Relative Efficacies of Interventions to Improve the Quality of Screening-Related Colonoscopy: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND & AIMS: Significant variability exists in colonoscopy quality indicators, including adenoma detection rate (ADR). We synthesized evidence from randomized trials in a network meta-analysis on interventions to improve colonoscopy quality. METHODS: We included trials from database inceptions to September 25, 2023, of patients undergoing screening-related colonoscopy and presented efficacies of interventions within domains (periprocedural parameters, endoscopist-directed interventions, intraprocedural techniques, endoscopic technologies, distal attachment devices, and additive substances) compared to standard colonoscopy. The primary outcome was ADR. We used a Bayesian random-effects model using Markov-chain Monte Carlo simulation, with 10,000 burn-ins and 100,000 iterations. We calculated odds ratios with 95% credible intervals and present surface under the cumulative ranking (SUCRA) curves. RESULTS: We included 124 trials evaluating 37 interventions for the primary outcome. Nine interventions resulted in statistically significant improvements in ADR compared to standard colonoscopy (9-minute withdrawal time, dual observation, water exchange, i-SCAN [Pentax Ltd], linked color imaging, computer-aided detection, Endocuff [Olympus Corp], Endocuff Vision [Olympus Corp], and oral methylene blue). Dual observation (SUCRA, 0.84) and water exchange (SUCRA, 0.78) ranked highest among intraprocedural techniques; i-SCAN (SUCRA, 0.95), linked color imaging (SUCRA, 0.85), and computer-aided detection (SUCRA, 0.78) among endoscopic technologies; WingCap (A&A Medical Supply LLC) (SUCRA, 0.87) and Endocuff (SUCRA, 0.85) among distal attachment devices and oral methylene blue (SUCRA, 0.94) among additive substances. No interventions improved detection of advanced adenomas, and only narrow-band imaging improved detection of serrated lesions (odds ratio, 2.94; 95% credible interval, 1.46-6.25). CONCLUSIONS: Several interventions are effective in improving adenoma detection and overall colonoscopy quality, many of which are cost-free. These results can inform endoscopists, unit managers, and endoscopy societies on relative efficacies.

The association between neighborhood-level income and cancer stage at diagnosis and survival in Alberta.

BACKGROUND: Socioeconomic status (SES) is associated with a range of health outcomes, including cancer diagnosis and survival. However, the evidence for this association is inconsistent between countries with and without single-payer health care systems. In this study, the relationships between neighborhood-level income, cancer stage at diagnosis, and cancer-specific mortality in Alberta, Canada, were evaluated. METHODS: The Alberta Cancer Registry was used to identify all primary cancer diagnoses between 2010 and 2020. Average neighborhood income was determined by linking the Canadian census to postal codes and was categorized into quintiles on the basis of income distribution in Alberta. Multivariable multinomial logistic regression was used to model the association between income quintile and stage at diagnosis, and the Fine-Gray proportional subdistribution hazards model was used to estimate the association between SES and cancer-specific mortality. RESULTS: Out of the 143,818 patients with cancer included in the study, those in lower income quintiles were significantly more likely to be diagnosed at stage III (odds ratio [OR], 1.07; 95% CI [confidence interval], 1.06-1.09) or IV (OR, 1.12; 95% CI, 1.11-1.14) after adjusting for age and sex. Lower income quintiles also had significantly worse cancer-specific survival for breast, colorectal, liver, lung, non-Hodgkin lymphoma, oral cavity, pancreas, and prostate cancers. CONCLUSIONS: Disparities were observed in cancer outcomes across neighborhood-level income groups in Alberta, which demonstrates that health inequities by SES exist in countries with single-payer health care systems. Further research is needed to better understand the underlying causes and to develop strategies to mitigate these disparities.

Next Generation Weight Loss Drugs for the Prevention of Cancer?

