Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver.

A hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these organs. Using biochemical, genetic, and confocal intravital imaging approaches, we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival in models of endotoxemia. Our data establish DPEP1 as a major adhesion receptor on the lung and liver endothelium and identify a therapeutic target for neutrophil-driven inflammatory diseases of the lungs.

Assessing Breast Cancer Screening and Outcomes Among First Nations Women in Alberta.

BACKGROUND: Breast cancer (BC) incidence rates for First Nations (FN) women in Canada have been steadily increasing and are often diagnosed at a later stage. Despite efforts to expand the reach of BC screening programs for FN populations in Alberta (AB), gaps in screening and outcomes exist. METHODS: Existing population-based administrative databases including the AB BC Screening Program, the AB Cancer Registry, and an AB-specific FN registry data were linked to evaluate BC screening participation, detection, and timeliness of outcomes in this retrospective study. Tests of proportions and trends compared the findings between FN and non-FN women, aged 50-74 years, beginning in 2008. Incorporation of FN principles of ownership, control, access, and possession (OCAP®) managed respectful sharing and utilization of FN data and findings. RESULTS: The average age-standardized participation (2013-8) and retention rates (2015-6) for FN women compared to non-FN women in AB were 23.8% (P < .0001) and 10.3% (P = .059) lower per year, respectively. FN women were diagnosed with an invasive cancer more often in Stage II (P-value = .02). Following 90% completion of diagnostic assessments, it took 2-4 weeks longer for FN women to receive their first diagnosis as well as definitive diagnoses than non-FN women. CONCLUSION: Collectively, these findings suggest that access to and provision of screening services for FN women may not be equitable and may contribute to higher BC incidence and mortality rates. Collaborations between FN groups and screening programs are needed to eliminate these inequities to prevent more cancers in FN women.

Associations between health-related fitness and quality of life in newly diagnosed breast cancer patients.

PURPOSE: Newly diagnosed breast cancer patients face substantial stress and uncertainty that may undermine their quality of life (QoL). The purpose of the present study was to examine the associations between health-related fitness (HRF) and QoL in newly diagnosed breast cancer patients from the Alberta Moving Beyond Breast Cancer Study. METHODS: Newly diagnosed breast cancer patients with early-stage disease (n = 1458) were recruited between 2012 and 2019 in Edmonton and Calgary, Canada to complete baseline HRF and QoL assessments within 90 days of diagnosis. HRF assessments included cardiorespiratory fitness (VO2peak treadmill test), muscular fitness (upper and lower body strength and endurance tests), and body composition (dual x-ray absorptiometry). QoL was assessed by the Medical Outcomes Study Short Form 36 (SF-36) version 2. We used logistic regression analyses to examine the associations between quartiles of HRF and poor/fair QoL (bottom 20%) after adjusting for key covariates. RESULTS: In multivariable analysis, the least fit groups compared to the most fit groups for relative upper body strength (OR = 3.19; 95% CI = 1.98-5.14), lean mass percentage (OR = 2.31; 95% CI = 1.37-3.89), and relative VO2peak (OR = 2.08; 95% CI = 1.21-3.57) were independently at a significantly higher risk of poor/fair physical QoL. No meaningful associations were found for mental QoL. CONCLUSIONS: The three main components of HRF (muscular fitness, cardiorespiratory fitness, and body composition) were independently associated with physical QoL in newly diagnosed breast cancer patients. Exercise interventions designed to improve these components of HRF may optimize physical QoL and help newly diagnosed breast cancer patients better prepare for treatments and recovery.

Plasma hPG80 (Circulating Progastrin) as a Novel Prognostic Biomarker for early-stage breast cancer in a breast cancer cohort.

