In a large population-level study, antibiotic exposure and specifically fluoroquinolones before treatment with immune checkpoint inhibitor (ICI) were associated with worse overall survival (OS), with fluoroquinolone exposure conferring up to a 65% increased risk of mortality among older adults with cancer. Dose effects were also observed based on duration and total doses of fluoroquinolones. The effects of antibiotic exposure up to 1 year before ICI may have an impact on subsequent ICI outcomes suggesting that clinicians should consider prior antibiotic exposure. This relationship was observed among patients receiving anti–PD1 drugs, which were the most common prescribed ICIs, and among patients with lung cancer and melanoma. The findings are published by Dr. Lawson Eng of the Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network in Toronto, Ontario, Canada and colleagues on 24 February 2023 in the Journal of Clinical Oncology.
Preclinical studies have shown that stool diversity and specific species of bacteria in the gut can have a direct impact on ICI effectiveness and immune-related side-effects. As antibiotic exposure can alter the gut microbiome, there has been interest in evaluating the impact of antibiotic exposure on ICI outcomes. Prior studies, including two systematic reviews and meta-analyses, suggest that antibiotic exposure may negatively affect ICI outcomes including OS. However, many individual studies included in the meta-analyses were small with sample size less than 200, conducted by single centre, and featured heterogeneity in antibiotic exposure period before ICI, class of ICI, and tumour types.
Evaluation of antibiotic exposure using a larger population-based cohort across multiple centres may allow for the evaluation of specific subgroups based on ICI type and antibiotic class. The aims of this population-level retrospective cohort study were to evaluate the association of prior antibiotic exposure on OS for patients receiving their first ICI, and to identify any specific associations based on ICI drug, tumour type, or antibiotic class.
Patients with cancer, age 65 years or older, who initiated treatment with ICIs between June 2012 and October 2018 in Ontario, Canada, were identified using systemic treatment administration data. The cohort was deterministically linked to other health care databases to obtain covariates and antibiotic prescription claim data at both 1 year and 60 days before treatment with ICI. Multivariable Cox models evaluated the association between exposure and OS.
Among the 2,737 patients with cancer who received ICIs, 59% received antibiotics 1 year before treatment with ICI and 19% received antibiotics 60 days before ICI. Median OS was 306 days. Any antibiotic exposure within 1 year before ICI was associated with worse OS (adjusted hazard ratio [aHR] 1.12, 95% confidence interval [CI] 1.12 to 1.23; p = 0.03).
In antibiotic class analysis, exposure to fluoroquinolones within 1 year (aHR 1.26, 95% CI 1.13 to 1.40; p < 0.001) or 60 days before ICI (aHR 1.20, 95% CI 0.99 to 1.45; p = 0.06) was associated with worse OS, with a dose effect seen based on total weeks of exposure over 1 year (aHR 1.07 per week, 95% CI 1.03 to 1.11; p < 0.001) and 60 days (aHR 1.12 per week, 95% CI 1.03 to 1.23; p = 0.01).
These results suggest that clinicians should potentially consider antibiotic exposure in the past year when patients start treatment with ICIs. More data are needed to mechanistically explore the relationship between antibiotic exposure, ICI treatment, and survival outcomes in diverse patients and settings. Interventions aimed at altering the gut microbiome to boost immunogenicity may help improve outcomes for patients receiving ICIs with prior antibiotic exposure.
In an accompanied editorial article, Drs. David J. Pinato of the Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital in London, UK and Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale in Novara, Italy and Alessio Cortellini of the Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital in London, UK and Medical Oncology, Fondazione Policlinico Universitario Campus BioMedico in Rome, Italy wrote that with ICIs now having become a standard first-line systemic treatment option for patients with cancer, the long latency between antibiotic exposure and treatment with ICI lasting up to a year makes this study particularly provocative in suggesting that antibiotic-mediated perturbation of the gut microbiome might precondition anticancer immunity even before the clinical diagnosis of cancer.
With progressively widening evidence and mechanistic insight supporting the relationship between gut homeostasis and outcomes from ICI, a key objective now is to demonstrate whether reversal of antibiotic-mediated gut dysbiosis might prove to be beneficial in abolishing an increasingly well-characterised mechanism of ICI resistance. Renewed enthusiasm in the therapeutic potential of microbiota-based interventions has been reasserted by pioneering early-phase clinical trials exploring tolerability and efficacy of foecal microbiota transplantation derived from immunotherapy-responsive donors as a mechanism to overcome refractoriness to ICI.
Further studies aimed at characterising the mechanisms underlying the therapeutic efficacy of microbiome-modulating therapy are perhaps the greatest challenge affecting their successful, rational development as treatment options for patients with cancer. As a widening number of biotherapeutic approaches including dietary prebiotic supplementation, use of single or multiple bacterial consortia, selective antibiotic treatment, or foecal microbial transplantation compete to prove themselves as effective anticancer treatments in the clinic, this study supports these efforts by providing credible evidence to the long-lasting deleterious effects stemming from a dysbiotic gut microenvironment, maintaining gut health at the top of the drug development research agenda.
The study was previously presented in part at the ESMO 2021 Congress in Paris, France (16-21 September) and the ASCO 2021 Quality Symposium in Boston, MA, US (24-25 September).
The study was supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. It was supported in part by the ASCO/Conquer Cancer Foundation—Young Investigator Award, Canadian Association of Medical Oncology Fellowship Award, and a Hold’Em for Life Oncology Fellowship Award.
References
- Eng L, Sutradhar R, Niu Y, et al. Impact of Antibiotic Exposure Before Immune Checkpoint Inhibitor Treatment on Overall Survival in Older Adults With Cancer: A Population-Based Study. JCO; Published online 24 February 2023. DOI: 10.1200/JCO.22.00074
- Pinato DJ, Cortellini A. Antibiotic Therapy: The Cornerstone of Iatrogenic Resistance to Immune Checkpoint Inhibitors. JCO; Published online 24 February 2023. DOI: 10.1200/JCO.23.00049