Background: Western populations are losing the battle over healthy weight management, and excess body weight is a notable cancer risk factor at the population level. There is ongoing interest in pharmacological interventions aimed at promoting weight loss, including GLP-1 receptor agonists (GLP-1RA), which may be a useful tool to stem the rising tide of obesity-related cancers. Purpose: To investigate the potential of next generation weight loss drugs (NGWLD) like GLP-1RA in population-level chemoprevention.Research Design: We used the OncoSim microsimulation tool to estimate the population-level reductions in obesity and the potentially avoidable obesity-related cancers in Canada over the next 25 years.Results: We estimated a total of 71 281 preventable cancers by 2049, with 36 235 and 35 046 cancers prevented for females and males, respectively. Among the 327 254 total projected cancer cases in 2049, 1.3% are estimated to be preventable through intervention with NGWLD.Conclusions: Pharmacologic intervention is not the ideal solution for the obesity-related cancer crisis. However, these agents and subsequent generations provide an additional tool to rapidly reduce body weight and adiposity in populations that have been extremely challenging to reduce weight with standard diet and exercise approaches. Additional research is needed around approaches to prevent initial weight gain and maintain long-term weight loss.

Development and Validation of a Prognostic Risk Model for Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Risk stratification tools for patients with advanced melanoma (AM) treated with immune checkpoint inhibitors (ICI) are lacking. We identified a new prognostic model associated with overall survival (OS). PATIENTS AND METHODS: A total of 318 treatment naïve patients with AM receiving ICI were collected from a multi-centre retrospective cohort study. LASSO Cox regression identified independent prognostic factors associated with OS. Model validation was carried out on 500 iterations of bootstrapped samples. Harrel's C-index was calculated and internally validated to outline the model's discriminatory performance. External validation was carried out in 142 advanced melanoma patients receiving ICI in later lines. RESULTS: High white blood cell count (WBC), high lactate dehydrogenase (LDH), low albumin, Eastern Cooperative Oncology Group (ECOG) performance status ≥1, and the presence of liver metastases were included in the model. Patients were parsed into 3 risk groups: favorable (0-1 factors) OS of 52.9 months, intermediate (2-3 factors) OS 13.0 months, and poor (≥4 factors) OS 2.7 months. The C-index of the model from the discovery cohort was 0.69. External validation in later-lines (N = 142) of therapy demonstrated a c-index of 0.65. CONCLUSIONS: Liver metastases, low albumin, high LDH, high WBC, and ECOG≥1 can be combined into a prognostic model for AM patients treated with ICI.

American Society for Gastrointestinal Endoscopy guideline on endoscopic submucosal dissection for the management of early esophageal and gastric cancers: methodology and review of evidence.

This document from the American Society for Gastrointestinal Endoscopy (ASGE) provides a full description of the methodology used in the review of the evidence used to inform the final guidance outlined in the accompanying Summary and Recommendations document regarding the role of endoscopic submucosal dissection (ESD) in the management of early esophageal and gastric cancers. This guideline used the Grading of Recommendations, Assessment, Development and Evaluation framework and specifically addresses the role of ESD versus EMR and/or surgery, where applicable, for the management of early esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric adenocarcinoma (GAC) and their corresponding precursor lesions. For ESCC, the ASGE suggests ESD over EMR for patients with early-stage, well-differentiated, nonulcerated cancer >15 mm, whereas in patients with similar lesions ≤15 mm, the ASGE suggests either ESD or EMR. The ASGE suggests against surgery for such patients with ESCC, whenever possible. For EAC, the ASGE suggests ESD over EMR for patients with early-stage, well-differentiated, nonulcerated cancer >20 mm, whereas in patients with similar lesions measuring ≤20 mm, the ASGE suggests either ESD or EMR. For GAC, the ASGE suggests ESD over EMR for patients with early-stage, well or moderately differentiated, nonulcerated intestinal type cancer measuring 20 to 30 mm, whereas for patients with similar lesions <20 mm, the ASGE suggests either ESD or EMR. The ASGE suggests against surgery for patients with such lesions measuring ≤30 mm, whereas for lesions that are poorly differentiated, regardless of size, the ASGE suggests surgical evaluation over endosic approaches.

Long-term projections of cancer incidence and mortality in Canada: The OncoSim All Cancers Model.