BACKGROUND: Recurrence and metastases are still frequent outcomes after initial tumour control in women diagnosed with breast cancer. Although therapies are selected based on tumour characteristics measured at baseline, prognostic biomarkers can identify those at risk of poor outcomes. Circulating progastrin or hPG80 was found to be associated with survival outcomes in renal and hepatocellular carcinomas and was a plausible prognostic biomarker for breast cancer. METHODS: Women with incident breast cancers from Calgary, Alberta, Canada enrolled in the Breast to Bone (B2B) study between 2010 to 2016 and provided blood samples prior to any treatment initiation. Plasma from these baseline samples were analysed for circulating progastrin or hPG80. Participant characteristics as well as tumour ones were evaluated for their association with hPG80 and survival outcomes (time to recurrence, recurrence - free survival, breast cancer specific survival and overall survival) in Cox proportional hazards regression models. RESULTS: The 464 participants with measurable hPG80 in this study had an average age of 57.03 years (standard deviation of 11.17 years) and were predominantly diagnosed with Stage I (52.2%) and Stage II (40.1%) disease. A total of 50 recurrences and 50 deaths were recorded as of June 2022. In Cox PH regression models adjusted for chemotherapy, radiation therapy, cancer stage and age at diagnosis, log hPG80 (pmol/L) significantly increased the risks for recurrence (Hazard Ratio (HR) = 1.330, 95% Confidence Interval (CI) = (0.995 - 1.777, p = 0.054)), recurrence-free survival (HR = 1.399, 95% CI = (1.106 - 1.770), p = 0.005) and overall survival (HR = 1.385, 95% CI = (1.046 - 1.834), = 0.023) but not for breast cancer specific survival (HR = 1.015, 95% CI = (0.684 - 1.505), p = 0.942). CONCLUSIONS: hPG80 levels measured at diagnosis were significantly associated with the risk of recurrence or death from any cause in women with breast cancer. Since the recurrence rates of breast cancer are still relatively high amongst women diagnosed at an early stage, identifying women at high risk of recurrence at their time of diagnosis is important. hPG80 is a promising new prognostic biomarker that could improve the identification of women at higher risk of poor outcomes.

The Alberta moving beyond breast cancer (AMBER) cohort study: baseline description of the full cohort.

PURPOSE: The Alberta Moving Beyond Breast Cancer (AMBER) Study is an ongoing prospective cohort study investigating how direct measures of physical activity (PA), sedentary behavior (SB), and health-related fitness (HRF) are associated with survival after breast cancer. METHODS: Women in Alberta with newly diagnosed stage I (≥ T1c) to IIIc breast cancer were recruited between 2012 and 2019. Baseline assessments were completed within 90 days of surgery. Measurements included accelerometers to measure PA and SB; a graded treadmill test with gas exchange analysis to measure cardiorespiratory fitness (VO2peak); upper and lower body muscular strength and endurance; dual-X-ray absorptiometry to measure body composition; and questionnaires to measure self-reported PA and SB. RESULTS: At baseline, the 1528 participants' mean age was 56 ± 11 years, 59% were post-menopausal, 62% had overweight/obesity, and 55% were diagnosed with stage II or III disease. Based on device measurements, study participants spent 8.9 ± 1.7 h/day sedentary, 4.4 ± 1.2 h/day in light-intensity activity, 0.9 ± 0.5 h/day in moderate-intensity activity, and 0.2 ± 0.2 h/day in vigorous-intensity activity. For those participants who reached VO2peak, the average aerobic fitness level was 26.6 ± 6 ml/kg/min. Average body fat was 43 ± 7.1%. CONCLUSION: We have established a unique cohort of breast cancer survivors with a wealth of data on PA, SB, and HRF obtained through both direct and self-reported measurements. Study participants are being followed for at least ten years to assess all outcomes after breast cancer. These data will inform clinical and public health guidelines on PA, SB, and HRF for improving breast cancer outcomes.

Health-Related and Behavioral Factors Associated With Lung Cancer Stage at Diagnosis: Observations From Alberta's Tomorrow Project.

