International Journal of Cancer

Background and objective: Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide. Early identification of high-risk individuals allows targeted prevention and early detection. Design: We constructed a polygenic risk score (PRS) for CRC risk using data from 1,448,354 individuals (103,401 cases). We evaluated its performance for identifying high-risk individuals in 6 major ancestries. Results: The PRS was strongly associated with CRC risk in Europeans (OR per SD =2.13, 95%CI=1.98-2.28), Africans (OR=1.35, 95%CI=1.11-1.64), Hispanics (OR=1.97, 95%CI =1.48-2.61), East Asians (OR=1.98, 95%CI=1.35-2.91), South Asians (OR=1.85, 95%CI=1.44 -2.37), and Middle Easterners (OR=3.10, 95%CI=1.38-6.95). Europeans in the top 10% genetic risk had 14-fold and 5-fold higher CRC risks compared to the bottom 10% (OR=13.50, 95%CI=8.67-21.00), and average (20-70%) risk groups (OR=4.64, 95%CI=3.89-5.52), respectively. The CRC risk in the top 10% individuals was equivalent to having three affected first degree relatives with CRC diagnosed at any age. Genetically high-risk individuals developed CRC up to 15 years earlier than the average. The PRS was strongly associated with early onset CRC risk e.g. in AFR (OR=3.22, 95%CI=1.79-5.81), and improved its prediction e.g. by 9% beyond clinical predictors in EUR. Conclusion: A comprehensive genetic prediction of CRC risk provides insights that could streamline screening and prevention guidelines.

BackgroundBlood-based metabolic and inflammatory biomarker levels prior to diagnosis might be associated with the risk of severe infections among cancer patients. ObjectivesTo investigate the longitudinal trajectories of circulating metabolic and inflammatory biomarkers before cancer diagnosis and assess their associations with the risk of severe infections after cancer diagnosis. MethodsWe conducted a cohort study including 10,837 patients with a first diagnosis of cancer during 1985-2005 within the Swedish AMORIS (Apolipoprotein-related MOrtality RISk) cohort. Severe infections were identified as a hospitalization for infectious diseases or a diagnosis of sepsis after cancer diagnosis throughout December 31, 2020. We focused on 18 biomarkers to identify biomarker trajectories during the 10 years before cancer diagnosis using latent class growth modeling. Through flexible parametric models, we then visualized and calculated hazards and hazard ratios (HRs) with 95% confidence intervals (CIs) of severe infections after cancer diagnosis in relation to different biomarker trajectories. ResultsThe included patients had a mean (SD) age at diagnosis of 65.9 (11.7), including 5476 men (50.5%) and 9385 who were born in Sweden (86.6%). A total of 3752 (34.6%) patients were hospitalized for infectious diseases whereas 1709 (15.8%) had a diagnosis of sepsis after cancer diagnosis. We identified several distinct trajectories for the selected biomarkers during the 10 years before cancer diagnosis. A 25% to 65% higher hazard of hospitalization for infectious diseases was observed in patients with persistently high levels of glucose [HR (95%CI): 1.54 (1.34-1.78)], fructosamine [1.65 (1.38-1.97)], or triglycerides [1.25 (1.13-1.37)], compared to patients with persistently low levels. An opposite trend was however noted for total cholesterol and high-density lipoprotein. Further, compared to patients with persistently low levels, patients with increasing levels of C-reactive protein [1.25 (1.10-1.43)] and immunoglobulin G [1.85 (1.24-2.76)] had an increased risk of hospitalization for infectious diseases after cancer diagnosis. Similar results were observed for sepsis. ConclusionTemporal trajectories in metabolic and inflammatory biomarkers during the 10 years before cancer diagnosis were linked to an altered risk of severe infections after cancer diagnosis. Longitudinal measurement of these biomarkers before cancer diagnosis, may therefore help provide a more comprehensive assessment of the risk for severe infections among cancer patients.

