In a large prospective study, we found that a reduced risk of HCC with coffee consumption, which was consistent with dose–response analysis and by coffee type, was apparent for instant coffee.

Our study is consistent with the inverse association between coffee consumption and HCC risk that has been judged as “convincing” evidence in the 2018 World Cancer Research Fund report,15 confirming previous individual studies16,17,23 and meta-analyses.24,25 Whilst we did not show marked differences in the inverse association between HCC and coffee consumption by type of coffee, an inverse association was apparent for instant coffee. Some previous studies have investigated caffeinated and decaffeinated coffee,16,17,23 but no previous studies, to date, have explored the association of instant coffee consumption and HCC.

The underlying biological mechanisms for a reduced risk of HCC with coffee consumption, especially with instant coffee, are not well known, but some mechanisms have been proposed. Coffee has high levels of antioxidants,26 including phenolic acids, diterpenes like cafestol and kahweol and tocopherols.27 Compounds, such as phenolic acids28,29 and caffeine,30 have also been shown to have chemopreventive properties, including in liver carcinogenesis.31 These compounds have been shown to inhibit the proliferation of HCC cell lines in vitro and suppress the progression of HCC in vivo,32 while chlorogenic acid has been shown to prevent oxidative damage in hepatocytes.33 Instant coffee, in comparison with ground and decaffeinated coffee, has been demonstrated to have higher levels of those biochemical compounds,3,4 which therefore could partly explain the more marked reduced risk of HCC in our study. The underlying potential anticancer mechanism of instant coffee has also been observed in previous experimental studies. An animal study5 showed that mice receiving instant coffee had a reduction in the size and the number of hepatocellular neoplastic lesions, compared with mice receiving ground coffee. Instant coffee administration in rats also resulted in a significantly higher expression of bax protein,5 which monitors cell apoptosis and is a known tumour suppressor.34,35 Another study in rats demonstrated that instant coffee powder inhibited hepatoma cell proliferation, reduced metastasis and positively altered lipoprotein profiles.36 Therefore, it is plausible that instant coffee may have stronger anticancer effects in comparison with other coffee types.

For other individual types of digestive cancer, we did not find any consistent association with coffee consumption. Our findings of no association between coffee and colorectal cancer confirm previous findings,10,37 although they contrast with suggestions that high levels of coffee drinking reduced the risk of colon cancer.11 For small intestine and oesophageal cancer, our findings are similar to previous meta-analyses of no association with coffee consumption.13,38 However, our study found an increased risk of oesophageal squamous cell carcinoma with high intake of coffee, which was not consistent with the literature. A study in a Norwegian population found no association between high coffee intake and the risk of oesophageal squamous cell carcinoma.31 Similarly, another study found that higher intake of isoflavones, for which coffee was the major source, was not associated with the risk of oesophageal squamous cell carcinoma.39

For gastric cancer, the results are inconclusive. Our findings of no association between coffee and the risk of gastric cancer are in line with a recent meta-analysis;12 however, contrasting two previous meta-analyses showed a decrease40 and an increase in the risk of gastric cancer with coffee use.41 In one meta-analysis, no association was observed following restriction to only cohort studies,40 while in the other meta-analysis, the positive association between coffee consumption and gastric cancer risk attenuated and became non-significant after adjusting for risk factors, such as smoking, alcohol intake and BMI.41

Our study is similar to a more recent meta-analysis of four large cohort studies of female non-smokers, which demonstrated no association between coffee intake and pancreatic cancer.42 Our study found no association between increasing the number of coffee cups consumed and pancreatic cancer risk, but there was suggestive evidence of an inverse association between decaffeinated coffee consumption and pancreatic cancer risk, which is in contrast to a previous US study, showing no association for decaffeinated coffee.43 The difference in the results might be explained by other underlying differences in population behaviours relevant for pancreatic cancer aetiology, or differences in coffee consumption patterns, but is difficult to fully understand. Further investigations are warranted to explore the association between decaffeinated coffee and pancreatic cancer.

Our findings of an increased risk of gallbladder cancer with decaffeinated coffee consumption are not consistent with a previous meta-analysis of any coffee intake and biliary tract cancer risk, although the previous study did not specifically investigate decaffeinated coffee.14 However, our result could be owing to chance, since there was no clear dose–response relationship, and the positive finding attenuated and became non-significant in sensitivity analysis.

Acrylamide is a chemical produced by the coffee-roasting process, particularly in the production of instant coffee,6 classified by IARC in group 2A as a probable human carcinogen.7 Acrylamide has been shown to have a carcinogenic effect in animal studies;44 however, in epidemiological studies of humans, the association with gastrointestinal cancer is controversial. For instance, a prospective study investigating daily acrylamide intake did not find an association with oesophageal, gastric, colorectal and pancreatic cancer.45 In contrast, another study from the European Prospective Investigation into Cancer and Nutrition cohort found a significantly increased risk of oesophageal cancer with acrylamide intake.46 Our study generally provides reassurance that coffee consumption, known to be high in acrylamide, does not appear to be associated with increased gastrointestinal cancer risk.

The main strength of our study is that within the UK Biobank, information on the type of coffee most commonly consumed was available, allowing for investigation of instant or ground or decaffeinated coffee and digestive cancer risk. Second, the UK Biobank contains over 500,000 participants who were prospectively followed for up to 7.5 years, allowing sufficient statistical power to detect even relatively weak associations. We were also able to investigate the impact of coffee consumption across a number of different digestive cancer sites, therefore minimizing potential measurement error. Finally, we were able to control for various important confounders, which are associated with coffee consumption and digestive cancer risk, such as BMI, alcohol and smoking habit, physical activity, fruit and vegetable intake, tea intake and comorbidities.

However, a number of weaknesses existed in our study. First, coffee consumption could have changed over time, so misclassification of coffee consumption is possible. However, other cohorts have shown coffee consumption to remain relatively stable over time in adult populations.47 Second, there were small numbers of cases of certain cancers in our study (e.g., small intestine cancer, intrahepatic bile duct carcinoma, gallbladder and extrahepatic bile duct carcinoma), and therefore for these cancers, we would have limited power to detect associations with coffee consumption. Third, we did not have information on H. pylori infection; therefore, we were unable to adjust for this potential confounder in analyses of oesophageal or gastric cancer. Fourth, we did not investigate the impact of milk, non-dairy creamer and sweeteners on the association between coffee and digestive cancer risk. Milk and non-dairy creamer have been found to alter the biochemical activities of coffee by interacting with coffee components like polyphenol;48 however, the extent of its impact on the association of coffee and cancer risk has not yet been substantiated. Measurement error of coffee intake might have affected our ability to identify true associations with cancers. In particular, it is possible that measurement error, which is likely to dilute any real associations, both reduced the magnitude of the association between coffee intake and HCC and dragged weaker associations between coffee intake and other GI cancers to the null. Finally, as a large number of tests were conducted, increasing the likelihood of Type 1 error, significant results should be interpreted cautiously. Further studies should investigate the underlying mechanisms of the inverse association between coffee and HCC. Additional large epidemiological studies are required to confirm the role of instant coffee among other types, as well as the impact of milk, non-dairy creamer and sweeteners in the association with digestive cancers.

In conclusion, our findings suggest an inverse association between coffee consumption and hepatocellular carcinoma, which was similar by coffee types. However, whether the observed association reflects a causal relationship, and if so, the underlying mechanisms are responsible, is worthy of further investigation.