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Is There a Detrimental Effect of Antibiotic Therapy in Patients with Muscle-invasive Bladder Cancer Treated with Neoadjuvant Pembrolizumab?

  • Filippo Pederzoli 1,
  • Marco Bandini 1,
  • Daniele Raggi 2,
  • Laura Marandino 2,
  • Giuseppe Basile 1,
  • Massimo Alfano 1,
  • Renzo Colombo 1,
  • Andrea Salonia 1,
  • Alberto Briganti 1,
  • Andrea Gallina 1,
  • Francesco Montorsi 1,
  • Andrea Necchi 3
1 Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy 2 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 3 Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy; Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy

In locally advanced and metastatic malignancies, antibiotic (ATB) therapy has a negative effect on immunotherapy efficacy. Therefore, we aimed to evaluate whether ATB therapy and use of specific ATB classes with concomitant neoadjuvant pembrolizumab affected pathologic complete response (ypT0N0) and relapse-free survival (RFS) for patients with clinical T2–4N0M0 bladder cancer enrolled in the PURE-01 study. Of the 149 patients evaluated, 48 (32%) received any concomitant ATB therapy. The ATB class most commonly administered was fluoroquinolones (16 patients; 33%). In the ATB cohort, seven patients (15%) achieved ypT0N0 status, compared to 50 (50%; p < 0.001) in the untreated group. Moreover, ATB use was negatively associated with ypT0N0 status (odds ratio 0.18, 95% confidence interval [CI] 0.05–0.48; p = 0.001). The 24-mo RFS rate was 63% (95% CI 48-83%) in the ATB group versus 90% (95% CI 83–97) in the untreated group. We found that ATB use was associated with a higher recurrence rate (hazard ratio [HR] 2.64, 95% CI 1.08–6.50; p = 0.03). Exploratory analyses showed that fluoroquinolone use was associated with a higher recurrence rate (HR 3.28, 95% CI 1.12–9.60; p = 0.03). Our study revealed an association between ATB use and neoadjuvant immunotherapy efficacy in an intention-to-cure population, highlighting the need for future studies to better investigate this relationship.

Commentary by Dr. Evanguelos Xylinas

In locally advanced and metastatic malignancies including bladder cancer, antibiotic (ATB) therapy has shown to be associated with decreased efficacy by modulating the intestinal microbiota towards a detrimental state of dysbiosis, eventually impairing anticancer immunity in the host. The authors of the article aimed to evaluate the evidence of this mechanism in a localised setting by conducting a post hoc analysis of the PURE-01 study, in which patients with cT2–4N0M0 MIBC received three cycles of neoadjuvant pembrolizumab followed by a radical cystectomy (RC).

Concomitant ATB therapy was defined as any ATB administration between 30 d before the first pembrolizumab dose and the planned RC.

A total of 48 patients (32%) received concomitant ATB therapy. Noteworthily, the median total number of mutations (TMB) (9.3 vs 11.4 mutation/Mb; p = 0.005) and combined positive score (CPS) (9.5% vs 20%; p = 0.04) were significantly lower in the ATB cohort. No difference in the rate of immune-related adverse events was noted between the two cohorts (p = 0.7). The ATB class most commonly administered was fluoroquinolones (n = 16; 33%), followed by beta-lactams (n = 14; 29%), trimethoprim/sulfamethoxazole (n = 5; 10%), fosfomycin (n = 5; 10%), and other compounds (n = 8; 17%). Out of the 48 patients, 36 (75%) received ATBs for urinary tract infections, seven (15%) for periprocedural prophylaxis, and five (10%) for other reasons. In the ATB cohort, ypT0N0 status was achieved by seven patients (15%), compared to 50 (50%; p < 0.001) in the untreated group. On multivariate analyses, ATB use was negatively and independently associated with pathologic complete response (OR: 0.18, 95% CI: 0.05-0.48; p = 0.001). The authors also found a detrimental effect of ATB use on recurrence-free survival at 12 months: 81% (95% CI 70–93%) in the ATB group and 95% (95% CI 91–99%) in the no-ATB group (see Figure 1: Kaplan-Meier curves of recurrence-free survival).  On multivariate analyses, ATB use was associated with higher rates of disease recurrence (HR: 2.64, 95% CI: 1.08–6.50; p = 0.03).

This study is the first one to validate the hypothesis that ATB therapy may impair ICI antitumor activity against localised bladder cancer treated with curative intent. The authors found that ATB use was associated with a worse response to neoadjuvant pembrolizumab, both in terms of pathological complete response and recurrence-free survival. At a pathobiological level, perturbations in the homeostatic gut microbiota caused by the bactericidal and bacteriostatic effects of ATBs lead to a state of dysbiosis, potentially characterised by an overgrowth of detrimental species at the expense of more beneficial bacteria. This shift in gut microbial ecology may have a great impact on the anticancer response in the host.