Using the OncoSim All Cancers Model, we estimated the annual cancer incidence, mortality and cancer management costs in Canada from 2020 to 2040. Incidence for each cancer type was estimated from logistic regression analyses of the Canadian Cancer Registry (1992-2017), with province/territory, sex, five-year age groups and year as covariates. Deaths were estimated by sex and tumour site for cancers diagnosed between 2000 and 2017 (deaths to the end of 2017). The total cost of a cancer type was the sum of costs for individuals across four phases of cancer care. The projections presented in this study were generated based on a simulation of 32 million cases. The OncoSim All Cancers Model projects a 40% increase in the overall number of incident cancer cases from 2020 to 2040. The number of the four most commonly diagnosed cancers in Canada (breast, colorectal, lung, and prostate) are projected to increase annually. The overall number of cancer deaths is projected to increase by 44% from 2020 to 2040. More cancer deaths are projected in males than in females. The age-standardized mortality rate is expected to remain relatively stable over time. Overall cancer management costs are projected to increase from $20.6B in 2020 to $31.4B in 2040. Due mainly to an aging population and population growth in Canada, we estimate that cancer incidence, mortality and cancer management costs will increase considerably between 2020 and 2040. These results highlight the importance of planning for increasing investment and capacity in cancer control.

Impact of the COVID-19 pandemic on cancer diagnoses, stage and survival in Alberta.

BACKGROUND: The COVID-19 pandemic is suspected to have affected cancer care and outcomes among patients in Canada. In this study, we evaluated the impact of the state of emergency period during the COVID-19 pandemic (Mar. 17 to June 15, 2020) on cancer diagnoses, stage at diagnosis and 1-year survival in Alberta. METHODS: We included new diagnoses of the 10 most prevalent cancer types from Jan. 1, 2018, to Dec. 31, 2020. We followed patients up to Dec. 31, 2021. We used interrupted time series analysis to examine the impact of the first COVID-19-related state of emergency in Alberta on the number of cancer diagnoses. We used multivariable Cox regression to compare 1-year survival of the patients who received a diagnosis during 2020 after the state of emergency with those who received a diagnosis during 2018 and 2019. We also performed stage-specific analyses. RESULTS: We observed significant reductions in diagnoses of breast cancer (incidence rate ratio [IRR] 0.67, 95% confidence interval [CI] 0.59-0.76), prostate cancer (IRR 0.64, 95% CI 0.56-0.73) and colorectal cancer (IRR 0.64, 95% CI 0.56- 0.74) and melanoma (IRR 0.57, 95% CI 0.47-0.69) during the state of emergency period compared with the period before it. These decreases largely occurred among early-stage rather than late-stage diagnoses. Patients who received a diagnosis of colorectal cancer, non-Hodgkin lymphoma and uterine cancer in 2020 had lower 1-year survival than those diagnosed in 2018; no other cancer sites had lower survival. INTERPRETATION: The results from our analyses suggest that health care disruptions during the COVID-19 pandemic in Alberta considerably affected cancer outcomes. Given that the largest impact was observed among early-stage cancers and those with organized screening programs, additional system capacity may be needed to mitigate future impact.

Association Between Endoscopist Specialty and Colonoscopy Quality: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Colonoscopy quality indicators provide measurable assessments of performance, but significant provider-level variations exist. We performed a systematic review and meta-analysis to assess whether endoscopist specialty is associated with adenoma detection rate (ADR) - the primary outcome - or cecal intubation rate, adverse event rates, and post-colonoscopy colorectal cancer rates. METHODS: We searched EMBASE, Google Scholar, MEDLINE, and the Cochrane Central Registry of Controlled Trials from inception to December 14, 2020. Two reviewers independently screened titles and abstracts. Citations underwent duplicate full-text review, with disagreements resolved by a third reviewer. Data were abstracted in duplicate. The DerSimonian and Laird random effects model was used to calculate pooled odds ratios (ORs) with respective 95% confidence intervals (CIs). Risk of bias was assessed using Risk of Bias in Non-randomised Studies of Interventions. RESULTS: Of 11,314 citations, 36 studies representing 3,500,832 colonoscopies were included. Compared with colonoscopies performed by gastroenterologists, those by surgeons were associated with lower ADRs (OR, 0.81; 95% CI, 0.74-0.88) and lower cecal intubation rates (OR, 0.76; 95% CI, 0.63-0.92). Compared with colonoscopies performed by gastroenterologists, those by other (non-gastroenterologist, non-surgeon) endoscopists were associated with lower ADRs (OR, 0.91; 95% CI, 0.87-0.96), higher perforation rates (OR, 3.02; 95% CI, 1.65-5.51), and higher post-colonoscopy colorectal cancer rates (OR, 1.23; 95% CI, 1.14-1.33). Substantial to considerable heterogeneity existed for most analyses, and overall certainty in the evidence was low according to the Grading of Recommendations, Assessment, Development, and Evaluations framework. CONCLUSION: Colonoscopies performed by surgeons or other endoscopists were associated with poorer quality metrics and outcomes compared with those performed by gastroenterologists. Targeted quality improvement efforts may be warranted.

