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While Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors have been shown to be effective in phase III randomized trials, the value of targeted therapies has been challenging to evaluate at the population-level. We examined the impact of population-level EGFR testing and treatment on survival outcomes among non-squamous metastatic Non-Small Cell Lung Cancer (NSCLC) patients.Real-world, population-level data were collected from all de novo non-squamous metastatic NSCLC patients in Alberta, Canada from 2004 to 2020. EGFR testing data were collected through Alberta Precision Laboratories. Differences in survival rates and overall survival (OS) pre (2004-2012) and post initiation (post) (2013-2019) testing periods were evaluated using interrupted time series analyses. The impact of testing and subsequent treatment was evaluated using multivariable Cox Proportional Hazards models.In total, 4,578 non-squamous metastatic NSCLC patients were diagnosed pre-EGFR testing and 4,457 patients were diagnosed post-EGFR testing (2013-2019). Among patients diagnosed in the pre-EGFR testing period, the 6-month, 1-year, and 2-year survival probabilities were 0.39 (95 % CI: 0.38-0.41), 0.22 (95 % CI: 0.21-0.23), and 0.09 (95 % CI: 0.08-0.10), while the survival probabilities for patients diagnosed in the post-EGFR testing period were 0.45 (95 % CI: 0.43-0.46), 0.29 (95 % CI: 0.27-0.30), and 0.16 (95 % CI: 0.15-0.17), respectively. After adjusting for baseline patient and clinical characteristics, OS in the post-EGFR period was significantly improved compared to the pre-EGFR period (HR: 0.81; 95 % CI: 0.78-0.85). Among patients who were treated with systemic therapy, those tested for an EGFR mutation had significantly greater survival than patients who were not tested HR of 0.81 (95 % CI: 0.70-0.95).These results show the considerable impact of population-based molecular testing and subsequent targeted therapies on survival among metastatic NSCLC patients. The estimates here can be used in future studies to evaluate the population-level cost-effectiveness of testing and treatment.

Real-world evidence surrounding EGFR positive NSCLC patients in Canada is limited. Administrative databases in Alberta, Canada were used to evaluate EGFR testing and mutation prevalence in de novo metastatic NSCLC, as well as the characteristics, treatment patterns, and outcomes of individuals with Exon 19, L858R and Exon20ins mutations. Between 2013–2019, 2974 individuals underwent EGFR testing, of which 451 (15.2%) were EGFR positive. Among EGFR positive individuals, 221 (49.0%) had an Exon 19 mutation, 159 (35.3%) had an L858R mutation, and 18 (4%) had an Exon20ins mutation. The proportion of individuals who initiated 1L systemic therapy was 89.1% for Exon19, 85.5% for L858R, and 72.2% for Exon20ins carriers. The primary front-line systemic therapy was gefitinib or afatinib monotherapy for individuals with Exon 19 (93.4%) and L858R (94.1%) mutations versus platinum combination therapy for individuals with Exon20ins mutations (61.5%). The Exon20ins cohort had worse median overall survival from initiation of 1L systemic therapy (10.5 months [95% CI: 8.0-not estimable]) than the Exon19 (20.6 months [95% CI: 18.4–24.9]), and L858R cohorts (19.1 months [95% CI: 14.5–23.1]). These findings highlight that Exon20ins mutations represent a rare subset of NSCLC in which treatment options are limited and survival outcomes are worse relative to individuals with more common types of EGFR mutations.

An absence of screening recommendations and the rapid progression of testicular germ cell tumours (TGCTs) offer a perspective on the potential impact of the COVID-19 pandemic on cancer presentations. We evaluated the presenting cancer stages of TGCTs in a real-world population before and during the pandemic to assess stage migration.We performed a retrospective review of all new patients with TGCT diagnoses in Alberta, Canada, from Dec. 31, 2018, to Apr. 30, 2021, using the Alberta Cancer Registry. Because potential changes in staging should not occur instantaneously, we used a 6-month lag time from Apr. 1, 2020, for seminomas, and a 3-month lag time for nonseminomas, to compare initial cancer stages at presentation before and during the pandemic. We evaluated monthly rates of presentation by stage and histology. Exploratory outcomes included the largest tumour dimension, tumour markers and, for advanced disease, risk category and treatment setting.Of 335 patients with TGCTs, 231 were diagnosed before the pandemic and 104 during the pandemic (using a lag time). In total, 18 (7.8%) patients diagnosed before the pandemic presented with stage III disease, compared to 16 (15.4%) diagnosed during the pandemic (relative risk 1.97, 95% confidence interval [CI] 1.05-3.72). We observed no significant differences for secondary outcomes. Without a lag time, the rate ratio for a stage II presentation decreased significantly during the pandemic (0.40, 95% CI 0.21-0.72).We observed signs of TGCT stage migration during the COVID-19 pandemic, driven by a decline in stage II disease and a potential rise in stage III disease. Management of TGCTs should remain a priority, even during a global pandemic.

