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Barrett’s oesophagus (BE) is the precursor of oesophageal adenocarcinoma, which has become the most common type of oesophageal cancer in many Western populations. Existing evidence on diet and risk of BE predominantly comes from case–control studies, which are subject to recall bias in measurement of diet. We aimed to investigate the potential effect of diet, including macronutrients, carotenoids, food groups, specific food items, beverages and dietary scores, on risk of BE in over 20 000 participants of the Melbourne Collaborative Cohort Study. Diet at baseline (1990–1994) was measured using a food frequency questionnaire. The outcome was BE diagnosed between baseline and follow-up (2007–2010). Logistic regression models were used to estimate OR and 95 % CI for diet in relation to risk of BE. Intakes of leafy vegetables and fruit were inversely associated with risk of BE (highest v. lowest quartile: OR = 0·59; CI: 0·38, 0·94; P-trend = 0·02 and OR = 0·58; CI: 0·37, 0·93; P-trend = 0·02 respectively), as were dietary fibre and carotenoids. Stronger associations were observed for food than the nutrients found in them. Positive associations were observed for discretionary food (OR = 1·54; CI: 0·97, 2·44; P-trend = 0·04) and total fat intake (OR per 10 g/d = 1·11; CI: 1·00, 1·23), the association for fat was less robust in sensitivity analyses. No association was observed for meat, protein, dairy products or diet scores. Diet is a potential modifiable risk factor for BE. Public health and clinical guidelines that incorporate dietary recommendations could contribute to reduction in risk of BE and, thereby, oesophageal adenocarcinoma.

Background While folate intake has not been associated with an increased risk of ovarian cancer overall, studies of other cancer types have suggested that high folate intake may promote carcinogenesis in pre-cancerous lesions. Women with endometriosis (a potential pre-cancerous lesion) have an increased risk of developing ovarian cancer; however, whether high folate intake increases risk in this group is unknown. Methods We conducted a pooled analysis of six case-control studies from the Ovarian Cancer Association Consortium to investigate the association between folate intake and risk of ovarian cancer among women with and without self-reported endometriosis. We included 570 cases/558 controls with and 5,171/7,559 without endometriosis. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for the association between folate intake (dietary, supplemental, total) and ovarian cancer risk. Finally, we used Mendelian randomization (MR) to evaluate our results using genetic markers as a proxy for folate status. Results Higher dietary folate intake was associated with an increased risk of ovarian cancer for women with endometriosis (OR 1.37[1.01-1.86]) but not for women without endometriosis. There was no association between supplemental folate intake and ovarian cancer risk for women with or without endometriosis. A similar pattern was seen using MR. Conclusions High dietary folate intake may be associated with an increased risk of ovarian cancer among women with endometriosis. Impact Women with endometriosis with high folate diets may be at increased risk of ovarian cancer. Further research is needed on the potential cancer-promoting effects of folate in this group.

Sedentary behaviours have been associated with increased risks of some common cancers in epidemiological studies; however, it is unclear if these associations are causal. We examined potential causal associations between self-reported leisure television watching and computer use and risks of breast, colorectal, and prostate cancer using a two-sample Mendelian randomization framework. Genetic variants were identified from a recent genome-wide association study (GWAS). Cancer data were obtained from cancer GWAS consortia. Additional sensitivity analyses were applied to examine the robustness of the results. A 1-standard deviation increment in hours of television watching increased risk of breast (OR: 1.15, 95% confidence interval [CI]: 1.05,1.26) and colorectal cancer (OR: 1.32, 95%CI: 1.16,1.49) with little evidence of an association for prostate cancer risk. In multivariable models adjusted for years of education, the effect estimates for television watching were attenuated (breast cancer, OR: 1.08, 95%CI: 0.92,1.27; colorectal cancer, OR: 1.08, 95%CI: 0.90,1.31). Post-hoc analyses showed that years of education might have a possible confounding and mediating role in the association between television watching with breast and colorectal cancer. Consistent results were observed by sex (colorectal cancer), anatomical subsites, and cancer subtypes. There was little evidence of associations between computer use and cancer risk. We found evidence of positive associations between hours of television watching and risks of breast and colorectal cancer. However, these findings should be interpreted cautiously given the complex role of education. Future studies using objective measures of exposure can provide new insights into the possible role of sedentary behaviour in cancer development.Novelty and impactEvidence from observational studies that examined associations between sedentary behaviours and common cancers is mixed and causality is uncertain. In our Mendelian randomization analyses, higher levels of leisure television watching were found to increase the risks of breast and colorectal cancer, suggesting that the that the promotion of lowering sedentary behaviour time could be an effective strategy in the primary prevention of these commonly diagnosed cancers.Article categoryCancer Epidemiology