Early-Onset Colorectal Cancer Incidence, Staging, and Mortality in Canada: Implications for Population-Based Screening.

INTRODUCTION: The incidence of early-onset colorectal cancer (eoCRC) has been increasing in North America. Debate remains as to whether the trends by topography, histology, stage, or mortality in this population are amenable to intervention from screening. METHODS: CRC incidence (2000-2017) and mortality (2000-2018) data were obtained from the Canadian Cancer Registry and Vital Statistics. Annual percentage changes (APC) in the incidence (topography and histology) and mortality of eoCRC were estimated using joinpoint regression. Incidence of late-stage CRC (III or IV) versus early-stage CRC (I or II) was compared between the eoCRC (age 20-49 years) and eligible screening (age 50-74 years) groups with Poisson regression. RESULTS: Among women aged 20-49 years, the incidence of CRC significantly increased from 2000 to 2017 in both the distal colon (APC = 1.40) and rectum (APC = 3.00), whereas for men aged 20-49 years, the CRC incidence increased in the proximal colon (APC = 1.10), distal colon (APC = 3.00), and rectum (APC = 3.70). Among both men and women aged 20-49 years, the incidence of nonmucinous adenocarcinomas significantly increased (APC: 1.90 and 2.30, respectively), whereas mucinous adenocarcinomas decreased for women (APC = -1.60) and remained stable for men. Adults aged 30 to 49 years, when diagnosed with CRC, had a significantly higher risk of being diagnosed with a late-stage CRC compared with those in the age group of 50-74 years. Rectal cancer mortality increased from 2000 to 2018 in the eoCRC group (APC for women and men 3.80 and 3.40, respectively). DISCUSSION: Emerging data support future modifications to guidelines on screening for eoCRC in Canada. Further research is required on the effect, cost-effectiveness, and risk prediction for targeted screening within this group.

Clip closure to prevent adverse events after EMR of proximal large nonpedunculated colorectal polyps: meta-analysis of individual patient data from randomized controlled trials.

BACKGROUND AND AIMS: After EMR, prophylactic clipping is often performed to prevent clinically significant post-EMR bleeding (CSPEB) and other adverse events (AEs). Prior evidence syntheses have lacked sufficient power to assess clipping in relevant subgroups or in nonbleeding AEs. We performed a meta-analysis of individual patient data (IPD) from randomized trials assessing the efficacy of clipping to prevent AEs after EMR of proximal large nonpedunculated colorectal polyps (LNPCPs) ≥20 mm. METHODS: We searched EMBASE, MEDLINE, Cochrane Central Registry of Controlled Trials, and PubMed from inception to May 19, 2021. Two reviewers screened citations in duplicate. Corresponding authors of eligible studies were invited to contribute IPD. A random-effects 1-stage model was specified for estimating pooled effects, adjusting for patient sex and age and for lesion location and size, whereas a fixed-effects model was used for traditional meta-analyses. RESULTS: From 3145 citations, 4 trials were included, representing 1248 patients with proximal LNPCPs. The overall rate of CSPEB was 3.5% and 9.0% in clipped and unclipped patients, respectively. IPD were available for 1150 patients, in which prophylactic clipping prevented CSPEB with an odds ratio (OR) of .31 (95% confidence interval [CI], .17-.54). Clipping was not associated with perforation or abdominal pain, with ORs of .78 (95% CI, .17-3.54) and .67 (95% CI, .20-2.22), respectively. CONCLUSIONS: Prophylactic clipping is efficacious in preventing CSPEB after EMR of proximal LNPCPs. Therefore, clip closure should be considered a standard component of EMR of LNPCPs in the proximal colon.

The efficacy of chemopreventive agents on the incidence of colorectal adenomas: A systematic review and network meta-analysis.