Immunotherapy and targeted therapies have been shown to considerably improve long-term survival outcomes in metastatic melanoma patients. Real-world evidence on the uptake of novel therapies and outcomes for this patient population in Canada are limited. We conducted a population-based retrospective cohort study of all metastatic melanoma patients diagnosed in Alberta, Canada (2015–2018) using electronic medical records and administrative data. Information on BRAF testing for patients diagnosed in 2017 or 2018 was obtained through chart abstraction. In total, 434 metastatic melanoma patients were included, of which 110 (25.3%) were de novo metastatic cases. The median age at diagnosis was 66 years (IQR: 57–76) and 70.0% were men. BRAF testing was completed for the majority of patients (88.7%). Among all patients, 60.4%, 19.1%, and 6.0% initiated first-line, second-line, and third-line systemic therapy. The most common therapies were anti-PD-1 and targeted therapies. The two-year survival probability from first-line therapy, second-line therapy, and third-line therapy was 0.50 (95% CI: 0.44–0.57), 0.26 (95% CI: 0.17–0.40), and 0.14 (95% CI: 0.40–0.46), respectively. In the first-line setting, survival was highest for patients that received ipilimumab or ipilimumab plus nivolumab, while targeted therapy had the highest survival in the second-line setting. This study indicates that novel therapies improve survival in the real world but a considerable proportion of patients do not receive treatment with systemic therapy.

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.

Endometrial cancer (EC) incidence has increased in recent decades. However, population-based outcomes data are limited. In this retrospective cohort study, we examined characteristics, treatment patterns, and clinical outcomes, including time to next treatment (TNNT) and overall survival (OS), among advanced/recurrent (A/R) EC patients between 2010 and 2018 in Alberta, Canada. Kaplan–Meier statistics evaluated TTNT and OS, stratified by patient (A/R) and treatment. A total of 1053 patients were included: 620 (58.9%) advanced and 433 (41.1%) recurrent. A total of 713 (67.7%) patients received first-line therapy: 466 (75.2%) advanced and 247 (57.0%) recurrent. Platinum-based chemotherapy (PBCT) was the most common first-line regimen (overall: 78.6%; advanced: 96.1%; recurrent: 45.3%). The median TTNT and OS from first-line therapy were 19.9 months (95% confidence interval [CI]: 17.5–23.5) and 35.9 months (95% CI: 31.5–53.5), respectively. Following first-line PBCT, the median OS from second-line chemotherapy (N = 187) was 10.4 months (95% CI: 8.9–13.3) and higher for those rechallenged with PBCT (N = 72; 38.5%) versus no rechallenge (N = 115; 61.5%) (13.3 months [95% CI: 11.2–20.9] vs. 6.4 months [95% CI: 4.6–10.4; p < 0.001]). The findings highlight poor outcomes in A/R EC, particularly following first-line therapy, and that additional tolerable therapeutic options are needed to improve patient outcomes.

Real-world evidence has been increasingly used to support evaluations of emerging therapies. These investigations are often conducted in settings that may not be representative of the underlying population. The purpose of this investigation was to empirically quantify the magnitude of this selection bias. Individuals diagnosed with solid metastatic cancer in Alberta, Canada, between 2010–2019 were identified using the provincial cancer registry for 13 common metastatic sites. Two outcomes used to support oncology reimbursement decisions were examined: the proportion of individuals who initiated systemic therapy and median overall survival (OS). These outcomes were assessed in the entire population and in a subset of individuals who were referred to a medical oncologist. Among the 23,152 individuals in the entire population, 40.8% (95% CI: 40.2–41.4) initiated systemic therapy, and the median OS from diagnosis was 5.4 months (95% CI: 5.3–5.6). Among those who were referred to a medical oncologist (n = 13,372; 57.8%), 67.4% (95% CI: 66.6–68.2) initiated systemic therapy, and the median OS from diagnosis was 11.2 months (95% CI: 10.9–11.5). The magnitude of bias varied by cancer site where lower referral rates were associated with greater bias. Non-referral is an important source of selection bias in real-world investigations. Studies that rely on limited-catchment real-world data should be interpreted with caution, particularly in metastatic cancer settings.

PURPOSE: Patients with colorectal cancer (CRC) experience a range of physical and psychologic symptoms, and supportive care needs throughout the illness trajectory. We used patient-reported outcomes and administrative health data to describe symptom burden and supportive care needs during and after adjuvant treatment and determine factors associated with changes to symptom burden. METHODS: A retrospective population-based cohort study of patients who were newly diagnosed with stage II-III CRC in Alberta, Canada, between January 1, 2016, and January 31, 2019. Adults age 18 years or older who completed a patient-reported outcomes survey (Edmonton Symptom Assessment System) and supportive care needs (Canadian Problem Checklist) within 3 months after starting adjuvant treatment (during treatment) and > 7 months after starting treatment (after treatment) were included. Changes to symptom severity were stratified as stable, improved, or deteriorated. Multivariable logistic regression was used to evaluate factors associated with these changes. RESULTS: We included 303 patients (median age 60 years, 62% male, 84.5% stage III, 51.2% rectal v colon). Prevalent symptoms included tiredness (80.5%), pain (50.8%), and poor well-being (50%) during treatment, and tiredness (71.3%), pain (44.2%), and poor well-being (62.1%) after treatment. The results were heterogeneous with respect to improvements, stability, or deterioration. Pain worsened for 25% of the cohort, tiredness for 28%, and depression, anxiety, and well-being for 21%, 22%, and 31%, respectively. Deterioration of some symptoms was associated with older age, stage II, comorbidities, rural setting, and higher income. CONCLUSION: We demonstrated symptom severity was generally low and most symptoms remained stable or improved after treatment. Particular groups of patients were at greater risk for more severe and/or more persistent symptoms. Ongoing assessments and interventions to address physical and psychologic symptoms, and supportive care needs in patients with CRC during and after treatment are needed.