ABSTRACT Background: Onset of cancer is linked to psychological distress and cancer is prevalent in older adults. Yet, the association to suicide is scarcely examined. The aim of this study was to assess whether cancer diagnosed in older adults is associated with suicide incidence. Methods: All older adults (65+ years) who lived in Austria in the years 2014-2021 (n=2,175,134) were followed. Of these, 223,932 were diagnosed with a new cancer. We used non-parametric survival models with inverse-probability-treatment weights to compare risk ratios (relative risk) and risk differences (absolute risk) of older adults with and without cancer. Results: Out of 2,158 suicide deaths, 442 (20.5%; 83.7% males) occurred among older adults with a new cancer diagnosis. The incidence rate was 74 among those with a new cancer diagnosis versus 23 per 100,000 person-years among those with no new cancer. One year after being diagnosed, older adults with a new cancer had a 4 times higher relative risk of dying by suicide compared to those without. The risk was highest within the first three months after diagnosis and for cancers with a poor prognosis (disseminated disease; lung, oesophagus, stomach, liver, pancreas, and brain cancers). The absolute risk of dying by suicide within 5 years after cancer diagnosis was 0.18% versus to 0.11% among those with no new cancer. Discussion: Older adults who received a new cancer diagnosis had elevated suicide risks. Provision of support to cope with mental distress should be considered at cancer diagnosis, especially for older adults with a poor prognosis.

BackgroundPopulation-based mammographic screening is primarily age-based. However, breast cancer risk is multifactorial, and women may benefit from personalized risk-based screening. This pilot study aimed to explore the use of polygenic risk score (PRS) as a tool for risk stratification in personalized screening. MethodsWe included 80 women aged 40-49 years referred for clinical mammography. Exclusion criteria were prior breast cancer or premalignant breast disease, and previous genetic testing. After DNA collection, PRS was calculated from 2805 Single Nucleotide Polymorphisms (SNPs). Screening recommendations were based on each participants relative 10-year breast cancer risk estimated from PRS and compared with the 10-year risk of an average woman of the same age. Women with a self-reported family history of cancer meeting standard criteria were referred for gene panel testing for pathogenic variants in high-risk genes. A follow up questionnaire regarding participants experiences was distributed 6-9 months after PRS testing. ResultsMean age was 45.2 years (SD 2.8). Mean relative 10-year breast cancer risk was 1.18 (SD 0.57). Based on PRS, 40 participants were recommended standard biennial screening 50-69 years, while 40 were advised to begin biennial screening before age 50. Among these, 7 were recommended annual mammography from when their 10-year risk reached twice that of an average 50-year-old. Twenty-one women underwent gene panel testing; no pathogenic variants in breast cancer genes were identified. Five women were advised annual mammography from 40-60 years due to family history of breast cancer, regardless of PRS. Most respondents viewed breast cancer risk assessment positively and did not report increased anxiety after testing. ConclusionsPolygenic risk score testing may influence current screening recommendations and contribute to more personalized risk-based breast cancer screening strategies.

ObjectiveTo investigate whether the higher risks of certain cancers associated with high cardiorespiratory fitness can be explained by increased detection and unobserved confounders. DesignNationwide sibling-controlled cohort study of adolescents. SettingSweden. Participants1 124 049 men of which 477 453 were full siblings, who underwent mandatory military conscription examinations between 1972 and 1995 at a mean age of 18.3 years. Main outcome measuresHazard ratios (HR) and 95% confidence intervals (CI) of overall cancer diagnosis and cancer mortality, and 14 site-specific cancers (diagnosis or death), as recorded in the Swedish National Patient Register or Cause of Death Register until 31 December 2023, modelled using flexible parametric regressions. ResultsParticipants were followed until a median (maximum) age of 55.9 (73.5) years, during which 98 410 were diagnosed with cancer and 16 789 had a cancer-related death (41 293 and 6908 among full siblings respectively). The most common cancers were non-melanoma skin (27 105 diagnoses & 227 deaths) and prostate cancer (24 211 diagnoses & 869 deaths). In cohort analysis, those in the highest quartile of cardiorespiratory fitness had a higher risk of prostate (adjusted HR 1.10; 95% CI: 1.05 to 1.16) and skin cancer (e.g., non-melanoma HR 1.44; 1.37 to 1.50) compared to those in the lowest quartile, which led to a higher risk of any type of cancer diagnosis (HR 1.08; 1.06 to 1.11). However, those in the highest quartile had a lower risk of cancer mortality (HR 0.71; 0.67 to 0.76). When comparing full siblings, and thereby controlling for all behavioural, environmental, and genetic factors they share, the excess risk of prostate (HR 1.01; 0.90 to 1.13) and skin cancer (e.g., non-melanoma HR 1.09; 0.99 to 1.20) attenuated to the null. In contrast, the lower risk of overall cancer mortality was still statistically significant after control for such shared confounders (HR 0.78; 0.68 to 0.89). For other site-specific cancers, the influence of such confounding tended to vary, but none showed the same excess risk as prostate and non-melanoma skin cancer. ConclusionsThe association between high levels of adolescent cardiorespiratory fitness and excess risk of some cancers, such as prostate and non-melanoma skin cancer, appears to be fully explained by unobserved confounders shared between full siblings. However, the protective association with cancer mortality persists even after control for such confounding. Summary boxWhat is already known on this topic O_LIAdolescent physical activity and cardiorespiratory fitness are considered important factors for the prevention of cancer based on evidence from observational studies. C_LIO_LIObservational studies are, however, vulnerable to unobserved confounders and bias processes, including health-seeking behaviours and genetic and environmental confounders. C_LIO_LIThese biases could explain why prior studies have found that high adolescent cardiorespiratory fitness is associated with higher risks of some cancers, typically low-mortality cancers such as prostate and non-melanoma skin cancer. C_LI What this study adds O_LIThis nationwide cohort study of 1.1 million male adolescents showed that while higher cardiorespiratory fitness was associated with excess risk of the most common cancers - prostate and non-melanoma skin - these associations attenuated to the null when accounting for behavioural, environmental, and genetic confounders shared between full siblings. C_LIO_LIIn contrast, high adolescent cardiorespiratory fitness was associated with a lower risk of overall cancer mortality, which remained after controlling for unobserved confounders shared between full siblings. C_LI

