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Evidence suggests that inflammation may be associated with a higher risk of endometrial cancer, but previous reviews have typically examined a limited number of biomarkers. This study aimed to critically appraise the evidence on the effect of 13 circulating inflammatory biomarkers on endometrial cancer risk. MEDLINE and EMBASE databases were searched for prospective cohort, (nested) case-control and case-cohort studies, and Mendelian randomization (MR) studies published up to 31 March 2023. We performed a random-effects meta-analysis to estimate the pooled risk ratio and 95 % confidence interval (CI) for the association between each biomarker and endometrial cancer risk. Heterogeneity between studies was assessed using the I 2 statistic. Eight studies were included in the meta-analysis. Comparing groups with the highest versus lowest concentration of biomarker, adiponectin levels were inversely associated with risk of endometrial cancer (risk ratio (RR) =0.75, 95 % CI: 0.57-0.99, I2: 9 %). Higher levels of CRP (RR=1.18, 95 % CI: 1.05-1.33, I 2 : 2 %) and TNF-α (RR=1.58, 95 % CI: 1.13-2.21, I 2 : 0 %) were positively associated with risk of endometrial cancer. There was suggestive evidence for a positive association was also found for IL-6 (RR=1.29, 95 % CI: 0.88-1.88, I 2 : 0 %) and leptin (RR=1.50, 95 % CI: 0.83-2.71, I 2 : 0 %). Our findings suggest that circulating inflammatory biomarkers are likely involved in the carcinogenesis of endometrial cancer. Future studies should consider prospective or MR design and measure a wider range of inflammatory markers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brigid M Lynch reports administrative support was provided by Cancer Council Victoria. Brigid M Lynch reports a relationship with Australasian Epidemiological Association that includes: board membership. Brigid M Lynch serves as an Associate Editor for Cancer Epidemiology If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer., Objective: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing., Design: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors., Results: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways., Conclusions: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC., Patients and Methods: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR., Results: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk., Conclusions: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Pre-diagnostic physical activity is reported to improve survival for women with breast cancer. However, studies of pre-diagnostic exposures and cancer survival are susceptible to bias, made clear when applying a target trial framework. We investigated the impact of selection bias, immortal time bias, confounding and bias due to inappropriate adjustment for post-exposure variables in a systematic review and meta-analysis of pre-diagnostic physical activity and survival after breast cancer., Methods: Medline, Embase and Emcare were searched from inception to November 2021 for studies examining pre-diagnostic physical activity and overall or breast cancer-specific survival for women with breast cancer. Random-effects meta-analysis was used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) comparing highest versus lowest pre-diagnostic physical activity. Subgroup meta-analyses were used to compare HRs of studies with and without different biases. ROBINS-E was used to assess risk of bias., Results: We included 22 studies. Women with highest versus lowest pre-diagnostic physical activity had higher overall and breast cancer-specific survival across most analyses. The overall risk of bias was high. We observed marked differences in estimated HRs between studies that did and did not adjust for post-exposure variables or have immortal time bias. All studies were at risk of selection bias due to participants becoming eligible for study when they have survived to post-exposure events (e.g., breast cancer diagnosis). Insufficient studies were available to investigate confounding., Conclusion: Biases can substantially change effect estimates. Due to misalignment of treatment assignment (before diagnosis), eligibility (survival to post-exposure events) and start of follow-up, bias is difficult to avoid. It is difficult to lend a causal interpretation to effect estimates from studies of pre-diagnostic physical activity and survival after cancer. Biased effect estimates that are difficult to interpret may be less useful for clinical or public health policy applications., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brigid Lynch reports financial support was provided by Victorian Cancer Agency. Frances Albers reports financial support was provided by Commonwealth of Australia. Ziyu Wang reports financial support was provided by China Scholarship Council. Brigid Lynch reports a relationship with SciLifeLab that includes: travel reimbursement., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC., Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk., Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO)., Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10 -8 ) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10 -8 ). No interactions were observed for dietary and total folate., Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Enhanced survival following a diagnosis of cancer has led to a steep rise in the number of individuals diagnosed with a second primary cancer. We examined the association between pre-cancer cigarette smoking and risk of second cancer in 9785 participants diagnosed with first invasive cancer after enrolment in the Melbourne Collaborative Cohort Study. Follow-up was from date of first invasive cancer until diagnosis of second primary invasive cancer, death, or 31 July 2019, whichever came first. Data on cigarette smoking was collected at enrolment (1990-94) along with information on other lifestyle factors including body size, alcohol intake and diet. We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for incident second cancer with several smoking measures, adjusted for potential confounders. After a mean follow-up of 7.3 years, 1658 second cancers were identified. All measures of smoking were associated with increased risk of second cancer. We observed a 44 % higher risk of second cancer for smokers of ≥ 20 cigarettes/day (HR=1.44, 95 % CI: 1.18-1.76), compared with never smokers. We also observed dose-dependent associations with number of cigarettes smoked (HR=1.05 per 10 cigarettes/day, 95 % CI: 1.01-1.09) and duration of smoking (HR=1.07 per 10 years, 95 % CI: 1.03-1.10). The risk of second cancer increased by 4 % per 10 pack-years of smoking (HR=1.04, 95 % CI: 1.02-1.06; p < 0.001). There was suggestive evidence of stronger associations with number of cigarettes smoked and pack-years of smoking for women (p interaction <0.05), particularly for the highest risk categories of both variables. These associations with pre-diagnostic smoking were markedly stronger for second cancers known to be smoking-related than for others (p homogeneity <0.001). Our findings for pre-diagnostic cigarette smoking indicated increased risk of second primary cancer for cancer sites considered smoking-related, highlighting the importance of assessing smoking habits in cancer survivors., Competing Interests: Declaration of Competing Interest All authors declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work; and no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Breast cancer treatment leads to several side effects. Exercise can help to reduce these side effects. However, it is unknown whether a mat Pilates or a belly dance intervention can improve the patient-reported outcomes of these women., Objective: Examine the effects of a 16-week exercise intervention (mat Pilates or belly dance) on patient reported outcomes (PROs) among breast cancer survivors, at 16 weeks, six months, and 12 months; and investigate sociodemographic and clinical predictors of intervention adherence., Methods: Seventy-four breast cancer survivors who were receiving hormone therapy were randomly allocated into mat Pilates (n = 25), belly dance (n = 25) or control group (educational sessions) (n = 24). Mat Pilates and belly dance groups received a 16-week intervention, delivered three days a week and 60 min a session. The control group received three education sessions and continue usual care. The patient reported outcomes assessed were depressive symptoms (Beck Depression Inventory), stress (Perceived Stress Scale), optimism (Life Orientation Test), fatigue (FACT-F), sleep quality (Pittsburgh Sleep Quality Index) and pain (VAS), clinical and sociodemographic characteristics, and habitual physical activity (IPAQ short)., Results: All three groups showed a significant improvement in fatigue, and this effect was maintained during follow-up. No significant effects were found for depressive symptoms, optimism, stress, or pain. A history of exercise prior to breast cancer and be inactive after diagnosis were significant predictors of adherence to interventions., Conclusion: Mat Pilates, belly dance and a few educational sessions can be effective in improving fatigue after 16 weeks of intervention., Registration: ClinicalTrials.gov (NCT03194997)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Physical activity is positively associated with survival and quality of life among breast cancer survivors. Despite these benefits, the majority of breast cancer survivors are insufficiently active. The potential health benefits of reducing sedentary behaviour (sitting time) in this population have not been extensively investigated. The ACTIVATE Trial will evaluate the efficacy of an intervention that combines wearable technology (the Garmin Vivofit2®) with traditional behavioural change approaches to increase physical activity and reduce sedentary behaviour performed by breast cancer survivors., Methods/design: This randomised controlled trial includes inactive, postmenopausal women diagnosed with stage I-III breast cancer who have completed their primary treatment. Participants are randomly assigned to the primary intervention group (Garmin Vivofit2®; behavioural feedback and goal setting session; and, five telephone-delivered health coaching sessions) or to the wait-list control group. The primary intervention is delivered over a 12-week period. The second 12-week period comprises