In this population-based study including 749 patients exposed to antibiotics compared with 1856 nonexposed patients, using an overlap weighting method based on a propensity score to balance characteristics of patients between groups, we evidenced that antibiotic use prior to anti-PD-1 antibody for advanced melanoma was not associated with worse outcome, whether for OS or for TTD. Consistent results were observed when the time frame of antibiotic exposure was reduced from 3 to 1 month prior to anti-PD-1 initiation or when exposure was restricted to antibiotics leading to more profound gut dysbiosis.
Considerable interest has been devoted to the investigation of how concomitant therapies with a potential immunomodulatory effect might interact with ICI among cancer patients. In particular, gut microbes could enhance antitumor immunity through T-cell responses to microbial antigens and cross-reactions with cancer antigens.[33,34] In keeping with this hypothesis, antibiotic treatment could decrease ICI efficacy by altering the composition and diversity of the gut microbiota.[12,13,35–40] However, there is no consensus on which bacterial species are associated with response to anti-PD-1 antibody.[13,37,38] In addition, only a minority of the taxa forming the human gut microbiota are able to colonize mice, which makes extrapolating findings from rodent studies hazardous.[41,42] Thus, the link between the gut microbiota and response to ICI still needs to be further understood, and to date, we lack experimental evidence on the issue of whether, how, and for how long induced gut dysbiosis can alter ICI efficacy.
In view of the immunological rationale, observational studies have investigated the effect of antibiotic exposure on ICI efficacy among cancer patients. The current body of knowledge derived from observational studies converges toward poorer prognosis among patients exposed to antibiotics in all cancers treated with ICI.[5,8–10,15,43,44] The association was often strong, but the data were heterogeneous, mixing different treatment lines, different ICIs, or even different types of cancer within the same studies. Relevant confounders could not be appropriately taken into account in most studies, because of small sample sizes and heterogeneity. For example, patients with certain comorbidities or locations of metastases could be more likely to receive antibiotics, and these data were absent or incomplete. This could also explain why the association between antibiotic exposure and poor prognosis was not related to the spectrum of the antibiotics used or, therefore, to their impact on the gut microbiota.[7,15] To disentangle the causal effect of antibiotic exposure from the confounding effect of patient characteristics, including patient fitness, comorbidities, and evolution of the metastatic disease, is a challenging issue.[14,15]
Confounding by indication is hard to fully capture with conventional methods, which inadequately control for prognostic variables.[16,45] However, confounding by indication can have a major impact on results. This bias can suggest an association that does not exist or even reverses the direction of an association. Regarding our population, we report in Figure 1 the proportion of patients receiving antibiotics, which increased with the approach of first-line antimelanoma treatment. The steady increase in antibiotic use in the months preceding the initiation of the first-line treatment for metastatic melanoma could be in line with the intensification of care related to a symptomatic or complicated cancer. Antibiotic prescription could be associated with the discovery of the metastatic stage (eg, pulmonary infections associated with lung metastases). In particular, a peak in antibiotic prescription was reached in the targeted therapy cohort in the month preceding the initiation of targeted therapy, which could suggest a strong confounding effect, and explain the statistically significantly increased crude hazard ratio for OS in the month prior to initiation in the targeted therapy cohort.
Our study has several strengths. First, although confounding is the alternative explanation for the shorter survival of patients receiving antibiotics in previous observational studies, the propensity score weighting method using overlap weights has been reported to show remarkable performance to avoid this bias.[30,46,47] Second, we identified a large number of comorbidities and provided precise information on metastatic locations using our database, which combines diagnosis-based and medication-based information with considerable historical depth.[17,28] These characteristics are relevant confounders in this context, and their identification enabled us to balance prognosis factors across groups. Third, the size of our nationwide database yielded a power of more than 99% to demonstrate the previously suggested association among patients receiving anti-PD-1 antibody.[7,44] The number of antibiotic-exposed patients in our study was similar to the number in meta-analyses mixing studies on all cancer types, treatment lines, and antibiotic time frames.[6,8–10,43] In addition, the exhaustiveness of the database, with no loss to follow-up, protected from selection and attrition bias. Fourth, as there is no underlying rationale for antibiotics to impact the efficacy of targeted therapy, using the targeted therapy cohort as a negative control was an original and relevant approach to address our question. Fifth, TTD corresponds to the time during which the disease is under control for a given treatment line and was therefore used to reflect the impact of antibiotics on the first antimelanoma treatment, irrespective of subsequent treatment lines.
Our study has limitations. First, prognostic factors like lactate dehydrogenase levels, performance status, or socioeconomic status were lacking in our database and could therefore not be used in the propensity score. Second, we used drug dispensations as a proxy for drug intake, but we could not ascertain the completion of antibiotic courses. However, even short antibiotic courses could have a prolonged effect on gut microbiota.[48,49] Third, antibiotics administered during hospital stays are not recorded in our database. Therefore, in a sensitivity analysis, we excluded patients who had been hospitalized for infection during the time frame of exposure, as they could have been misclassified. In addition, infections requiring hospitalization often correspond to severe infections, and patients could have a competing risk of death, which justified excluding them. Fourth, participation in a clinical trial could not be identified in our database, because clinical trials entail no billing to the National Health Insurance. Fifth, strictly speaking, our results apply only to metastatic melanoma, and one could be reluctant to extrapolate to other cancers. However, the 2 hypotheses discussed (antibiotic-induced gut dysbiosis impairing ICI efficacy and confounding by indication) concern general phenomena and should apply across other cancers treated with ICI.
Our results bring a robust contribution to the question of the impact of antibiotics on ICI efficacy and overall prognosis among cancer patients. Unlike previous findings, we show that antibiotic treatment before anti-PD-1 antibody initiation is not associated with decreased efficacy of anti-PD-1 antibody among metastatic melanoma patients. Although some may consider that the jury is still out, we argue that strong and reasonable doubt exists for confounding by indication as the culprit accounting for a so-called antibiotic-induced detrimental effect on ICI efficacy. As a consequence, from a clinical point of view, we suggest that physicians should not delay ICI for patients who have recently received antibiotics on the grounds of a risk of lack of efficacy. In addition, no data exist to substantiate what would be an appropriate and safe time lag. Avoiding delaying immunotherapy is certainly a widely shared attitude in metastatic settings, but it should also be recalled when administering ICI in adjuvant settings.
This work was supported by the Ligue Contre le Cancer ([French] League Against Cancer) (PhD grant to FP).
Role of the funder
The funding source had no role in the study design, the conduct or the management for the study; in the collection, analysis, or the interpretation of the data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.
This work was presented at the Journées Dermatologiques de Paris 2020, December 2, 2020, in Paris, France.
The protocol and the statistical code are available on justified request. Under French law and regulations, databases extracted from the Systeme National des Données de Santé cannot be made available.
J Natl Cancer Inst. 2022;114(5):686-694. © 2022 Oxford University Press