BackgroundImprovements in cancer control have led to a drastic increase in cancer survivors who may be at an elevated risk of developing a subsequent primary cancer (SPC). In this study, we assessed the risk and patterns of SPC development among 134,693 adult cancer survivors in Alberta, Canada. MethodsWe used data from the Alberta Cancer Registry to identify all first primary cancers (FPC) occurring between 2004 and 2015. A SPC was considered as the next primary cancer occurring in a different site. We estimated standardized incidence ratios (SIR) for SPC development as the observed number of SPC (O) divided by the expected number of SPC (E), where E is a weighted-sum of the population-based year-age-sex-specific incidence rates and the corresponding person-years of follow-up. ResultsThe risk of developing a SPC up to fifteen years after an initial cancer was 16.1% for males and 12.3% for females, though these estimates vary considerably by cancer site. Survivors of initial head and neck cancers had a 21.3% fifteen-year cumulative incidence and a 2.5-fold relative risk of SPC development. Overall, both males (SIR=1.50) and females (SIR=1.64) had an increased risk of a SPC. There were significant increases in SPC risk for nearly all age groups, with a greater than 5-fold increase for survivors of cancers diagnosed between ages 18-39. ConclusionsCancer survivors of nearly every FPC site had substantially increased risk of a SPC, compared to the cancer risk in the general population. Screen-detectable cancers (breast, cervical, colorectal, lung) were common SPC sites and highlights the need to investigate optimal strategies for screening the growing population of cancer survivors.

Although it is known that social deprivation is associated with higher risks of cardiovascular and cancer mortality in the general population, these associations may not be directly applicable to cancer survivors. Using data from the National Health Interview Survey (NHIS) 2013-2017 with follow-up till the end of 2019, we examined the associations between social determinants of health (SDOH) and the risk of all-cause, cardiovascular, and cancer mortality in cancer survivors, with separate modelling in individuals without cancer for comparison. Two Cox regression models were fitted for each outcome, the first being adjusted for demographics and the second being additionally adjusted for comorbidities and risk factors. Altogether, 37,882 individuals were analysed (representing a weighted population of 57,696,771), including 4179 cancer survivors and 33,703 individuals without cancer. Amongst cancer survivors, worse SDOH was associated with higher all-cause, cardiovascular, and cancer mortality when adjusted for demographics, which were attenuated but remained significant when further adjusted for comorbidities and risk factors. Amongst individuals without cancer, worse SDOH was associated with higher all-cause and cardiovascular mortality only when adjusted for demographics, but not when further adjusted for comorbidities and risk factors. These suggested that in cancer survivors, associations between SDOH and cardiovascular/cancer mortality may be driven by factors beyond comorbidities and risk factors, contrasting individuals without cancer in whom similar associations were probably driven mostly by comorbidities and risk factors.