Background Incidence of testicular cancer is highest among young adults and has been increasing dramatically for men born since 1945. This study aimed to elucidate the factors driving this trend by investigating differences in mutational signatures by age of onset. Methods We retrieved somatic variant and clinical data pertaining to 135 testicular tumors from The Cancer Genome Atlas. We compared mutational load, prevalence of specific mutated genes, mutation types, and mutational signatures between age of onset groups ( Results Mutational load was significantly higher among older-onset tumors (p p > 0.05). Signatures 1, 8 and 29 were more common among young-onset tumors, while signatures 11 and 16 had higher prevalence among older-onset tumors (p Conclusions Signature contributions differ by age with signatures 1, 8 and 29 were more common among younger-onset tumors. While these signatures are connected with endogenous deamination of 5-methylcytosine, late replication errors and chewing tobacco, respectively, additional research is needed to further elucidate the etiology of young-onset testicular cancer. Large studies of mutational signatures among young-onset patients are required to understand epidemiologic trends as well as inform targeted prevention and treatment strategies.

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. 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. 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). 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.

Real-world evidence surrounding

Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. We assessed tumor features, individually and in combination, in whole-exome sequenced (WES) colorectal cancers (CRCs) and in panel sequenced CRCs, endometrial cancers (ECs) and sebaceous skin tumors (SSTs) for their accuracy in detecting dMMR. CRCs (n=300) with WES, where MMR status was determined by immunohistochemistry, were assessed for microsatellite instability (MSMuTect, MANTIS, MSIseq, MSISensor), COSMIC tumor mutational signatures (TMS) and somatic mutation counts. A 10-fold cross-validation approach (100 repeats) evaluated the dMMR prediction accuracy for 1) individual features, 2) Lasso statistical model and 3) an additive feature combination approach. Panel sequenced tumors (29 CRCs, 22 ECs, 20 SSTs) were assessed for the top performing dMMR predicting features/models using these three approaches. For WES CRCs, 10 features provided >80% dMMR prediction accuracy, with MSMuTect, MSIseq, and MANTIS achieving ≥99% accuracy. The Lasso model achieved 98.3%. The additive feature approach with ≥3/6 of MSMuTect, MANTIS, MSIseq, MSISensor, INDEL count or TMS ID2+ID7 achieved 99.7% accuracy. For the panel sequenced tumors, the additive feature combination approach of ≥3/6 achieved accuracies of 100%, 95.5% and 100%, for CRCs, ECs, and SSTs, respectively. The microsatellite instability calling tools performed well in WES CRCs, however, an approach combining tumor features may improve dMMR prediction in both WES and panel sequenced data across tissue types.

Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. Tumor features, individually and in combination, derived from whole-exome sequenced (WES) colorectal cancers (CRCs) and panel-sequenced CRCs, endometrial cancers (ECs), and sebaceous skin tumors (SSTs) were assessed for their accuracy in detecting dMMR. CRCs (n = 300) with WES, where mismatch repair status was determined by immunohistochemistry, were assessed for microsatellite instability (MSMuTect, MANTIS, MSIseq, and MSISensor), Catalogue of Somatic Mutations in Cancer tumor mutational signatures, and somatic mutation counts. A 10-fold cross-validation approach (100 repeats) evaluated the dMMR prediction accuracy for i) individual features, ii) Lasso statistical model, and iii) an additive feature combination approach. Panel-sequenced tumors (29 CRCs, 22 ECs, and 20 SSTs) were assessed for the top performing dMMR predicting features/models using these three approaches. For WES CRCs, 10 features provided80% dMMR prediction accuracy, with MSMuTect, MSIseq, and MANTIS achieving ≥99% accuracy. The Lasso model achieved 98.3% accuracy. The additive feature approach, with three or more of six of MSMuTect, MANTIS, MSIseq, MSISensor, insertion-deletion count, or tumor mutational signature small insertion/deletion 2 + small insertion/deletion 7 achieved 99.7% accuracy. For the panel-sequenced tumors, the additive feature combination approach of three or more of six achieved accuracies of 100%, 95.5%, and 100% for CRCs, ECs, and SSTs, respectively. The microsatellite instability calling tools performed well in WES CRCs; however, an approach combining tumor features may improve dMMR prediction in both WES and panel-sequenced data across tissue types.

400 Background: The incidence of advanced unresectable hepatocellular carcinoma (HCC) is increasing in several developed countries and the prognosis of advanced HCC remains poor. Real-world evidence of treatment patterns and patient outcomes can highlight the unmet clinical need within this population. Methods: We conducted a retrospective population-based cohort study of advanced unresectable HCC patients diagnosed in Alberta, Canada between 2008-2018 using electronic medical records and administrative claims data. A chart review was conducted among patients treated with systemic therapy to capture additional treatment information that is not available in the administrative data. The objectives of this study were to describe the treatment patterns, overall survival, and healthcare resource utilization of advanced HCC patients. Results: A total of 1,297 advanced HCC patients were included in this study, of which 555 (42.8%) were recurrent cases and the remainder were advanced unresectable cases at diagnosis. Median age at diagnosis was 64 (range: 21-94) and 82.1% were men. Only 274 patients (21.1%) received first-line systemic therapy and of those 32 patients (11.7%) initiated second-line therapy. Nearly all of the patients treated with systemic therapy received sorafenib (> 96.4%) in first-line and over half of these patients (55.8%) had a dose reduction during the course of treatment. Patients who received systemic therapy had considerably higher median overall survival (12.23 months; 95% CI: 10.72-14.10) compared to patients not treated with systemic therapy (2.66 months; 95% CI: 2.33-3.12; log-rank p-value < 0.001). Among patients who received first-line systemic therapy, the 2-year and 5-year survival rates were 17.9% (95% CI: 13.7-23.4) and 3.9% (95% CI: 1.8-8.6), respectively. Among patients treated with systemic therapy, overall survival was highest for recurrent cases, patients with Child-Pugh A, patients with hepatitis C virus or multiple known HCC risk factors, and for recurrent patients who received transarterial chemoembolization and ablation (separate procedures) in early stage (log-rank: p < 0.05). No significant differences in survival were observed for dose reduction in first-line therapy, age group, sex, the presence of cirrhosis, or the presence of metastatic disease (log-rank: p > 0.05). Among patients that received first-line systemic therapy, the average time spent in hospital was 9, 9, and 8 days per patient within years 1, 2, and 3, respectively. Conclusions: In a Canadian real-world setting, patients who received systemic therapy had considerably greater survival than those who did not, but the initiation rate was low and dose reductions were common. The low uptake of systemic therapy and the modest survival gains highlight the importance of earlier diagnosis and the need for novel and more effective first-line therapies.