Colorectal cancer (CRC) is the fourth most common cancer and third leading cause of cancer-related death worldwide. Use of chemopreventive agents (CPAs) to reduce the incidence of precursor colorectal adenomas could lower the future burden of CRC. Many classes of potential CPAs have been investigated. To identify the most effective CPAs, we conducted a systematic review and a network meta-analysis (NMA). An electronic search was performed through August 2020 to identify all randomized controlled trials (RCTs) assessing the efficacy of CPAs in reducing the incidence of colorectal adenomas at the time of surveillance colonoscopy among patients who had previously undergone polypectomy during an index colonoscopy. In total, 33 RCTs were included in the NMA, which was conducted under a Bayesian inference framework. Random effects models were used with adjustment for follow-up length and control group event rates to yield relative risks (RRs) and 95% credible intervals (CrIs). Our full network consisted of 13 interventions in addition to a placebo arm. Of 20,925 included patients, 7766 had an adenoma. Compared to placebo, the combination of difluoromethylornithine (DFMO) + Sulindac (RR 0.24, CrI 0.10-0.55) demonstrated a protective effect, while aspirin had a RR of 0.77 (CrI 0.60-1.00), celecoxib 800 mg had a RR of 0.56 (CrI 0.31-1.01) and metformin had a RR of 0.56 (CrI 0.22-1.39). Our results suggest that select CPAs may be efficacious in preventing the development of adenomas. Further studies are needed to identify those patients most likely to benefit and the minimum effective dosages of CPAs.

Long-term Use of Hormone Replacement Therapy is Associated With a Lower Risk of Developing High-risk Serrated Polyps in Women.

GOALS/BACKGROUND: Hormone replacement therapy (HRT) and parity have been suggested protective factors against the development of colorectal polyps. However, there are a limited number of studies that have examined the relationship of these factors with high-risk adenomatous polyps (HRAP) or high-risk serrated polyps (HRSP), which may have different causes and therefore implications for screening programs. STUDY: Data from a cross-sectional study of 1384 women undergoing screening-related colonoscopy between 2008 and 2016 were analyzed. Modified Poisson regression models with robust error variance were used to determine the relative risk of developing adenomatous polyps, serrated polyps, HRAPs, and HRSPs associated with pregnancy, menopausal status, and the use of HRT (duration and type). RESULTS: Women that used HRT for ≥6 years were at a significantly lower risk of developing a HRSP [risk ratios (RR): 0.53; 95% confidence interval (CI): 0.29-0.97]. Irrespective of the duration of use, the use of HRT that included progesterone alone or with estrogen was associated with a significantly lower risk of developing a HRSP (RR: 0.54; 95% CI: 0.30-0.95). The use HRT with progesterone for ≥6 years was associated with a nonsignificant lower risk of developing a HRSP (RR: 0.42; 95% CI: 0.17-1.04). None of the reproductive factors assessed or HRT were associated with the development of adenomatous polyps or HRAPs. CONCLUSIONS: The results of this study suggests that the long-term use of HRT, and therapies that include progesterone are associated with a lower risk of developing HRSPs. These results could have implications for targeted screening for serrated polyps among women.

Association Between Time to Colonoscopy After Positive Fecal Testing and Colorectal Cancer Outcomes: A Systematic Review.

BACKGROUND & AIMS: Colonoscopy is required following a positive fecal screening test for colorectal cancer (CRC). It remains unclear to what extent time to colonoscopy is associated with CRC-related outcomes. We performed a systematic review to elucidate this relationship. METHODS: An electronic search was performed through April 2020 for studies reporting associations between time from positive fecal testing to colonoscopy and outcomes including CRC incidence (primary outcome), CRC stage at diagnosis, and/or CRC-specific mortality. Our primary objective was to quantify these relationships following positive fecal immunochemical testing (FIT). Two authors independently performed screening, abstraction, and risk of bias assessments. RESULTS: From 1,612 initial studies, 8 were included in the systematic review, with 5 reporting outcomes for FIT. Although meta-analysis was not possible, consistent trends between longer time delays and worse outcomes were apparent in all studies. Colonoscopy performed beyond 9 months from positive FIT compared to within 1 month was significantly associated with a higher incidence of CRC, with adjusted odds ratios (AORs) of 1.75 and 1.48 in the two largest studies. These studies also reported significant associations between colonoscopy performed beyond 9 months and higher incidence of advanced stage CRC (stage III or IV) at diagnosis, with AORs of 2.79 and 1.55, respectively. CONCLUSIONS: Colonoscopy for positive FIT should not be delayed beyond 9 months. Given the additional time required for urgent referrals and surgical planning for CRC, colonoscopy should ideally be performed well in advance of 9 months following a positive FIT.