ObjectivePolygenic risk scores (PRSs) derived from genome-wide association studies are strong predictors of colorectal cancer (CRC) risk. We applied the straightforward approach of risk advancement periods (RAPs) to derive risk-adapted starting ages of CRC screening according to sex and PRS in the UK Biobank. MethodsAmong 242,779 participants (40-69 years; no previous CRC screening; no family history of CRC), we assessed associations of sex and a PRS with CRC risk and mortality using Cox regression models. Hazard ratios (HRs) were translated to RAPs to quantify how many years of age earlier men and women in defined PRS deciles reach comparable risks as those in the reference group (5th and 6th PRS deciles). ResultsDuring a median follow-up of 11.2 and 12.8 years, 2,714 participants were diagnosed with CRC and 758 died from CRC, respectively. HRs (95% CIs) of CRC risk were 1.57 (1.46, 1.70) for men versus women and ranged from 0.51 (0.41, 0.62) to 2.29 (2.01, 2.62) across PRS deciles compared to the reference. RAPs (95% CI) were 5.6 (4.6, 6.6) years for men versus women, and ranged from -8.4 (-11.0, -5.9) to 10.3 (8.5, 12.1) years across PRS deciles compared to the reference. Risk-adapted starting ages would vary by 24 years between men in the highest PRS decile and women in the lowest PRS decile. Very similar results were obtained regarding CRC mortality. ConclusionConsideration of sex and a standard PRS alone could have far-reaching implications for starting ages of CRC screening in the "average risk population". SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPolygenic risk scores (PRSs) are strong predictors of colorectal cancer (CRC) risk. C_LIO_LIMen have substantially higher CRC incidence and mortality than women. C_LIO_LICRC risk information from the combination of PRS and genetically determined sex, which are constant factors over lifetime, is so far not used for risk-adapted CRC screening in the "average risk population". C_LI What this study addsO_LIRisk advancement periods (RAPs) of CRC by PRS and sex were derived at high levels of precision from the large database of the UK Biobank. C_LIO_LIBy joint consideration of PRS and genetically defined sex, risk-adapted starting ages would vary by as much as 24 years between men in the highest PRS decile and women in the lowest PRS decile. C_LI How this study might affect research, practice or policyO_LIOur study demonstrates a straightforward way to translate CRC risk information from a large population-based cohort into risk-adapted starting ages of screening. C_LIO_LIPersonalized, risk-adapted starting ages of CRC screening could be derived from a single blood test performed in middle adulthood. C_LIO_LIThe RAP approach could be easily extended for defining personalized starting ages by incorporating additional risk factors in the regression models. C_LI

BackgroundDeleterious germline variants in ATM and CHEK2 have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear, and require further investigation. MethodsCancer associations for coding variants in ATM and CHEK2 were evaluated using whole-exome sequenced data from UK Biobank linked to cancer registration data (348,488 participants), and analysed both as a retrospective case-control and a prospective cohort study. Odds ratios, hazard ratios, and combined relative risks (RRs) were estimated by cancer type and gene. Separate analyses were performed for protein-truncating variants (PTVs) and rare missense variants (rMSVs; allele frequency <0{middle dot}1%). ResultsPTVs in ATM were associated with increased risks of nine cancers at p<0{middle dot}001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia [LL]), and two at p<0{middle dot}05 (colon, diffuse non-Hodgkins lymphoma [DNHL]). Carriers of rMSVs had increased risks of four cancers (p<0{middle dot}05: stomach, pancreas, prostate, Hodgkins disease [HD]). RRs were highest for breast, prostate, and any cancer where rMSVs lay in the FAT or PIK domains, and had a CADD score in the highest quintile. PTVs in CHEK2 were associated with three cancers at p<0{middle dot}001 (breast, prostate, HD), and six at p<0{middle dot}05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia). Carriers of rMSVs had increased risks of five cancers (p<0{middle dot}001: breast, prostate, LL; p<0{middle dot}05: melanoma, multiple myeloma). ConclusionPTVs in ATM and CHEK2 are associated with a wide range of cancers, with the highest RR for pancreatic cancer in ATM PTV carriers. These findings can inform genetic counselling of carriers. WHAT IS ALREADY KNOWN ON THIS TOPICO_LIWhile previous research shows there is evidence for association between variants in ATM or CHEK2 and multiple cancer types in individual smaller studies, the associations have not been consistently evaluated across all cancer types and, with the exception of breast cancer, the strengths of association are unclear. C_LI WHAT THIS STUDY ADDSO_LIWe examined data from a large cohort study to derive relative and absolute risks for all cancer types for carriers of PTVs and rMSVs in CHEK2 and ATM . C_LIO_LIATM PTVs were associated with significantly increased risk for 11 of 23 sites examined (nine at p<0{middle dot}001), with the relative risk being highest for pancreatic cancer (approximately seven-fold). Carriers of rMSVs had increased risks of four cancers, with a RR of approximately 1{middle dot}5. C_LIO_LIFor CHEK2 PTVs, statistically significant risks were observed for seven of the 21 sites examined (one at p<0{middle dot}001). Carriers of rMSVs had increased risks of five cancers with the risk being highest for lymphoid leukaemia (approximately two-fold). C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYO_LIATM and CHEK2 are included on many cancer gene panels used in family cancer clinics, and the risk estimates from these analyses can inform genetic counselling for carriers. C_LIO_LIThe estimated absolute risks for pancreatic cancer in ATM PTV carriers (11% in males and 8% in females by age 85) are notably higher than for other major pancreatic susceptibility genes including BRCA2, CDK2NA, and PALB2. Our findings can also inform NICE guidelines for pancreatic cancer, which do not currently include ATM . C_LI