Background: This study aimed to investigate the associations between hysterectomy for benign indications and risk of breast, colorectal, kidney, and thyroid cancer, and to explore whether these associations are modified by removal of ovaries at the time of surgery or by age at surgery. Methods: We conducted a retrospective cohort study of the female population of Western Australia (n = 839,332) linking data from electoral, hospital, births, deaths, and cancer records. We used Cox regression to estimate HRs and 95% confidence intervals (CI) for the associations between hysterectomy and diagnosis of breast, colorectal, kidney, and thyroid cancers. Results: Compared with no surgery, hysterectomy without oophorectomy (hysterectomy) and hysterectomy with bilateral salpingo-oophorectomy (hysterectomy-BSO) were associated with higher risk of kidney cancer (HR, 1.32; 95% CI, 1.11–1.56 and HR, 1.29; 95% CI, 0.96–1.73, respectively). Hysterectomy, but not hysterectomy-BSO, was related to higher risk of thyroid cancer (HR, 1.38; 95% CI, 1.19–1.60). In contrast, hysterectomy (HR, 0.94; 95% CI, 0.90–0.98) and hysterectomy-BSO (HR, 0.92; 95% CI, 0.85–1.00) were associated with lower risk of breast cancer. We found no association between hysterectomy status and colorectal cancer. Conclusions: The associations between hysterectomy and cancer varied by cancer type with increased risks for thyroid and kidney cancer, decreased risk for breast cancer, and no association for colorectal cancer. Impact: As breast, colorectal, and gynecologic cancers comprise a sizeable proportion of all cancers in women, our results suggest that hysterectomy is unlikely to increase overall cancer risk; however, further research to understand the higher risk of thyroid and kidney cancer is warranted.

Background: Mechanisms for how Helicobacter pylori infection affects risk of gastroesophageal reflux disease (GERD) and Barrett's esophagus are incompletely understood and might differ by sex. Methods: In a case–control study nested in the Melbourne Collaborative Cohort Study with 425 GERD cases and 169 Barrett's esophagus cases (identified at 2007–2010 follow-up), we estimated sex-specific odds ratios for participants who were H. pylori seronegative versus seropositive at baseline (1990–1994). To explore possible mechanisms, we (i) compared patterns of H. pylori-induced gastritis by sex using serum pepsinogen-I and gastrin-17 data and (ii) quantified the effect of H. pylori seronegativity on Barrett's esophagus mediated by GERD using causal mediation analysis. Results: For men, H. pylori seronegativity was associated with 1.69-fold [95% confidence interval (CI), 1.03–2.75] and 2.28-fold (95% CI, 1.27–4.12) higher odds of GERD and Barrett's esophagus, respectively. No association was observed for women. H. pylori-induced atrophic antral gastritis was more common in men (68%) than in women (56%; P = 0.015). For men, 5 of the 15 per 1,000 excess Barrett's esophagus risk from being seronegative were mediated by GERD. Conclusions: Men, but not women, who were H. pylori seronegative had increased risks of GERD and Barrett's esophagus. A possible explanation might be sex differences in patterns of H. pylori-induced atrophic antral gastritis, which could lead to less erosive reflux for men. Evidence of GERD mediating the effect of H. pylori on Barrett's esophagus risk among men supports this proposed mechanism. Impact: The findings highlight the importance of investigating sex differences in the effect of H. pylori on risk of GERD and Barrett's esophagus in future studies.