Examining the etiology of early-onset breast cancer in the Canadian Partnership for Tomorrow's Health (CanPath).

PURPOSE: Breast cancer incidence among younger women (under age 50) has increased over the past 25 years, yet little is known about the etiology among this age group. The objective of this study was to investigate relationships between modifiable and non-modifiable risk factors and early-onset breast cancer among three prospective Canadian cohorts. METHODS: A matched case-control study was conducted using data from Alberta's Tomorrow Project, BC Generations Project, and the Ontario Health Study. Participants diagnosed with breast cancer before age 50 were identified through provincial registries and matched to three control participants of similar age and follow-up. Conditional logistic regression was used to examine the association between factors and risk of early-onset breast cancer. RESULTS: In total, 609 cases and 1,827 controls were included. A body mass index ≥ 30 kg/m2 was associated with a lower risk of early-onset breast cancer (OR 0.65; 95% CI 0.47-0.90), while a waist circumference ≥ 88 cm was associated with an increased risk (OR 1.58; 95% CI 1.18-2.11). A reduced risk was found for women with ≥ 2 pregnancies (OR 0.76; 95% CI 0.59-0.99) and a first-degree family history of breast cancer was associated with an increased risk (OR 1.95; 95% CI 1.47-2.57). CONCLUSIONS: In this study, measures of adiposity, pregnancy history, and familial history of breast cancer are important risk factors for early-onset breast cancer. Evidence was insufficient to conclude if smoking, alcohol intake, fruit and vegetable consumption, and physical activity are meaningful risk factors. The results of this study could inform targeted primary and secondary prevention for early-onset breast cancer.

Association Between Endoscopist Annual Procedure Volume and Colonoscopy Quality: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: In addition to monitoring adverse events (AEs) and post-colonoscopy colorectal cancers (PCCRC), indicators for assessing colonoscopy quality include adenoma detection rate (ADR) and cecal intubation rate (CIR). It is unclear whether there is an association between annual colonoscopy volume and ADR, CIR, AEs, or PCCRC. METHODS: We searched publication databases through March 2019 for studies assessing the relationship between annual colonoscopy volume and outcomes, including ADR, CIR, AEs, or PCCRC. Pooled odds ratios (ORs) were calculated using DerSimonian and Laird random effects models. Sensitivity analyses were performed to assess for potential methodological or clinical factors associated with outcomes. RESULTS: We performed a systematic review of 9235 initial citations, generating 27 retained studies comprising 11,276,244 colonoscopies. There was no association between procedural volume and ADR (OR, 1.00; 95% CI, 0.98-1.02 per additional 100 annual procedures). CIR improved with each additional 100 annual procedures (OR, 1.17; 95% CI, 1.08-1.28). There was a non-significant trend toward decreased overall AEs per additional 100 annual procedures (OR, 0.95; 95% CI, 0.90-1.00). There was considerable heterogeneity among most analyses. CONCLUSIONS: In a systematic review and meta-analysis, we found higher annual colonoscopy volumes to correlate with higher CIR, but not with ADR or PCCRC. Trends toward fewer AEs were associated with higher annual colonoscopy volumes. There are few data available from endoscopists who perform fewer than 100 annual colonoscopies. Studies are needed on extremes in performance volumes to more clearly elucidate associations between colonoscopy volumes and outcomes.

Mutational landscape differences between young-onset and older-onset breast cancer patients.

BACKGROUND: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. METHODS: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages "deconstructSigs" and "SomaticSignatures" to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. RESULTS: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young-onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young-onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. Signatures resembling COSMIC signatures 2 and 13 were observed among both age groups. We identified a class of tumours with a unique combination of signatures that may be associated with young age of onset. CONCLUSIONS: The results of this exploratory study provide some evidence that the mutational landscape and mutational signatures among young-onset breast cancer are different from those of older-onset patients. The characterization of young-onset tumours could provide clues to their etiology which may inform future prevention. Further studies are required to confirm our findings.

Estimates of the future burden of cancer attributable to infections in Canada.