Head and neck cancer (HNC) is the sixth most common cancer globally. Incidence and survival rates vary significantly across geographic regions and tumor subsites. This is partly due to differences in risk factor exposure, which includes tobacco smoking, alcohol consumption and human papillomavirus (HPV) infection, alongside detection and treatment strategies. The VOYAGER (human papillomaVirus, Oral and oropharYngeal cAncer GEnomic Research) consortium is a collaboration between five large North American and European studies which generated data on 10,530 participants (7,233 cases and 3,297 controls). The primary goal of the collaboration was to improve understanding of the role of HPV and genetic factors in oral cavity and oropharyngeal cancer risk and outcome. Demographic and clinical data collected by the five studies were harmonized, and HPV status was determined for the majority of cases. In addition, 999 tumors were sequenced to define somatic mutations. These activities generated a comprehensive biomedical resource that can be utilized to answer critical outstanding research questions to help improve HNC prevention, early detection, treatment, and surveillance.

PURPOSERandomized controlled trials have failed to validate that neutralizing oxidative stress (OxS) through antioxidant supplementation reduces cancer risk. This study aims to prospectively investigate whether the relationship between systemic OxS and colorectal cancer (CRC) risk changes over the course of cancer development. METHODSThis study utilized a nested case-control design in two Shanghai cohorts for primary analysis and one US cohort for replication analysis. During a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each. In the US cohort, 285 incident CRC cases were included with two matched controls per case. Systemic OxS was assessed by urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) using UPLC-MS/MS assays. Multivariable-adjusted odds ratios (ORs) for CRC risk were calculated. RESULTSAfter adjusting for potential confounders, we observed an inversion association between OxS markers and CRC risk in the Shanghai cohorts, which was independently replicated in the US cohort. Moreover, the inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years of enrollment. ORs (95% CI) for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (1.39 to 2.53) and 0.48 (0.37 to 0.63), respectively, demonstrating an approximate 4-fold difference in risk between the two groups, with P for overall association of < 0.001. A similar pattern was observed for 8-oxo-Guo. No significant association was found for CRC diagnosed beyond 5 years of enrollment. CONCLUSIONThis novel finding of an inverse and time-dependent relationship between systemic OxS and CRC risk, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention. CONTEXTO_ST_ABSBackgroundC_ST_ABSAlmost all large randomized controlled trials have failed to validate the hypothesis that neutralizing oxidative stress through antioxidant supplementation can lower cancer risk, which has puzzled the public and researchers for decades. Key FindingsA reduced risk for colorectal cancer (CRC) with increasing systemic oxidative stress, measured by two urinary biomarkers of DNA and RNA oxidation, was observed in two large prospective cohort studies in Shanghai, China, and was replicated in an independent cohort in the United States. This association was time-dependent, with the inverse relationship strengthening as the biomarker assessment neared the time of CRC diagnosis. RelevanceOur study, for the first time, suggests an inverse and time-dependent relationship between systemic oxidative stress and CRC development, which, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.