We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone–binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS-E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose–response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for postmenopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer. See related reviews by Lynch et al., p. 11 and Swain et al., p. 16

The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity–sex hormone–breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer. See related reviews by Lynch et al., p. 11 and Drummond et al., p. 28

Background Helicobacter pylori (H.pylori) infection causes atrophic gastritis and gastric cancer. Ironically, decreased gastric acid production in those with atrophic gastritis might reduce harmful gastroesophageal refluxate, thereby reducing gastroesophageal reflux disease (GERD) and Barrett’s oesophagus (BE) risk. Methods In two nested case-control studies with 425 GERD and 169 BE cases, we compared sex-specific GERD and BE risk in H.pylori seronegative participants with seropositive participants. Where seronegativity was associated with increased BE risk, we quantified the effect mediated by GERD using a Monte Carlo simulation-based g-computation approach to estimate interventional effects. Moreover, we classified participants into gastritis types using serum pepsinogen-I and gastrin-17 data. Results For men, H.pylori seronegativity was associated with 1.69-fold (CI:1.03-2.75) and 2.14-fold (CI:1.18-3.88) higher odds for GERD and BE respectively. Five (33%) out of the 15 per 1000 excess BE risk from being seronegative was mediated by GERD. No association was observed for women. Among those seropositive, the proportion with atrophic antral gastritis was higher for men than for women (68% vs 56%; p = 0.015). Conclusions H.pylori seronegativity was associated with increased GERD and BE risk for men but not women, which could be partly explained by the higher proportion of H.pylori-associated atrophic antral gastritis in men. Evidence of GERD mediating seronegativity’s effect on BE supports this explanation. Key messages Whilst H.pylori infection might reduce GERD and BE risk, this is potentially a by-product of atrophic gastritis, a risk factor for gastric cancer. Treating GERD could partly reduce the excess BE risk for seronegative individuals.

Background Greater physical activity (PA) and less sitting time (ST) have been associated with lower breast cancer (BC) risk in observational studies, but causality is undetermined. Mendelian randomization (MR) investigates causality by using genotype to simulate randomized trials within observational data. A recent summary-data MR study assessed PA and BC by estrogen-receptor (ER) status. We aimed to examine PA and ST in relation to invasive BC risk overall and by molecular subtype. Methods We performed two-sample MR using individual-level Breast Cancer Association Consortium data from 125,684 women (69,869 cases), and summary-level UK Biobank genetic data for the exposure (n = 91,105). We used imputed single nucleotide polymorphisms (SNPs) previously associated (p Results Greater PA was associated with lower risk of BC (OR = 0.48;95%CI=0.30-0.78 per standard deviation [SD] in activity). Estimates were inverse for all subtypes, particularly ER + (OR=0.45; 95%CI=0.25-0.83), PR + (OR=0.43;95%CI=0.22-0.85), and HER2 + (OR = 0.48; 95%CI=0.26-0.89). Greater ST was associated with higher risk of hormone-receptor-negative tumours, particularly triple-negative (ER-/PR-/HER2-) (OR = 2.04; 95%CI=1.06-3.93 per SD in ST). Estimates overall and for most other subtypes were elevated but had wide CIs crossing null. Sensitivity analyses (weighted-median MR and MR-Egger) did not suggest strong pleiotropic effects for either exposure. Conclusions Greater PA and lower ST reduces risk of all breast cancers, and hormone-receptor negative tumours, respectively. More widespread adoption of active lifestyles will lower burden from the most common cancer in women. Key messages More active and less sedentary lifestyles reduce risk of breast cancer.

Objective:To examine associations between diet and risk of developing gastro-oesophageal reflux disease (GERD).Design:Prospective cohort with a median follow-up of 15·8 years. Baseline diet was measured using a FFQ. GERD was defined as self-reported current or history of daily heartburn or acid regurgitation beginning at least 2 years after baseline. Sex-specific logistic regressions were performed to estimate OR for GERD associated with diet quality scores and intakes of nutrients, food groups and individual foods and beverages. The effect of substituting saturated fat for monounsaturated or polyunsaturated fat on GERD risk was examined.Setting:Melbourne, Australia.Participants:A cohort of 20 926 participants (62 % women) aged 40–59 years at recruitment between 1990 and 1994.Results:For men, total fat intake was associated with increased risk of GERD (OR 1·05 per 5 g/d; 95 % CI 1·01, 1·09; P = 0·016), whereas total carbohydrate (OR 0·89 per 30 g/d; 95 % CI 0·82, 0·98; P = 0·010) and starch intakes (OR 0·84 per 30 g/d; 95 % CI 0·75, 0·94; P = 0·005) were associated with reduced risk. Nutrients were not associated with risk for women. For both sexes, substituting saturated fat for polyunsaturated or monounsaturated fat did not change risk. For both sexes, fish, chicken, cruciferous vegetables and carbonated beverages were associated with increased risk, whereas total fruit and citrus were associated with reduced risk. No association was observed with diet quality scores.Conclusions:Diet is a possible risk factor for GERD, but food considered as triggers of GERD symptoms might not necessarily contribute to disease development. Potential differential associations for men and women warrant further investigation.