BACKGROUND: Lung cancer is the leading cause of cancer death in Canada, with stage at diagnosis among the top predictors of lung cancer survival. Identifying factors associated with stage at diagnosis can help reduce lung cancer morbidity and mortality. This study used data from a prospective cohort study of adults living in Alberta, Canada to examine factors associated with lung cancer stage at diagnosis. METHODS: This cohort study used data from adults aged 35-69 years enrolled in Alberta's Tomorrow Project. Partial Proportional Odds models were used to examine associations between sociodemographic characteristics and health-related factors and subsequent lung cancer stage at diagnosis. RESULTS: A total of 221 participants (88 males and 133 females) developed lung cancer over the study period. Nearly half (48.0%) of lung cancers were diagnosed at a late stage (stage IV), whereas 30.8 % and 21.3% were diagnosed at stage I/II and III, respectively. History of sunburn in the past year was protective against late-stage lung cancer diagnosis (odds ratio (OR) .40, P=.005). In males, a higher number of lifetime prostate specific antigen tests was associated with reduced odds of late-stage lung cancer diagnosis (odds ratio .66, P=.02). Total recreational physical activity was associated with increased odds of late-stage lung cancer diagnosis (OR 1.08, P=.01). DISCUSSION: Lung cancer stage at diagnosis remains a crucial determinant of prognosis. This study identified important factors associated with lung cancer stage at diagnosis. Study findings can inform targeted cancer prevention initiatives towards improving early detection of lung cancer and lung cancer survival.

Evidence to Support Change of Clinical Pathway Following Colposcopy Treatment for Cervical Intraepithelial Neoplasia in Canada.

OBJECTIVES: Human papillomavirus (HPV) testing can be incorporated into the post-treatment pathway of cervical intraepithelial neoplasia (CIN) to confirm disease-free status. To inform a post-treatment strategy based on risk of recurrence, we modelled disease and economic outcomes. METHODS: The current Alberta, Canada, post-treatment care pathway-cytology testing with colposcopy assessment-was compared with 6 other scenarios incorporating cytology, HPV testing, or both tests at different time points in a modelling study based on a microsimulation program. Input parameter values for the screening participation, screening age groups, and follow-up options and test compliance for HPV, cytology, and colposcopy were varied, based on Alberta cervical cancer screening program data. Health outcomes over the short- and long-term were projected, which incorporated the increasing population-level coverage of HPV vaccination. Lifetime incremental cost-effectiveness ratios (ICERs) were used to evaluate economic outcomes and descriptive statistics compared with numbers of tests, visits, and procedures as well as changes in incidence and mortality rates between the scenarios. RESULTS: At 5 years after implementation of the "HPV testing alone at 6 and 18 months" post-treatment pathway, the number of colposcopies dropped by 36% and the number of pre-cancer treatments, by 6%. Lifetime ICERs were CAD $6170 versus $248,495 per quality-adjusted life-year compared with the status quo pathway. Cervical cancer incidence and mortality rates decreased significantly and similarly in all scenarios. CONCLUSION: Strategies that involve HPV testing in CIN post-treatment follow-up care are expected to be more cost effective with improved clinical outcomes than traditional cytology and colposcopy-based follow-up.

FamEvent: An R Package for Generating and Modeling Time-to-Event Data in Family Designs.

FamEvent is a comprehensive R package for simulating and modelling age-at-disease onset in families carrying a rare gene mutation. The package can simulate complex family data for variable time-to-event outcomes under three common family study designs (population, high-risk clinic and multi-stage) with various levels of missing genetic information among family members. Residual familial correlation can be induced through the inclusion of a frailty term or a second gene. Disease-gene carrier probabilities are evaluated assuming Mendelian transmission or empirically from the data. When genetic information on the disease gene is missing, an Expectation-Maximization algorithm is employed to calculate the carrier probabilities. Penetrance model functions with ascertainment correction adapted to the sampling design provide age-specific cumulative disease risks by sex, mutation status, and other covariates for simulated data as well as real data analysis. Robust standard errors and 95% confidence intervals are available for these estimates. Plots of pedigrees and penetrance functions based on the fitted model provide graphical displays to evaluate and summarize the models.

Novel Allosteric Pathway of Eg5 Regulation Identified through Multivariate Statistical Analysis of Hydrogen-Exchange Mass Spectrometry (HX-MS) Ligand Screening Data.

