Introduction:
Early-onset colorectal cancer (EOCRC, i.e., CRC diagnosed <50 years) has increased dramatically over the past three decades. However, little is known about what may be driving this alarming trend.With greater appreciation for the critical role of the gut microbiome in gastrointestinal disease development, so too has concern that antibiotics can perturb the microbial communities and generate the dysregulated host/microbial interactions that promote early colorectal carcinogenesis. Despite this compelling rationale, the relationship between antibiotic usage and subsequent risk of EOCRC remains to be elucidated. Therefore, we examined the relationship between oral antibiotic use and the risk of EOCRC in a large nationally representative population from the United States.

Methods:
We conducted a population-based nested case control study at Kaiser Permanente Northern California. We identified 1,359 EOCRC cases matched to 4,711 controls between January 1, 1998 to December 31, 2020. Controls were selected using incidence density sampling and matched by age, sex, race and ethnicity, primary care facility, and duration of drug benefits on match date. Exposures (i.e., oral antibiotics only), confounders and outcomes were ascertained using electronic databases. Associations were estimated using conditional logistic regression.

Results:
EOCRC cases were comparable to their matched control based on age (mean age 44.3 years), sex (47% female), race and ethnicity, primary care facility, and duration of drug benefits. Overall, there was no association between antibiotic use and EOCRC risk in both unadjusted (Odds Ratio (OR): 1.09; 95% confidence interval (CI): 0.94-1.26) and adjusted models (aOR: 1.04; 95% CI: 0.90-1.22). When stratified by antibiotic spectrum or class, we found no association between antibiotic use and EORCRC risk (Table 1). There was also no association between antibiotic use and EOCRC risk when stratified by the number of antibiotic dispensations. However, when stratified by the number of cumulative days of antibiotic use, we found an increased risk of EOCRC among those with >120 cumulative days of any antibiotic use when compared to no antibiotic use (aOR: 1.54; 95% CI: 1.15-2.06); this finding was also consistent across antibiotic spectrums (Table 2).

Discussion:
In a large, population-based case-control study, we found no association between oral antibiotic use and risk of EOCRC. We also found no association between antibiotic use and EOCRC risk when stratified by antibiotic spectrum, class, and dispensations. However, we found an increased risk of EOCRC among individuals who had >120 days of oral antibiotic use compared to no use; this finding will need further exploration in a different but larger population. Overall, these findings provide reassurance, but antibiotic stewardship remains critical in patient care.

Jingrong Yang

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