• Esophageal squamous cell carcinoma (ESCC) accounts for nearly 90% of esophageal cancers worldwide and has a high mortality rate. • Gastro-esophageal reflux disease (GERD) symptoms have inconsistently been associated with an increased risk of ESCC. • However, GERD symptoms as a whole do not distinguish between acid and non-acid reflux, which may have differing associations with ESCC risk. Objective To assess the association between GERD symptoms overall, heartburn alone, or regurgitation and ESCC risk in a population with low exposure to tobacco and alcohol.

• Population-based cohort study from a region of high ESCC incidence in northeastern Iran. • All cohort intake data was collected via face-to-face interviews and examinations. • GERD symptoms were categorized into those with ≥ weekly symptoms of: • GERD (any heartburn or regurgitation) • Heartburn (heartburn only) • Regurgitation (regurgitation only or both symptoms) • ESCC was defined as a histologic diagnosis, confirmed by active surveillance, telephone follow up, and manual chart review. • Cohort members with missing GERD symptom data, any cancer diagnosis within 3 years of enrollment, or a diagnosis of ESCC within 1 year after enrollment were excluded. • Multivariate Cox regression models were used to assess the adjusted hazard ratios between GERD symptoms and risk of ESCC.

49,604 individuals were included in the study, of which 306 developed ESCC. There was significant interaction between sex and the association of GERD with ESCC. 9,037 (18.2%) reported ≥ weekly GERD symptoms: 2,390 had heartburn only and 6,618 had regurgitation only or both symptoms. GERD was significantly associated with female sex (p<0.001), lower socioeconomic status (p<0.001), low fruit and vegetable consumption (p<0.001), drinking hot tea (p=0.004), excess missing teeth (p<0.001), current tobacco smoking (p<0.001), and opium use (p<0.001). Median follow up time was 13.0 years, until January 1, 2020.

In a region of high ESCC incidence, GERD symptoms were significantly associated with decreased risk of ESCC in men, but not in women. Additional longitudinal studies using tailored GERD symptom questionnaires with objective assessment of acid and non-acid reflux are needed to explore reasons underlying this inverse association.