The objective of this study was to identify distinct clusters of individuals that exhibit unique patterns of modifiable lifestyle-related behaviours and to determine how these patterns are associated with the risk of developing colorectal cancer (CRC). The study consisted of 26,460 participants and 267 CRC cases from Alberta’s Tomorrow Project. Exploratory latent class analysis of risk behaviours (obesity, physical inactivity, meat consumption, smoking, alcohol consumption, and fruit and vegetable consumption) and Cox proportional hazard models were utilized. Seven unique behavioural groups were identified, where the risk of CRC was 2.34 to 2.87 times greater for high risk groups compared to the low risk group. Sex-specific models identified higher risk groups among men (Hazard Ratios [HRs]: 3.15 to 3.89) than among women (HRs: 1.99 to 2.19). Targeting groups defined by clustering of behaviours could potentially lead to more effective prevention of CRC on a population level.

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.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.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).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.

Early-onset diagnosis, defined by age 60 years. The pooled odds of achieving pCR were significantly higher in early-onset patients. Future studies should evaluate the role of locoregional management of TNBC and the implementation of novel therapies such as PARP inhibitors in real-world settings, and whether they improve outcomes.

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.

The inaugural Early-Age-Onset Colorectal Cancer Symposium was convened in June 2021 to discuss the implications of rapidly rising rates of early-age-onset colorectal cancer (EAO-CRC) in Canadians under the age of 50 and the impactful outcomes associated with this disease. While the incidence of CRC is declining in people over the age of 50 in Canada and other developed countries worldwide, it is significantly rising in younger people. Canadians born after 1980 are 2 to 2.5 times more likely to be diagnosed with CRC before the age of 50 than previous generations at the same age. While the etiology of EAO-CRC is largely unknown, its characteristics differ in many key ways from CRC diagnosed in older people and warrant a specific approach to risk factor identification, early detection and treatment. Participants of the symposium offered directions for research and clinical practice, and developed actionable recommendations to address the unique needs of these individuals diagnosed with EAO-CRC. Calls for action emerging from the symposium included: increased awareness of EAO-CRC among public and primary care practitioners; promotion of early detection programs in younger populations; and the continuation of research to identify unique risk factor profiles, tumour characteristics and treatment models that can inform tailored approaches to the management of EAO-CRC.

76 Background: In recent years, treatment intensification beyond androgen deprivation therapy (ADT) with several novel therapies have shown survival benefit in patients with metastatic castration-sensitive prostate cancer (mCSPC). Given the rapidly evolving landscape in mCSPC treatment, there is a need to better understand how treatment strategies fit in real-world clinical practice and are combined/sequenced with other available therapies. Methods: Using electronic medical records and administrative data, a population-based retrospective cohort study was conducted. Patients aged ≥18 years of age who were newly diagnosed with de novo mCSPC and initiated ADT post-diagnosis between 2010 to 2020 in Alberta, Canada, were included. Treatment intensification was defined as the receipt of apalutamide, abiraterone acetate, enzalutamide, or chemotherapy (e.g. docetaxel) within 180 days of ADT initiation. Results: A total of 2,515 de novo mCSPC were identified during study period with 2,098 (83%) patients initiating ADT post-diagnosis. Of those, 525 (25%) received intensification beyond ADT. The percentage of patients who were intensified was 3% in 2010-2013 and gradually increased to 67% in 2020. Between 2014-2017, docetaxel was the most common therapy for intensification, but its use decreased considerably in 2018-2020 with abiraterone acetate, apalutamide and enzalutamide becoming increasingly available in the mCSPC setting. Upon progression, 46% and 22% in the intensified group versus 38% and 13% in the ADT-alone group initiated one and two-lines of subsequent therapies respectively. Abiraterone acetate and enzalutamide were the most common subsequent therapy for both the intensified (32% and 31% respectively) and the ADT-alone (56% and 38% respectively) groups. Docetaxel (24%) was used as subsequent therapy among mCSPC patients who were intensified with oral systemic agents. In multivariable logistic regression analyses of patients diagnosed in 2014-2020, significant predictors of intensification were younger age at diagnosis, lower Charlson comorbidity index, greater number of metastatic sites, shorter time to ADT initiation, referral to a specialists/cancer centres, surgery or radiation prior to ADT, and more recent year of diagnosis (all p