The mitotic kinesin Eg5 is an important target in cancer chemotherapy. A structurally diverse collection of canonical loop L5 inhibitors engage an allosteric pathway that includes elements of its microtubule binding region. However, recent evidence suggests that Eg5 may permit alternative allosteric mechanisms. Terpendole E, a natural-product Eg5 inhibitor, is active against mutants resistant to canonical loop L5 inhibitors and appears to offer a unique mode of inhibition. To investigate the variety of inhibitor responses, the structure-function properties of eighteen kinesin inhibitors were quantified with hydrogen-exchange mass spectrometry (HX-MS), functional analysis and molecular modeling. A unique strategy for high-density data analysis was implemented, based on a scalable multivariate statistical method, as current HX-MS routines have a limited capacity to guide a characterization of ligands when additional functional data is available. Inhibitor evaluation was achieved using orthogonal partial least squares projection to latent structures discriminant analysis (OPLS-DA). The strategy generated a model that identified functionally-significant conformational elements involved in kinesin inhibition, confirming the canonical allosteric pathway and identifying a novel response pathway. Terpendole E is demonstrated to be an atypical L5 site inhibitor, where binding induces an allosteric effect mediated by a destabilization in the ß-sheet core of the molecular motor, an element involved in mechanochemical coupling for structurally-related kinesins. The analysis suggests that a different approach to inhibitor development may be fruitful.

Post-diagnosis alcohol intake and prostate cancer survival: A population-based cohort study.

Alcohol consumption has been declared a Group 1 carcinogen by the International Agency for Research on Cancer (IARC) and is a potential risk factor for several types of cancer mortality. However, evidence for an association with prostate cancer survival remains inconsistent. We examined how alcohol consumption post-diagnosis was associated with survival after prostate cancer diagnosis. Men diagnosed with prostate cancer (n = 829) in Alberta, Canada between the years 1997 and 2000 were recruited into a population-based case-control study and then followed for up to 19 years for survival outcomes. Pre- and post-diagnosis alcohol consumption, clinical characteristics and lifestyle factors were collected through in-person interviews shortly after diagnosis and again 2-3 years post-diagnosis. Cox proportional hazards were used to examine how post-diagnosis alcohol consumption was associated with all-cause and prostate cancer-specific mortality (competing risk analysis too), in addition to first recurrence/progression or new primary cancer. Most participants reported drinking alcohol (≥once a month for 6 months) post-diagnosis (n = 589, 71.0%). Exceeding Canadian Cancer Society (CCS) alcohol consumption recommendations (≥2 drinks/day) post-diagnosis was associated with prostate cancer-specific mortality relative to non-drinkers (aHR: 1.82, 95% CI: 1.07-3.10) with borderline evidence of a linear trend. Interestingly, those in the highest quartile of drinks/week pre- and post-diagnosis also had a twofold increase for prostate-specific mortality (aHR: 2.67, 95% CI: 1.28-5.56) while controlling for competing risks. Our results support post-diagnosis alcohol consumption was associated with increased mortality after prostate cancer diagnosis, specifically for prostate cancer-related death. Future studies focused on confirming this burden of disease are warranted.

Anthropometric measurements and survival after a prostate cancer diagnosis.

BACKGROUND: Evidence regarding the role of anthropometrics in prostate cancer survival is inconsistent. We examined the associations between anthropometric measures and survival outcomes. METHODS: Men diagnosed with prostate cancer (n=987) were recruited into a population-based case-control study between 1997 and 2000 then a prospective cohort study between 2000 and 2002 where anthropometric measurements (weight, height, body mass index, waist circumference, waist-hip ratio) were taken and participants were followed up to 19 years for survival outcomes. Cox proportional hazards were used to examine these associations. RESULTS: Survival analyses suggested no clear pattern of associations between post-diagnosis anthropometric measurements and all-cause mortality, prostate-specific mortality, first recurrence/progression or new primary cancer. CONCLUSIONS: We did not find a significant trend relating anthropometrics to survival outcomes after prostate cancer diagnosis. Continued assessment of objective measurements of body composition over the life-course is warranted to determine true associations between anthropometrics and survival after prostate cancer.

A quantitative multimodal metabolomic assay for colorectal cancer.