PurposeTobacco use is an independent adverse prognostic feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Despite this, the biologic features associated with tobacco use have not been systematically investigated in this population. We sought to characterize the genomic and immunologic features of HPV(+) OPSCC associated with tobacco use and adverse oncologic outcomes. Experimental DesignWhole exome sequencing of 47 primary HPV(+) OPSCC tumors was performed to investigate mutational differences associated with tobacco exposure. To characterize the tumor immune microenvironment (TIME), targeted mRNA hybridization was performed and immunohistochemical (IHC) staining was used to validate these findings. ResultsLow expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at the time of diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T>C substitutions and a lower proportion of mutational signatures typically observed in HPV(+) OPSCC tumors, but was not associated with increases in mutational burden or the rate of recurrent oncogenic mutations. ConclusionsIn HPV(+) OPSCC, low T cell infiltration of primary tumors is associated with current tobacco use and worse oncologic outcomes. Rather than an increased mutational burden, tobaccos primary and clinically relevant association is immunosuppression of the primary TIME. An objective clinical assay like the TGEP, which quantifies immune infiltration of the primary TIME, may have value for HPV(+) OPSCC risk stratification in future clinical trials.

Differentiated thyroid cancers (DTCs) are malignancies with ill-defined hereditary predisposition. Some germline variants influencing the risk of DTCs localize in disrupted in renal carcinoma 3 (DIRC3), a poorly characterized long non-coding RNA (lncRNA) gene. Here, we characterized the function of DIRC3 in DTCs. We established that DIRC3 is downregulated in DTCs, and its high expression may reduce the risk of cancer recurrence in patients. DIRC3 transcripts were enriched in cell nuclei in vitro, where they upregulated insulin-like growth factor binding protein 5 (IGFBP5), a gene known to modulate the cellular response to insulin-like growth factor 1 (IGF-1). Silencing of DIRC3 in thyroid cancer cell lines produced a phenotypic dichotomy: it augmented cell migration and invasiveness, reduced apoptosis, but abrogated the MTT reduction rate. We demonstrated that the pro-migratory phenotype was produced by the downregulation of IGFBP5. Transcriptomic profiling confirmed a functional redundancy in the activities of DIRC3 and IGFBP5. Moreover, downregulation of DIRC3 enhanced the susceptibility of cancer cells to IGF-1 stimulation and promoted Akt signaling. In conclusion, DIRC3 expression alters the phenotype of thyroid cancer cells and modulates the activity of IGFBP5/IGF-1/Akt axis. We propose an interplay between DIRC3 and IGF signaling as a mechanism that promotes thyroid carcinogenesis.

Background Conversion surgery for stage IV gastric cancer is supported by a pooled overall survival hazard ratio of 0.36 (95% confidence interval 0.32-0.40) and, in the largest international cohort, median survival of 36.7 versus 12.5-13.8 months on chemotherapy. Survival is measured from diagnosis; the median diagnosis-to-gastrectomy interval is 124 days, which patients must survive to be counted surgical. Methods We simulated cohorts of 3,177 stage IV gastric cancer patients from published parameters: background median survival 14.5 months; median diagnosis-to-surgery interval 124 days (category-specific 92-174 days). Surgery had no effect (true hazard ratio 1.00 by construction). Data were analysed as the literature analyses them (exposure fixed at baseline, follow-up from diagnosis), and by time-varying Cox and landmark analysis. Confounding by indication was added in a second scenario. Results Under immortal time bias alone the naive analysis returned a hazard ratio of 0.794 (95% simulation interval 0.743-0.851), median survival 16.8 versus 12.8 months. Time-varying Cox recovered 1.000 and landmark analysis 1.000-1.004. Bias scaled with the interval: 0.849 at 92 days, 0.715 at 174 days. Adding confounding, the naive estimate fell to 0.601 (0.560-0.644) at strength 0.5 and 0.356 (0.323-0.385) at strength 1.5, overlapping the published estimate; median survival 21.9 versus 8.7 months. Correcting immortal time alone left residual bias (hazard ratio 0.439). Conclusions The reported survival advantage of conversion surgery is reproducible where the operation does nothing; published estimates cannot distinguish benefit from bias. Resolving this requires individual patient data analysed with methods that assign person-time correctly, or completion of JCOG2301.