Background Factors that are prognostic of early discontinuation of adjuvant chemotherapy among stage III colon cancer patients have yet to be described. To address this gap, a survey of medical oncologists and a systematic review and meta‐analysis were conducted. Methods A survey was distributed in March 2019 to medical oncologists who treat colon cancer within Alberta, Canada. Clinicians were asked to rank the prognostic importance of a set of variables using a Likert scale and agreement was quantified using a weighted Cohen's kappa. In addition, we systematically searched four databases up to July 2019. Meta‐analyses were conducted using a random‐effects model. Results Of the 25 clinicians who were sent the survey, 14 responded. Overall, there was no agreement regarding which variables were prognostic of early discontinuation (weighted Cohen's kappa = 0.12; 95% CI = 0.05‐0.18). From an initial 3927 articles, 18 investigations were identified for inclusion in our review. Based upon evidence from both the survey and the systematic review, the following four variables were identified as being prognostic of early discontinuation: (a) comorbidity (OR2+ vs 0 = 1.53; 95% CI = 1.30‐1.79); (b) performance status (ORECOG 2+ vs 0‐1 = 1.33; 95%CI = 1.07‐1.65); (c) T stage (ORT4 vs T1‐2 = 1.57; 95% CI = 0.99‐2.50); and (d) chemotherapy regimen (estimates not pooled due to heterogeneity). In addition to these factors, there was some suggestion that age, marital status/social support, muscle mass, N stage, and tumor grade had prognostic value. Conclusions Current evidence is heterogeneous and limited. Additional research is needed to confirm our findings and to explore additional prognostic factors., This figure presents results from a meta‐analysis of the proportion of patients who discontinued chemotherapy stratified by study design.

The effect of acute and long-term exposures to outdoor particulate air pollution on lung function in healthy adults is not well established. The objective of this study was to conduct a systematic literature review and meta-analysis of studies that assessed the relationship of outdoor particulate air pollution and lung function in healthy adults. Studies that contained data on outdoor air particulate matter levels (PM10or PM2.5) and forced expiratory volume in 1 s (FEV1) in healthy adults were eligible for inclusion. Effect estimates, in relation to long-term and acute exposures, were quantified separately using random effects models. A total of 27 effect estimates from 23 studies were included in this review. Acute exposures were typically assessed with PM2.5, while long-term exposures were predominantly represented by PM10. A 10 µg/m3 increase in short-term PM2.5exposure (days) was associated with a −7.02 mL (95% CI −11.75 to –2.29) change in FEV1. A 10 µg/m3difference in long-term PM10exposure was associated with a −8.72 mL (95% CI −15.39 to –2.07) annual change in FEV1and an absolute difference in FEV1of −71.36 mL (95% CI −134.47 to –8.24). This study provides evidence that acute and long-term exposure to outdoor particulate air pollution are associated with decreased FEV1in healthy adults. Residual confounding from other risk factors, such as smoking, may explain some of the effect for long-term exposures. More studies are required to determine the relationship of long-term exposure to PM2.5and short-term exposure to PM10, which may have different biologic mechanisms.

Radon is widely recognized as a human carcinogen and findings from epidemiologic studies support a causal association between residential radon exposure and lung cancer risk. Our aim was to derive population attributable risks (PAR) to estimate the numbers of incident lung cancer due to residential radon exposure in Canada in 2015. Potential impact fractions for 2042 were estimated based on a series of counterfactuals. A meta-analysis was conducted to estimate the relative risk of lung cancer per 100 Becquerels (Bq)/m3 increase in residential radon exposure, with a pooled estimate of 1.16 (95% CI: 1.07–1.24). The population distribution of annual residential radon exposure was estimated based on a national survey with adjustment for changes in the population distribution over time, the proportion of Canadians living in high-rise buildings, and to reflect annual rather than winter levels. An estimated 6.9% of lung cancer cases in 2015 were attributable to exposure to residential radon, accounting for 1741 attributable cases. If mitigation efforts were to reduce all residential radon exposures that are above current Canadian policy guidelines of 200 Bq/m3 (3% of Canadians) to 50 Bq/m3, 293 cases could be prevented in 2042, and 2322 cumulative cases could be prevented between 2016 and 2042. Our results show that mitigation that exclusively targets Canadian homes with radon exposures above current Canadian guidelines may not greatly alleviate the future projected lung cancer burden. Mitigation of residential radon levels below current guidelines may be required to substantially reduce the overall lung cancer burden in the Canadian population.

Nearly one in two Canadians are expected to be diagnosed with cancer in their lifetime. However, there are opportunities to reduce the impact of modifiable cancer risk factors through well-informed interventions and policies. Since no comprehensive Canadian estimates have been available previously, we estimated the proportion of cancer diagnosed in 2015 and the future burden in 2042 attributable to lifestyle and environmental factors, and infections. Population-based historical estimates of exposure prevalence and their associated risks for each exposure-cancer site pair were obtained to estimate population attributable risks, assuming the exposures were distributed independently and that the risk estimates were multiplicative. We estimated that between 33 and 37% (up to 70,000 cases) of incident cancer cases among adults aged 30 years and over in 2015 were attributable to preventable risk factors. Similar proportions of cancer cases in males (34%) and females (33%) were attributable to these risk factors. Tobacco smoking and a lack of physical activity were associated with the highest proportions of cancer cases. Cancers with the highest number of preventable cases were lung (20,100), colorectal (9800) and female breast (5300) cancer. If current trends in the prevalence of preventable risk factors continue into the future, we project that by 2042 approximately 102,000 incident cancer cases are expected to be attributable to these risk factors per year, which would account for roughly one-third of all incident cancers. Through various risk reduction interventions, policies and public health campaigns, an estimated 10,600 to 39,700 cancer cases per year could be prevented by 2042.