BACKGROUND: Early diagnosis of colorectal cancer (CRC) simplifies treatment and improves treatment outcomes. We previously described a diagnostic metabolomic biomarker derived from semi-quantitative gas chromatography-mass spectrometry. Our objective was to determine whether a quantitative assay of additional metabolomic features, including parts of the lipidome could enhance diagnostic power; and whether there was an advantage to deriving a combined diagnostic signature with a broader metabolomic representation. METHODS: The well-characterized Biocrates P150 kit was used to quantify 163 metabolites in patients with CRC (N = 62), adenoma (N = 31), and age- and gender-matched disease-free controls (N = 81). Metabolites included in the analysis included phosphatidylcholines, sphingomyelins, acylcarnitines, and amino acids. Using a training set of 32 CRC and 21 disease-free controls, a multivariate metabolomic orthogonal partial least squares (OPLS) classifier was developed. An independent set of 28 CRC and 20 matched healthy controls was used for validation. Features characterizing 31 colorectal adenomas from their healthy matched controls were also explored, and a multivariate OPLS classifier for colorectal adenoma could be proposed. RESULTS: The metabolomic profile that distinguished CRC from controls consisted of 48 metabolites (R2Y = 0.83, Q2Y = 0.75, CV-ANOVA p-value < 0.00001). In this quantitative assay, the coefficient of variance for each metabolite was <10%, and this dramatically enhanced the separation of these groups. Independent validation resulted in AUROC of 0.98 (95% CI, 0.93-1.00) and sensitivity and specificity of 93% and 95%. Similarly, we were able to distinguish adenoma from controls (R2Y = 0.30, Q2Y = 0.20, CV-ANOVA p-value = 0.01; internal AUROC = 0.82 (95% CI, 0.72-0.93)). When combined with the previously generated GC-MS signatures for CRC and adenoma, the candidate biomarker performance improved slightly. CONCLUSION: The diagnostic power for metabolomic tests for colorectal neoplasia can be improved by utilizing a multimodal approach and combining metabolites from diverse chemical classes. In addition, quantification of metabolites enhances separation of disease-specific metabolomic profiles. Our future efforts will be focused on developing a quantitative assay for the metabolites comprising the optimal diagnostic biomarker.

Identification and prediction of health-related quality of life trajectories after a prostate cancer diagnosis.

The aim of our study was to identify physical and mental health-related quality of life (HRQoL) trajectories after a prostate cancer diagnosis and systematically characterize trajectories by behaviours and prognostic factors. Prostate cancer survivors (n = 817) diagnosed between 1997 and 2000 were recruited between 2000 and 2002 into a prospective repeated measurements study. Behavioural/prognostic data were collected through in-person interviews and questionnaires. HRQoL was collected at three post-diagnosis time-points, approximately 2 years apart using the Short Form (SF)-36 validated questionnaire. To identify physical and mental HRQoL trajectories, group-based trajectory modelling was undertaken. Differences between groups were evaluated by assessing influential dropouts (mortality/poor health), behavioural/prognostic factors at diagnosis or during the follow-up. Three trajectories of physical HRQoL were identified including: average-maintaining HRQoL (32.2%), low-declining HRQoL (40.5%) and very low-maintaining HRQoL (27.3%). In addition, three trajectories for mental HRQoL were identified: average-increasing HRQoL (66.5%), above average-declining HRQoL (19.7%) and low-increasing HRQoL (13.8%). In both physical and mental HRQoL, dropout from mortality/poor health differed between trajectories, thus confirming HRQoL and mortality were related. Furthermore, increased Charlson comorbidity index score was consistently associated with physical and mental HRQoL group membership relative to average maintaining groups, while behaviours such as time-varying physical activity was associated with physical HRQoL trajectories but not mental HRQoL trajectories. It was possible to define three trajectories of physical and mental HRQoL after prostate cancer. These data provide insights regarding means for identifying subgroups of prostate cancer survivors with lower or declining HRQoL after diagnosis whom could be targeted for interventions aimed at improving HRQoL.

A validated metabolomic signature for colorectal cancer: exploration of the clinical value of metabolomics.