ObjectivesTo evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC). DesignPopulation based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women. Setting and participantsUK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts. Main outcome measuresPrediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models. FindingsPRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds. ConclusionsIntegrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted. Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIRisk stratification based on genetic or environmental risk factors could improve cancer screening outcomes C_LIO_LINo previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond age C_LIO_LIQCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRC C_LI What this study addsO_LIAdding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention C_LI

BACKGROUNDCancer is associated with significant economic impacts. Quantifying the scale of these impacts is challenged by confounding variables that jointly influence both cancer status and economic outcomes such as healthcare costs and quality of life. Moreover, the increasing costs attributed to cancer drug development complicate the cost-effective provision of cancer care. METHODSWe address both challenges in this paper by using germline genetic variation in the risk of incident cancer as instrumental variables in Mendelian Randomization analyses of eight cancers. We developed causal estimates of the genetically predicted effect of bladder, breast, colorectal, lung, multiple myeloma, ovarian, prostate and thyroid cancers on healthcare costs and quality adjusted life years (QALYs) using outcome data drawn from the UK Biobank cohort. We then used Mendelian Randomization to model a hypothetical population-wide preventative intervention based on a repurposed class of anti-diabetic drugs known as sodium-glucose co-transporter-2 (SGLT2) inhibitors very recently shown to reduce the odds of incident prostate cancer. RESULTSGenetic liability to prostate cancer and to breast cancer had material causal impacts on healthcare costs and QALYs. Mendelian Randomization results for the less common cancers were associated with considerable uncertainty. SGLT2 inhibition was unlikely to be a cost-effective preventative intervention for prostate cancer, although this conclusion depended on the price at which these drugs would be offered for a novel anti-cancer indication. IMPLICATIONSOur new causal estimates of cancer exposures on health economic outcomes may be used as inputs into decision analytic models of cancer interventions such as screening programmes or simulations of longer-term outcomes associated with therapies investigated in RCTs with short follow-ups. Our new method allows us to rapidly and efficiently estimate the cost-effectiveness of a hypothetical population-scale anti-cancer intervention to inform and complement other means of assessing long-term intervention cost-effectiveness.

Differences in cancer rates have been documented in Japan between Okinawa and mainland Japan. Limited data exist on whether these differences are also present for established populations of Okinawans and mainland Japanese in the United States. Dimensionality reduction techniques for genetic data combined with Okinawan surnames were used to identify Multiethnic Cohort Japanese American participants (N=24,484) of Okinawan or mainland descent. Cox proportional hazards models were used to compare cancer incidence between Okinawan and mainland Japanese participants. Geometric means were examined on a subset of MEC participants for circulating blood biomarker levels (N=2,980) and body composition (N=399). The Okinawan cluster included 3,649 individuals and the mainland cluster included 19,611 individuals. Okinawan individuals were more likely to have a higher average body mass index and shorter stature, better diet quality score, higher total energy intake, more alcohol consumption among drinkers, and a history of never smoking compared to mainland Japanese (all p-values<0.0001). In multivariable adjusted models, Okinawan women were more likely to be diagnosed with breast cancer (HR=1.36, 95% CI=1.07-1.73) and Okinawan men were less likely to be diagnosed with aggressive prostate cancer (HR=0.67, 95% CI=0.51-0.87) compared to their mainland Japanese counterparts. In subsets of MEC participants, adiponectin levels were lower, and C-reactive protein levels, visceral adipose tissue area (VAT) and the VAT-to- subcutaneous adipose tissue area ratio were higher, in Okinawans compared to mainland Japanese (all p-values<0.05). Results in this US-based sample are consistent with recent trends of higher breast and lower prostate cancer incidence rates in Okinawans reported from Japan. Novelty and impactCancer rate differences have been documented in Japan between Okinawa and mainland Japan; however, limited data exist on whether these differences are present in Japanese Americans of Okinawan or mainland descent. We report significant differences in breast cancer, prostate cancers, body composition, and obesity-related biomarkers for these two groups. Our findings suggest that these cancer risk disparities may not be solely due to lifestyle, but could be explained by body composition, genetics, or unmeasured factors.