a maintenance phase for the primary intervention group, and an abridged intervention (Garmin Vivofit2® only) for the wait-list control group. Moderate- to vigorous-intensity physical activity (MVPA) and sedentary behaviour are assessed by accelerometry at baseline (T1), end of intervention (T2), and end of maintenance phase (T3)., Discussion: The ACTIVATE Trial is one of the first studies to incorporate wearable technology into an intervention for cancer survivors. If the use of wearable technology (in combination with behaviour change strategies, or alone) proves efficacious, it may become an inexpensive and sustainable addition to the health promotion strategies available to health care providers in the cancer survivorship context., Trial Registration: ACTRN12616000175471., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: How cancer adversely affects an individual's work role is an understudied survivorship issue. There are no Australian studies quantifying work participation after cancer or the potential barriers to work continuance. Using a large, population-based cohort of working adults with colorectal cancer, we assessed changes in work participation separately for men (n=621) and women (n=354)., Methods: Telephone survey methods collected data on colorectal cancer survivors identified through the Queensland Cancer Registry. Status at baseline and one-year post-diagnosis were described, and logistic regression models assessed correlates of work cessation., Results: Among working adults who were diagnosed with colorectal cancer, 33% of men and 40% of women were not working at one-year post-diagnosis. Radiation therapy among men (OR=2.55, 95%CI: 1.35-4.83) and chemotherapy among women (OR=2.49, 95% Cl: 1.23-5.04) were associated with a higher prevalence of work cessation. Having private health insurance was linked with resuming work for both men and women., Conclusion: A large proportion of working men and women leave the workforce by 12 months following a diagnosis of colorectal cancer. Factors correlated with work cessation after colorectal cancer appear different for men and women., Implications: A better understanding of how cancer affects working adults and contributes to unwanted work cessation is required to identify individuals who may benefit from occupational rehabilitation programs.

Objective: To investigate the reliability of collecting colorectal stage information from pathology reports and general practitioners in Queensland, Australia., Methods: A longitudinal study of colorectal cancer survivors conducted in 2003 and 2004 (n=1966, response rate=57%) obtained stage information from clinical specialists (n=1334), general practitioners (GP) (n=1417) and by extracting stage from pathology reports (n=1484). Reliability of stage information was determined by comparing stage from GPs and pathology reports with that reported by the clinical specialists, using a weighted kappa., Results: GPs and pathology reports each had a similar level of agreement with clinical specialists, with kappa scores of 0.77 (0.75-0.80) (n=1042) and 0.78 (0.75-0.81) (n=1152), respectively. Results were similar when restricting to records staged by all three methods (n=847). GPs had similar levels of agreement with clinical specialists within each stage, although pathology reports tended to under-stage patients in Stage D (0.37). Collapsing stage into two categories (A or B, C or D) increased the reliability estimates from the pathology reports to 0.91 (0.88-0.93), but there was little change in GP estimates 0.79 (0.75-0.83)., Conclusions: Extractions from pathology reports are a valid source of broad stage information for colorectal cancer., Implications: In the absence of clinical stage data, access to pathology records by population-based cancer registries enables a more accurate assessment of survival inequalities in colorectal cancer survival.

Objective: Self-report is commonly used in epidemiologic studies; however, few data exist on the reliability and validity of this method for eliciting information related to the diagnosis of colorectal cancer. We examined the test-retest reliability and validity of colorectal cancer patients reporting on the process of their diagnosis., Study Design and Setting: One hundred and sixteen participants completed two telephone interviews, 1 month apart, and 95 general practitioners (GPs) completed a written questionnaire, to elicit information relating to key elements of the process of diagnosis of colorectal cancer., Results: Acute symptoms such as rectal bleeding had higher reliability and validity than more general symptoms. Colonoscopy was the most accurately recalled diagnostic test. Recall of diagnosis date, and date of colonoscopy, had high test-retest reliability. There were considerable differences between dates of diagnostic tests given by participants and GPs, but there was no evidence of a bias in a particular direction. Accuracy of recall did not diminish as time from diagnosis increased., Conclusion: This study confirms that self-reported symptoms, tests, and dates in the colorectal cancer diagnostic pathway are generally reliable; however, the validity of reported symptoms and tests can be moderate to poor.