More than 7000 incident cancers diagnosed in Canada in 2015 were attributable to infections. The future infection-associated cancer burden can be lowered by reducing the prevalence of major cancer-causing infections; hepatitis B virus (HBV), hepatitis C virus (HCV), Helicobacter pylori (H. pylori) and human papillomavirus (HPV). We modeled the future impact of (1) 10%, 25%, and 50% relative reductions in the prevalence of HBV, HCV and H. pylori and (2) different school-based HPV vaccination coverage levels (lower, current, higher) on Canadian cancer incidence by the year 2042. We modeled counterfactual reductions in HBV, HCV and H. pylori prevalence in 2018, assuming a latency period of 15-years, to estimate the impact on cancer incidence starting in 2033. The number of HPV-attributable cancers among vaccinated cohorts was a function of pre-2018 vaccine coverage levels and the 2018 counterfactuals. A 50% counterfactual reduction in the prevalence of HBV, HCV and H. pylori could prevent an estimated 10,585 cancers from 2018 to 2042; a 25% reduction could prevent 5293 cancers and a 10% reduction could prevent 2117 cancers. Assuming continuity of current estimated country-wide HPV vaccine coverage, 3977 anogenital and 1073 head and neck cancers could be prevented from 2018 to 2042, whereas vaccine coverage of 80% in girls and boys could prevent an additional 311 cancers. Almost 16,000 cancers could be prevented in Canada from 2018 to 2042 with a 50% relative reduction in HBV, HCV and H. pylori prevalence and 80% HPV vaccine coverage of girls and boys.

Cancers attributable to infections in Canada.

Infections are estimated to cause approximately 15% of the world's cancers with large geographic variations. Yet, Canadian estimates for specific cancer-causing infections are not available. To estimate the number of infection-associated cancers diagnosed among Canadian adults in 2015, we calculated population attributable risks (PARs) and the number of attributable cases for seven carcinogenic infections and their 20 associated cancers. A systematic literature search was performed for each infection to obtain data on infection prevalence in the population and the relative risk or odds ratio associated with the cancer it causes. When mechanistic evidence suggested that detection of a given infection within cancer tissue was sufficient to attribute the cancer to the infection, prevalence among cancer cases was used to approximate the PAR. Data from 61 studies formed the basis of our analyses. The estimated number of infection-attributable cancer cases for 2015 was: 3828 for human papillomavirus (HPV), 2052 for Helicobacter pylori, 578 for Epstein-Barr virus, 509 for hepatitis B and C viruses (HBV, HCV), 100 for human herpesvirus type 8, and 30 cases for human T-cell lymphotropic virus type 1. These seven infections were responsible for 3.7% of cancers diagnosed among Canadian adults in 2015; 3.5% among men and 4.0% among women. The infections with the highest number of attributable cases are largely preventable or treatable through vaccination (HBV and HPV), antibiotic therapy (H. pylori), or a combination of interventions (HCV), thereby representing an important target for reducing the infection-caused cancer burden among Canadians.

Estimates of the current and future burden of cancer attributable to alcohol consumption in Canada.

Alcohol consumption is associated with elevated risk of oropharyngeal, laryngeal, esophageal, colon, rectal, breast, liver, pancreatic and stomach cancers. The purpose of this analysis was to provide national and provincial estimates of the number and proportion of cancers attributable to alcohol consumption in Canada and to project the numbers of potentially avoidable cancers using possible intervention scenarios. We estimated the population attributable risk (PAR) for cancers associated with alcohol consumption levels (drinks/day) using: i) relative risks obtained from the World Cancer Research Fund/(WCRF) reports or meta-analyses, ii) alcohol consumption (prevalence) data from the 2003 Canadian Community Health Survey, and iii) cancer incidence data from the 2015 Canadian Cancer Registry. We used potential impact fractions (PIFs) to estimate the future avoidable cancer burden under four counterfactual scenarios: (1) lowering alcohol consumption to meet the WCRF low risk guidelines, (2) meeting the Canada's Low-Risk Drinking Guidelines, (3) reducing daily intake by one drink/day, and (4) decreasing consumption to 50% of the 2003 levels by 2032. We estimated that 3282 incident cancer cases (5.2% of alcohol-associated cancers and 1.8% of all cancers) diagnosed in Canada in 2015 were attributable to alcohol consumption. At the current consumption levels, alcohol-attributable cancers are expected to increase to 10,122 (8.8% of cases among alcohol-associated cancers) by 2042. Under the best case scenario, reducing alcohol consumption to 50% of 2003 levels by 2032, could prevent 70,261 cases by 2042. Strategies that effectively reduce alcohol consumption at a population level can have a meaningful impact on reducing the cancer burden in Canada.