Exposure to ultraviolet radiation (UVR) is an established cause of cutaneous melanoma. The purpose of this study was to estimate the current attributable and future avoidable burden of melanoma related to exposure to UVR and modifiable UVR risk behaviors (sunburn, sunbathing, and indoor tanning). The population attributable risk (PAR) associated with UVR in 2015 was estimated by comparing Canadian melanoma incidence rates in 2015 to estimated incidence rates of a 1920 birth cohort. Rates were adjusted for changes in reporting and ethnicity. We estimated PARs for modifiable UVR risk behaviors using Caucasian prevalence data from the Second National Sun Survey and relative risks that are generalizable to Canada from meta-analyses of relevant studies. Attributable cases apply to 98.9% of melanomas in Canada that occur in Caucasians. We also estimated the future burden of UVR risk behaviors using the potential impact fraction framework and potential reductions in prevalence of 10% to 50% from 2018 to 2042. Adult sunburn and sunbathing were associated with increased risks of melanoma of 1.28 (95% CI: 1.15, 1.43) and 1.44 (95% CI: 1.18, 1.76), respectively. In 2015, we estimate that 62.3% of melanomas in Canada were attributable to exposure to UVR and that 29.7% were attributable to the combination of sunburn (7.4%), sunbathing (17.8%), and indoor tanning (7.0%). A 50% reduction in modifiable UVR behaviors could avoid an estimated 11,980 melanoma cases by 2042. Prevention strategies aimed at modifiable UVR behaviors are crucial to reduce the growing burden of melanoma in Canada.

Background Cancer is the leading cause of death in Canada and the estimated annual spending associated with cancer is approximately $7.5 billion. Projecting the future burden of cancer in Canada is essential for health planning and evaluation. We aimed to estimate the future incidence of cancer in Canada to 2042. Methods Age-sex-region-specific cancer incidence data were obtained for the years 1983-2012 and cancer incidence was projected from 2013 to 2042 for the top five cancer sites. The modelling algorithm combined a mixture of cancer projection methods to select the best-fitted model. When the chosen model produced by the modelling algorithm resulted in estimates that were not consistent with expert opinion, an alternate model was selected that took into consideration historical changes in policy, screening and lifestyle behaviours. Incidence projections were made for Canada and its provinces. Results Lung cancer incidence is estimated to rise to 14,866 cases in men and 19,162 in women in 2042. Colorectal cancer incidence is estimated to rise to 28,146 in men and 21,102 in women. Cases of bladder cancer are projected to rise to 10,708 and 3,364 in men and women, respectively. Breast cancer incidence is predicted to rise to 40,712 and prostate cancer incidence is projected to rise to 92,949. Conclusion These cancer incidence projections up to 2042 can be used for planning cancer control strategies and prevention programs. Given the ongoing changes in the prevalence of risk factors and in cancer prevention policies, these estimates should be interpreted with caution.

ImportanceThe external validity of survival outcomes derived from clinical practice data from US patients with advanced non–small cell lung cancer (NSCLC) is not known and is of potential importance because it may be used to support regulatory decision-making and health technology assessment outside of the US.ObjectiveTo evaluate whether overall survival (OS) estimates for a selected group of patients with advanced NSCLC from a large US clinical practice database are transportable to Canadian patients receiving the same systemic therapies.Design, Setting, and ParticipantsThis retrospective multicenter cohort study used transportability analysis to assess whether adjustment for pretreatment characteristics of eligible patient cohorts could reliably approximate OS estimated from US-based samples to Canadian populations. A total of 17 432 eligible adult patients who were diagnosed de novo with advanced NSCLC on or after January 1, 2011, were included in the analysis and followed up until September 30, 2020. Because data on race and ethnicity were available in the US database but not the Canadian database and because racial and ethnic distribution was likely to be similar between US and Canadian patients, these characteristics were not analyzed.ExposuresInitiation of platinum-doublet chemotherapy or pembrolizumab monotherapy as first-line systemic treatment for advanced NSCLC.Main Outcomes and MeasuresOS measured from the time of initiation of the respective treatment regimen.ResultsAmong 17 432 eligible patients, 15 669 patients from the US and 1763 patients from Canada were included in the analysis. Of those, 11 863 patients (sample size–weighted estimates of mean [SD] age, 68.0 [9.3] years; 6606 [55.7%] male; 10 100 from the US and 1763 from Canada) were included in the subset of patients with complete data for baseline covariates. A total of 13 532 US patients received first-line chemotherapy, and 2137 received first-line pembrolizumab monotherapy. Of those, 8447 patients (62.4%) in the first-line chemotherapy group and 1653 patients (77.3%) in the first-line pembrolizumab group had complete data on baseline covariates for outcome model estimation. A total of 1476 Canadian patients who received first-line chemotherapy and 287 patients who received first-line pembrolizumab monotherapy were identified from the target population. After standardization to baseline patient covariates in the Canadian cohorts, transported OS estimates revealed a less than 5% mean absolute difference from the observed OS in the target population (0.56% over 60 months of follow-up in the first-line chemotherapy group and 4.54% over 30 months of follow-up in the first-line pembrolizumab group). Negative control analysis using a mismatched outcome model revealed a 6.64% discrepancy and an incompatible survival curve shape. The results were robust to assumptions of random missingness for baseline covariates, to unadjusted differences in baseline metastases and comorbidities, and to differences in the standard of care between the US and Canada related to administration of second-line anti–programmed cell death 1 ligand 1 immunotherapy for patients who initiated first-line chemotherapy.Conclusions and RelevanceThe results of this cohort study suggest that, under specific circumstances, OS estimates from US clinical practice data can be adjusted using baseline clinical characteristics to closely approximate OS in selected groups of Canadian patients with advanced NSCLC. These results may have implications for regulatory decision-making and health technology assessment in target populations outside of the US.