Objective A recent paper suggested all women with endometrial cancer should take statins but it is unclear whether there is sufficient evidence to justify this recommendation. Methods We identified all women diagnosed with uterine cancer in Australia between July 2003 and December 2013 (2012 in New South Wales) through the Australian Cancer Database (N = 16,501) and linked these to the national prescription database and National Death Index to identify statin use and survival outcomes to December 2015. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between statin use and survival. Results Among the 15,703 women with endometrial cancer, pre-diagnosis statin use was not associated with survival. Endometrial cancer-specific mortality was lower among women who used statins after diagnosis (time-varying models: HR = 0.92; 95%CI 0.82–1.03) but the association was only seen among women with type 1 cancers (0.87; 0.76–1.00), for hydrophilic statins (0.84; 0.68–1.03) and for new use of statins after diagnosis (0.75; 0.59–0.95). There was a weak dose-response with increasing number of statin prescriptions. Sensitivity analyses using inverse probability of treatment weights were similar. Conclusion Women with endometrial cancer who take statins after diagnosis may have better survival than those who do not use statins. However, it is impossible to completely rule out bias, particularly reverse causation where disease status may affect statin use. We believe it is too early to recommend all women with endometrial cancer take statins, but there is sufficient evidence to justify a randomized trial.

Background Questions remain about the effect on mortality of physical activity and sedentary behaviour over time. We summarized the evidence from studies that assessed exposure from multiple time points and critiqued the analytic approaches used. Methods A search was performed on MEDLINE, Embase, Emcare, Scopus and Web of Science up to January 2021 for studies of repeatedly assessed physical activity or sedentary behaviour in relation to all-cause or cause-specific mortality. Relative risks from individual studies were extracted. Each study was assessed for risk of bias from multiple domains. Results We identified 64 eligible studies (57 on physical activity, 6 on sedentary behaviour, 1 on both). Cox regression with a time-fixed exposure history (n = 45) or time-varying covariates (n = 13) were the most frequently used methods. Only four studies used g-methods, which are designed to adjust for time-varying confounding. Risk of bias arose primarily from inadequate adjustment for time-varying confounders, participant selection, exposure classification and changes from measured exposure. Despite heterogeneity in methods, most studies found that being consistently or increasingly active over adulthood was associated with lower all-cause and cardiovascular-disease mortality compared with being always inactive. Few studies examined physical-activity changes and cancer mortality or effects of sedentary-behaviour changes on mortality outcomes. Conclusions Accumulating more evidence using longitudinal data while addressing the methodological challenges would provide greater insight into the health effects of initiating or maintaining a more active and less sedentary lifestyle.

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible., Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

Background: It is not always clear whether physical activity is causally related to health outcomes, or whether the associations are induced through confounding or other biases. Randomized controlled trials of physical activity are not feasible when outcomes of interest are rare or develop over many years. Thus, we need methods to improve causal inference in observational physical activity studies. Methods: We outline a range of approaches that can improve causal inference in observational physical activity research, and also discuss the impact of measurement error on results and methods to minimize this. Results: Key concepts and methods described include directed acyclic graphs, quantitative bias analysis, Mendelian randomization, and potential outcomes approaches which include propensity scores, g methods, and causal mediation. Conclusions: We provide a brief overview of some contemporary epidemiological methods that are beginning to be used in physical activity research. Adoption of these methods will help build a stronger body of evidence for the health benefits of physical activity.