Age-related differences in colon and rectal cancer survival have been observed, even after accounting for differences in background mortality. To determine to what extent stage, tumour site, or histology could contribute to these differences, we estimated 1-year relative survival (RS) age stratified by these factors. Colon and rectal cancer cases diagnosed between 2012 and 2016 and followed up until 2017 were retrieved from 18 United States Surveillance Epidemiology and End Results cancer registries. For colon cancer, 1-year RS ranged from 87.8% [95% Confidence Interval: 87.5-88.2] in the 50-64-year-old age group to 62.3% [61.3-63.3] in the 85-99-year-old age group and for rectal cancer ranged from 92.3% [91.8-82.7] to 65.0% [62.3-67.5]. With respect to stage, absolute differences in RS between 50-64-year-old and 75-84-year-old in RS increased with increasing stage (from 6 [5-7] %-points in localized disease to 27 [25-29] %-points in distant disease) and were the highest for cancers of unknown stage (>28%-points). With respect to topography, age-related differences in survival were smallest for those in right-sided colon (8 [7-9] %-points) and largest for tumours of the colon without topography further specified (25 [21-29] %-points). While age-related differences in survival varied by histology and tumour site, the overall age-related differences in survival could not be explained by differences in distribution of these factors by age, consistent with a hypothesis that stage at diagnosis or treatment are more likely drivers. Incorporating data on geriatric conditions such as frailty and comorbidity would support further understanding of the age gap in colon and rectal cancer survival.

PurposeExposure to Agent Orange, a known carcinogen, might increase risk of prostate cancer (PCa). We sought to investigate the association of Agent Orange exposure and PCa risk when accounting for race/ethnicity, family history, and genetic risk in a diverse population of US Vietnam War veterans. Methods & MaterialsThis study utilized the Million Veteran Program (MVP), a national, population-based cohort study of United States military veterans conducted 2011-2021 with 590,750 male participants available for analysis. Agent Orange exposure was obtained using records from the Department of Veterans Affairs (VA) using the US government definition of Agent Orange exposure: active service in Vietnam while Agent Orange was in use. Only veterans who were on active duty (anywhere in the world) during the Vietnam War were included in this analysis (211,180 participants). Genetic risk was assessed via a previously validated polygenic hazard score calculated from genotype data. Age at diagnosis of any PCa, diagnosis of metastatic PCa, and death from PCa were assessed via Cox proportional hazards models. ResultsExposure to Agent Orange was associated with increased PCa diagnosis (HR 1.04, 95% CI 1.01-1.06, p=0.003), primarily among Non-Hispanic White men (HR 1.09, 95% CI 1.06- 1.12, p<0.001). When accounting for race/ethnicity and family history, Agent Orange exposure remained an independent risk factor for PCa diagnosis (HR 1.06, 95% CI 1.04-1.09, p<0.05). Univariable associations of Agent Orange exposure with PCa metastasis (HR 1.08, 95% CI 0.99-1.17) and PCa death (HR 1.02, 95% CI 0.84-1.22) did not reach significance on multivariable analysis. Similar results were found when accounting for polygenic hazard score. ConclusionsAmong US Vietnam War veterans, Agent Orange exposure is an independent risk factor for PCa diagnosis, though associations with PCa metastasis or death are unclear when accounting for race/ethnicity, family history, and/or polygenic risk.

BackgroundUnderstanding about the changing burden of head and neck cancers (HNC) is essential to guide public health interventions and inform cancer care strategies. MethodsWe conducted a population-based cohort study using routinely collected primary care data Clinical Practice Research Datalink (CPRD) GOLD from the United Kingdom. Adults aged [&ge;]18 years with [&ge;]1 year of prior history were included. We estimated crude and age-standardised incidence rates (IRs) and one-, five-, and ten-year survival from 2000 to 2021, stratified by age and calendar year. Findings from CPRD GOLD were compared with primary care data from CPRD Aurum, which includes patients from England only. ResultsThere were 12,455 patients with a diagnosis of HNC from CPRD GOLD (69.2% male; median age 64 years). Crude incidence in GOLD increased from 9.08 (95% CI: 7.88-10.42) per 100,000 person-years in 2000 to 15.59 (14.07-17.23) in 2021, with similar trends observed in CPRD Aurum. Age-standardised incidence trends were attenuated overall but remained elevated for oropharyngeal and tongue cancers. Five-year survival improved modestly, from 53.8% (95% CI: 51.4-56.3%) in 2000-2004 to 58.7% (56.5-60.9%) in 2015-2019. ConclusionsHNC increases over recent decades are likely due to ageing with increases in oropharyngeal cancers likely due to changing behavioural risk factors. Small improvements in long term survival highlights more research is needed to improve earlier diagnosis which will lead to better patient outcomes.