228 Background: Medical cannabis (MC) and prescription opioid medication (POM) use is common among cancer patients. There is conflicting evidence on the association of cannabis with POM as to whether cannabis can help decrease/ cease opioid use. In this population-based study, we examine the association between MC authorization and cessation or reduction in POM use among patients with early stage cancer. Methods: This is a retrospective, population-based study of patients with early stage (stage I-III) cancer diagnosed between January 1, 2014 and December 31, 2018 in the province of Alberta, Canada. Cases were identified from the Alberta Cancer Registry (ACR) and linked to the provincial pharmacy information network (PIN) and the database from the College of Physician and Surgeons of Alberta (CPSA). Patient and treatment characteristic were used to identify a comparable non-MC group with prior POM use via probabilistic modelling. Descriptive statistics were used to describe differences between patients with and without a MC authorization. Modified Poisson regression was used to compare the likelihood of opioid cessation and reduction among groups. Results: We identified 8,801 patients of whom 326 (3.7%) had a MC authorization. Patients with a MC authorization were younger, had higher stage disease, underwent radiation and/or systemic therapy and had a higher total oral morphine equivalent (OME) use at baseline (p < 0.01). Patients with a MC authorization were less likely to cease POM at 9-12 months post MC authorization (RR 0.63, 95% CI 0.57-0.70), and less likely to reduce their POM dose by 25% (RR 0.79, 95% CI 0.74-0.85) and 50%. (RR 0.73, 95% CI 0.67-0.79). Conclusions: Patients with early stage, non-metastatic cancer with a MC authorization have higher rates of baseline POM use and are less likely to cease or reduce their POM use up to 1 year after MC authorization. Further study is required to understand the harms of concomitant MC and POM use and the impact on survivorship care.

IntroductionEndoscopic retrograde cholangiopancreatography (ERCP) is performed to diagnose and manage conditions of the biliary and pancreatic ducts. Though effective, it is associated with common adverse events (AEs). The purpose of this study is to systematically review ERCP AE rates and report up-to-date pooled estimates.Methods and analysisA comprehensive electronic search will be conducted of relevant medical databases through 10 November 2020. A study team of eight data abstracters will independently determine study eligibility, assess quality and abstract data in parallel, with any two concordant entries constituting agreement and with discrepancies resolved by consensus. The primary outcome will be the pooled incidence of post-ERCP pancreatitis, with secondary outcomes including post-ERCP bleeding, cholangitis, perforation, cholecystitis, death and unplanned healthcare encounters. Secondary outcomes will also include rates of specific and overall AEs within clinically relevant subgroups determined a priori. DerSimonian and Laird random effects models will be used to perform meta-analyses of these outcomes. Sources of heterogeneity will be explored via meta-regression. Subgroup analyses based on median dates of data collection across studies will be performed to determine whether AE rates have changed over time.Ethics and disseminationEthics approval is not required for this study as it is a planned meta-analysis of previously published data. Participant consent is similarly not required. Dissemination is planned via presentation at relevant conferences in addition to publication in peer-reviewed journals.PROSPERO registration numberCRD42020220221.

The United States Preventive Services Task Force (USPSTF) recently issued an updated recommendation for population-based colorectal cancer (CRC) screening starting at age 45, due to a sustained increase in the incidence of early-age-at-onset CRC (eoCRC). A similar increase in the incidence of eoCRC has been observed in Canada since the early 2000s. However, the inherent differences between the US and Canadian health care systems with many different reimbursement and capacity considerations limit the applicability of the recommendations to the Canadian context. In order to facilitate further discussion around Canadian guidelines and recommendations, several research gaps need to be addressed: 1) a detailed understanding of trends in histology, topography, initial stage at diagnosis, and mortality among eoCRC; 2) a detailed analysis of cost-effectiveness outlining the impacts to the current screening programs with potential harms and benefits; 3) a comprehensive understanding of risk factor profiles that may lead to meaningful recommendations for screening decisions within the 40-49 age group in the absence of wide-spread screening programs; and 4) an evaluation of the effectiveness of current and novel screening tests or biomarkers specifically in the 40-49 age group. In the meantime, we suggest that physicians and patients begin discussions about screening at age 45 by reviewing family history and alerting patients to symptoms of CRC, which may increase screening adherence at age 50. This issue will remain an active area of debate with Canada as a careful laggard in changing recommendations, while attempting to balance system considerations with eoCRC trends and patient outcomes.

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.

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 ≥30kg/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=1.40; 95% CI: 1.06-1.84). A reduced risk was found for women with ≥2 pregnancies (OR=0.80; 95% CI: 0.64-1.00) and a first-degree family history of breast cancer was associated with an increased risk (OR=2.06; 95% CI: 1.54-2.75).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.