Background Recent studies have called into question the long-held belief that hysterectomy without oophorectomy protects against ovarian cancer. This population-based longitudinal record-linkage study aimed to explore this relationship, overall and by age at hysterectomy, time period, surgery type, and indication for hysterectomy. Methods We followed the female adult Western Australian population (837 942 women) across a 27-year period using linked electoral, hospital, births, deaths, and cancer records. Surgery dates were determined from hospital records, and ovarian cancer diagnoses (n = 1640) were ascertained from cancer registry records. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer incidence. Results Hysterectomy without oophorectomy (n = 78 594) was not associated with risk of invasive ovarian cancer overall (HR = 0.98, 95% CI = 0.85 to 1.11) or with the most common serous subtype (HR = 1.05, 95% CI = 0.89 to 1.23). Estimates did not vary statistically significantly by age at procedure, time period, or surgical approach. However, among women with endometriosis (5.8%) or with fibroids (5.7%), hysterectomy was associated with substantially decreased ovarian cancer risk overall (HR = 0.17, 95% CI = 0.12 to 0.24, and HR = 0.27, 95% CI = 0.20 to 0.36, respectively) and across all subtypes. Conclusions Our results suggest that for most women, having a hysterectomy with ovarian conservation is not likely to substantially alter their risk of developing ovarian cancer. However, our results, if confirmed, suggest that ovarian cancer risk reduction could be considered as a possible benefit of hysterectomy when making decisions about surgical management of endometriosis or fibroids.

Background Hysterectomy is one of the most commonly performed gynecological surgeries, with an estimated 30% of women in Australia undergoing the procedure by age 70. In the USA, about 45% of women have a hysterectomy in their lifetime. Some studies have suggested this procedure increases the risk of premature mortality. With many women making the decision to have a hysterectomy for a benign indication each year, additional research is needed to clarify whether there are long-term health consequences of hysterectomy. Objective Our aim was to examine the association between hysterectomy for benign indications, with or without removal of the ovaries, and cause-specific and all-cause mortality. Study Design Our cohort of 666,588 women comprised the female population of Western Australia with linked hospital and health records from 1970 to 2015. We used Cox regression models to assess the association between hysterectomy and all-cause, cardiovascular disease, cancer and other mortality by oophorectomy type (categorized as none, unilateral and bilateral), with no hysterectomy or oophorectomy as the reference group. We repeated these analyses using hysterectomy without oophorectomy as the reference group. We also investigated whether associations varied by age at the time of surgery, although small sample size precluded this analysis in women who had a hysterectomy with unilateral salpingo-oophorectomy. In our main analysis, women who had hysterectomy and/or oophorectomy undertaken as part of treatment for cancer were retained in the analysis and considered unexposed to that surgery. As a sensitivity analysis, we censored procedures undertaken for cancer. Results Compared to no surgery, having a hysterectomy without oophorectomy before age 35 was associated with an increase in all-cause mortality (HR=1.29, 95% CI:1.19-1.40); for surgery after age 35, there was an inverse association (35-44 years: HR=0.93, 95%CI:0.89,0.97). Similarly, hysterectomy with bilateral salpingo-oophorectomy was associated with increased all-cause mortality when undertaken before age 45 (35-44 years: HR=1.15, 95%CI:1.04-1.27), but decreased mortality rates when surgery was undertaken after age 45. In our sensitivity analysis, censoring gynecological surgeries for cancer resulted in many cancer-related deaths being excluded for women who did not have surgery for benign indications, and thus increased the hazard ratios for the associations between both hysterectomy without oophorectomy and hysterectomy with bilateral salpingo-oophorectomy and risk of all-cause and cancer-specific mortality. The sensitivity analysis therefore potentially biased the results in favor of no surgery. Conclusion Among women having surgery for benign indications, hysterectomy without oophorectomy performed prior to 35 years and hysterectomy with bilateral salpingo-oophorectomy performed prior to 45 years were associated with an increase in all-cause mortality. These procedures are not associated with poorer long-term survival when performed at older ages.

Background:\ud \ud Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.\ud Methods:\ud \ud We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.\ud Results:\ud \ud Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01–1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01–1.11) and borderline (pOR = 1.15; 95% CI: 1.02–1.29) tumours.\ud Conclusions:\ud \ud Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.