BACKGROUND: Timely diagnosis and classification of colorectal cancer (CRC) are hindered by unsatisfactory clinical assays. Our aim was to construct a blood-based biomarker series using a single assay, suitable for CRC detection, prognostication and staging. METHODS: Serum metabolomic profiles of adenoma (N=31), various stages of CRC (N=320) and healthy matched controls (N=254) were analysed by gas chromatography-mass spectrometry (GC-MS). A diagnostic model for CRC was derived by orthogonal partial least squares-discriminant analysis (OPLS-DA) on a training set, and then validated on an independent data set. Metabolomic models suitable for identifying adenoma, poor prognosis stage II CRC and discriminating various stages were generated. RESULTS: A diagnostic signature for CRC with remarkable multivariate performance (R(2)Y=0.46, Q(2)Y=0.39) was constructed, and then validated (sensitivity 85%; specificity 86%). Area under the receiver-operating characteristic curve was 0.91 (95% CI, 0.87-0.96). Adenomas were also detectable (R(2)Y=0.35, Q(2)Y=0.26, internal AUROC=0.81, 95% CI, 0.70-0.92). Also of particular interest, we identified models that stratified stage II by prognosis, and classified cases by stage. CONCLUSIONS: Using a single assay system, a suite of CRC biomarkers based on circulating metabolites enables early detection, prognostication and preliminary staging information. External population-based studies are required to evaluate the repeatability of our findings and to assess the clinical benefits of these biomarkers.

The Sedentary Time and Activity Reporting Questionnaire (STAR-Q): reliability and validity against doubly labeled water and 7-day activity diaries.

We determined measurement properties of the Sedentary Time and Activity Reporting Questionnaire (STAR-Q), which was designed to estimate past-month activity energy expenditure (AEE). STAR-Q validity and reliability were assessed in 102 adults in Alberta, Canada (2009-2011), who completed 14-day doubly labeled water (DLW) protocols, 7-day activity diaries on day 15, and the STAR-Q on day 14 and again at 3 and 6 months. Three-month reliability was substantial for total energy expenditure (TEE) and AEE (intraclass correlation coefficients of 0.84 and 0.73, respectively), while 6-month reliability was moderate. STAR-Q-derived TEE and AEE were moderately correlated with DLW estimates (Spearman's ρs of 0.53 and 0.40, respectively; P < 0.001), and on average, the STAR-Q overestimated TEE and AEE (median differences were 367 kcal/day and 293 kcal/day, respectively). Body mass index-, age-, sex-, and season-adjusted concordance correlation coefficients (CCCs) were 0.24 (95% confidence interval (CI): 0.07, 0.36) and 0.21 (95% CI: 0.11, 0.32) for STAR-Q-derived versus DLW-derived TEE and AEE, respectively. Agreement between the diaries and STAR-Q (metabolic equivalent-hours/day) was strongest for occupational sedentary time (adjusted CCC = 0.76, 95% CI: 0.64, 0.85) and overall strenuous activity (adjusted CCC = 0.64, 95% CI: 0.49, 0.76). The STAR-Q demonstrated substantial validity for estimating occupational sedentary time and strenuous activity and fair validity for ranking individuals by AEE.

Identification of prognostic inflammatory factors in colorectal liver metastases.

BACKGROUND: The modified Glasgow Prognostic Score (mGPS) has been reported to be an important prognostic indicator in a number of tumor types, including colorectal cancer (CRC). The features of the inflammatory state thought to accompany elevated C-reactive protein (CRP), a key feature of mGPS, were characterized in patients with colorectal liver metastases. Additional inflammatory mediators that contribute to prognosis were explored. METHODS: In sera from 69 patients with colorectal liver metastases, a panel of 42 inflammatory mediators were quantified as a function of CRP levels, and as a function of disease-free survival. Multivariate statistical methods were used to determine association of each mediator with elevated CRP and truncated disease-free survival. RESULTS: Elevated CRP was confirmed to be a strong predictor of survival (HR 4.00, p = 0.001) and recurrence (HR 3.30, p = 0.002). The inflammatory state associated with elevated CRP was comprised of raised IL-1ß, IL-6, IL-12 and IL-15. In addition, elevated IL-8 and PDGF-AB/BB and decreased eotaxin and IP-10 were associated with worse disease-free and overall survival. CONCLUSIONS: Elevated CRP is associated with a proinflammatory state. The inflammatory state is an important prognostic indicator in CRC liver metastases. The individual contributions of tumor biology and the host to this inflammatory response will require further investigation.

Estimating successive cancer risks in Lynch Syndrome families using a progressive three-state model.

