beta Defensin Levels

et al. 2022

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Balance between the microbiome associated with bladder mucosa and human beta defensin (HBD) levels in urine is a dynamic, sensitive and host-specific relationship. HBD1—possessing both antitumor and antibacterial activity—is produced constitutively, while the inducible production of antibacterial HBD2 and HBD3 is affected by bacteria. Elevated levels of HBD2 were shown to cause treatment failure in anticancer immunotherapy. Our aim was to assess the relationship between microbiome composition characteristic of tumor tissue, defensin expression and HBD levels measured in urine. Tissue samples for analyses were removed during transurethral resection from 55 bladder carcinoma and 12 prostatic hyperplasia patients. Microbiome analyses were carried out with 16S rRNS sequencing. Levels of HBD mRNA expression were measured with qPCR from the same samples, and urinary amounts of HBD1, 2 and 3 were detected with ELISA in these patients, in addition to 34 healthy volunteers. Mann–Whitney U test, Wilcoxon rank sum test (alpha diversity) and PERMANOVA analysis (beta diversity) were performed. Defensin-levels expressed in the tumor did not clearly determine the amount of defensin measurable in the urine. The antibacterial and antitumor defensin (HBD1) showed decreased levels in cancer patients, while others (HBD2 and 3) were considerably increased. Abundance of Staphylococcus, Corynebacterium and Oxyphotobacteria genera was significantly higher, the abundance of Faecalibacterium and Bacteroides genera were significantly lower in tumor samples compared to non-tumor samples. Bacteroides, Parabacteroides and Faecalibacterium abundance gradually decreased with the combined increase in HBD2 and HBD3. Higher Corynebacterium and Staphylococcus abundances were measured together with higher HBD2 and HBD3 urinary levels. Among other factors, defensins and microorganisms also affect the development, progression and treatment options for bladder cancer. To enhance the success of immunotherapies and to develop adjuvant antitumor therapies, it is important to gain insight into the interactions between defensins and the tumor-associated microbiome.

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Antibiotic use and survival of patients receiving pembrolizumab for chemotherapy-resistant metastatic urothelial carcinoma

Cited by 15 publications

References 27 publications

Associations of concomitant medications with immune-related adverse events and survival in advanced cancers treated with immune checkpoint inhibitors: a comprehensive pan-cancer analysis

Associations of concomitant medications with immune-related adverse events and survival in advanced cancers treated with immune checkpoint inhibitors: a comprehensive pan-cancer analysis

Prognostic Factors of Platinum-Refractory Advanced Urothelial Carcinoma Treated with Pembrolizumab

Bladder Tissue Microbiome Composition in Patients of Bladder Cancer or Benign Prostatic Hyperplasia and Related Human Beta Defensin Levels

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