Lynch Syndrome (LS) families harbor mutated mismatch repair genes,which predispose them to specific types of cancer. Because individuals within LS families can experience multiple cancers over their lifetime, we developed a progressive three-state model to estimate the disease risk from a healthy (state 0) to a first cancer (state 1) and then to a second cancer (state 2). Ascertainment correction of the likelihood was made to adjust for complex sampling designs with carrier probabilities for family members with missing genotype information estimated using their family's observed genotype and phenotype information in a one-step expectation-maximization algorithm. A sandwich variance estimator was employed to overcome possible model misspecification. The main objective of this paper is to estimate the disease risk (penetrance) for age at a second cancer after someone has experienced a first cancer that is also associated with a mutated gene. Simulation study results indicate that our approach generally provides unbiased risk estimates and low root mean squared errors across different family study designs, proportions of missing genotypes, and risk heterogeneities. An application to 12 large LS families from Newfoundland demonstrates that the risk for a second cancer was substantial and that the age at a first colorectal cancer significantly impacted the age at any LS subsequent cancer. This study provides new insights for developing more effective management of mutation carriers in LS families by providing more accurate multiple cancer risk estimates.

Stage Shifting by Modifying the Determinants of Breast Cancer Stage at Diagnosis: A Simulation Study.

BACKGROUND: Breast cancer is the most common cancer in Canadian women; nearly 25% of women diagnosed with cancer have breast cancer. The early detection of breast cancer is a major challenge because tumours often grow without causing symptom. The diagnosis of breast cancer at an early stage (stages I and II) improves survival outcomes because treatments are more effective and better tolerated. To better inform the prevention of and screening for breast cancer, simulations using modifiable rather than non-modifiable risk factors may be helpful in shifting the stage at diagnosis downward. METHODS: Breast cancer stages were simulated using the data distributions from Alberta's Tomorrow Project participants who developed breast cancer. Using multivariable partial proportional odds regression models, modifiable lifestyle factors associated with the stage of cancer at diagnosis were evaluated. The proportions or mean levels of these lifestyle factors in the simulated population were systematically changed, then multiplied by their corresponding estimated odds ratios from the real data example. The effects of these changes were evaluated singly as well as cumulatively. RESULTS: Increasing total dietary protein (g/day) intake was the single most important lifestyle factor in shifting the breast cancer stage downwards followed by decreasing total dietary energy intake (kcal/day). Increasing the proportion of women who spend time in the sun between 11 am and 4 pm in the summer months, who have had a mammogram, who have been pregnant or reducing the proportion who are in stressful situations had much smaller effects. The percentage of Stage I diagnoses could be increased by approximately 12% with small modifications of these lifestyle factors. CONCLUSION: Shifting the breast cancer stage at diagnosis of a population may be achieved through changes to lifestyle factors. This proof of principle study that evaluated multiple factors associated with the stage at diagnosis in a population can be expanded to other cancers as well, providing opportunities for cancer prevention programs to target specific factors and identify populations at higher risk.

Case-control study of lifetime alcohol intake and prostate cancer risk.

PURPOSE: Alcohol consumption may be a modifiable risk factor for prostate cancer, but previous results have been inconsistent and limited by a lack of data on lifetime exposure and specific beverages. Furthermore, the effect of tumor stage and severity of disease on the association between alcohol and prostate cancer risk has not been fully investigated. METHODS: We examined the relation between both current and lifetime alcohol intake and prostate cancer risk in a population-based case-control study in Alberta, Canada with 947 cases with stage T2 and higher prostate cancer diagnosed between 1997 and 2000 and frequency matched to 1,039 controls, identified through random digit dialing. Cases were classified on cancer stage and severity into 619 non-aggressive (Stage II and Gleason score <8) and 328 aggressive cases (Stage III/IV or Gleason score ≥8). In-person interviews were completed on current and lifetime history of alcohol consumption and all other prostate cancer risk factors. RESULTS: Current alcohol intake did not increase prostate cancer risk but lifetime intake increased risk for both non-aggressive and aggressive cases, with an odds ratio of 1.78 (95 % CI 1.19-2.66) and 2.00 (95 % CI 1.19-3.36), respectively, for the highest intake quartile compared to non-drinkers with evidence for a linear trend. Associations with alcohol intake remained after exclusion of non-drinkers for non-aggressive prostate cancer cases. Only lifetime beer intake was significantly associated with increased risk, however, intakes of liquor and wine by participants were low. CONCLUSIONS: Results support the evidence for an increased risk of prostate cancer from lifetime alcohol consumption.