e17624 Background: Endometrial cancer (EC) incidence in Canada is steadily increasing and a paucity of real-world data exists. This study aimed to examine treatment (tx) patterns and clinical outcomes for patients (pts) with advanced and recurrent (A/R) EC in Canada. Methods: A retrospective observational cohort study was conducted among pts with primary advanced EC (de novo stage IIIB, IIIC, IV) or recurrent EC (progression from de novo stage I, II, IIIA) between 2010 and 2018 in Alberta, Canada. Health administrative data were used to describe baseline characteristics, time to next tx (TTNT), and overall survival (OS). Using Kaplan-Meier methods, TTNT was defined from tx initiation to initiation of subsequent tx or death from any cause, and OS was examined from tx initiation until death from any cause. Outcomes were stratified by pt type (A/R) and tx. Results: 1,053 pts were included: 620 (58.9%) advanced and 433 (41.1%) recurrent pts. 713 (67.7%) pts received first-line (1L) systemic therapy; this differed by pt type (75.2% of advanced and 57.0% of recurrent pts). Advanced pts who received chemotherapy were more likely to have prior surgery (p < 0.001), radiotherapy (p = 0.01), were younger (p < 0.001), and had fewer comorbidities (p < 0.001) than those without chemotherapy. Platinum-based chemotherapy (PBCT) was the most common 1L regimen (78.6%), differing by pt type (96.1% for advanced and 45.4% for recurrent pts). Hormone therapy in 1L was higher for recurrent compared to advanced pts (27.9% vs 3.2%). Median TTNT and OS from 1L systemic therapy was 19.9 months (95% confidence interval [CI]: 17.5–23.5) and 35.9 months (95% CI: 31.5–53.5), differing by therapy (p < 0.05). Median OS from 1L ranged from 8.5 months (95% CI: 6.2–20.0; platinum monotherapy) to 62.5 months (95% CI: 59.2–NA; hormone therapy). 257 pts received second-line (2L) chemotherapy, with a median TTNT of 7.0 months (95% CI: 6.1–8.2) and median OS of 12.6 months (95% CI: 10.0–14.6). Outcomes differed by tx (p < 0.05), with median OS ranging from 8.0 months (95% CI: 5.9–13.2; non-platinum monotherapy) to 17.1 months (95% CI: 12.7–NA; non-platinum combination). Among pts who received a 1L PBCT, median OS from 2L chemotherapy (N = 187) was 10.4 months (95% CI: 8.9–13.3) and was significantly higher for those rechallenged with PBCT compared to no rechallenge (13.3 months [95% CI: 11.2–20.9] vs 6.4 months [95% CI: 4.6–10.4]). Median OS in third-line (N = 71) and fourth-line (N = 26) chemotherapy was 11.0 months (95% CI: 8.2–13.5) and 12.0 months (95% CI: 7.5–NA), respectively. Outcomes did not differ significantly by pt type (A/R; p≥0.05). Conclusions: Outcomes for pts with A/R EC in Alberta, Canada are poor, particularly following 1L therapy where tx options are limited. Novel therapies with proven efficacy could address this unmet need and improve pt outcomes. Funding: GSK (216962; diana.d.martins@gsk.com).

e20504 Background: The prognosis of eNSCLC remains uniformly poor. An understanding of current therapies and outcomes can provide insights into how novel therapies can be integrated into our management paradigm. Methods: We conducted a large, retrospective, population-based cohort study of de novo eNSCLC patients (stages IB, IIA, IIB, and IIIA) diagnosed in Alberta, Canada between 2010-2019 using electronic medical records and administrative claims data. The primary objectives were to describe treatment patterns and survival outcomes among eNSCLC patients. In addition, we examined the association between systemic therapy (ST) and overall survival (OS) using multivariable Cox proportional hazards models. Results: A total of 5,126 eNSCLC patients were included. The stage distributions were: 31.0% IB, 13.4% IIA, 17.7% IIB, and 37.9% IIIA. The mean (SD) age was 71.3 (10.3) years and 52.5% were female. 45.3% of patients were referred to a medical oncologist, ranging from 23.7% in stage IB and 58.3% of IIIA. Among stage IB and II patients, 59.2% and 58.1% received surgery, respectively, while 25.7% of stage IIIA patients underwent surgery. 23.6% of patients initiated ST, ranging from 3.5% in stage IB to 38.5% in IIIA. ST use increased over the study period by 9.3% and 19.5% in stage IIB and IIIA disease, respectively. Median follow-up for the cohort was 21.86 months; median OS was 28.18 months (95% CI: 26.56-29.69). Median OS for stage IB, IIA, IIB, and IIIA were 49.01 (95% CI: 45.00-54.15), 36.56 (95% CI: 32.94-42.25), 29.23 (95% CI: 25.32-33.11), and 16.50 (95% CI: 15.39-17.59). Findings from the Cox analyses are tabulated (see Table). For stage IIB and IIIA individuals who received surgery, adjuvant ST was also associated with a decreased likelihood of death [hazard ratios (HR) of 0.77 (95% CI: 0.56-1.07) and 0.69 (95% CI: 0.54-0.89), respectively]. Conclusions: In a Canadian real-world setting, stage IIB and IIIA patients who received adjuvant ST tended to have better survival than patients who did not. However, a considerable proportion of patients are not referred to a medical oncologist to be considered for ST. Improving referral pathways appears to be an essential step to ensure that emerging novel therapies are implemented effectively in the real world so that potential survival gains from new drugs can be realized.[Table: see text]

e21139 Background: While Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors have been shown to be effective in phase III randomized trials, the value of targeted therapies have been challenging to evaluate at the population level. We examined the impact of population-level EGFR testing and treatment on survival outcomes among metastatic Non-Small Cell Lung Cancer (NSCLC) patients. Methods: Real-world, population-level data were collected from all de novo metastatic non-squamous NSCLC patients in Alberta, Canada from 2004 to 2020. EGFR testing data were collected through Alberta Precision Laboratories using various text mining approaches. Differences in survival rates and overall survival (OS) pre (2004-2012) and post-initiation (post) (2013-2019) testing periods were evaluated using interrupted time series analyses. The impact of testing and subsequent treatment weas evaluated using multivariable Cox Proportional Hazards models. Results: In total, 4,578 metastatic NSCLC patients with a confirmed non-squamous cell carcinoma histology were diagnosed pre- EGFR testing and 4,457 patients were diagnosed post- EGFR testing (2013-2019). Among patients diagnosed in the pre- EGFR testing period, the 6-month, 1-year, and 2-year survival probabilities were 0.39 (95% CI: 0.38-0.41), 0.22 (95% CI: 0.21-0.23), and 0.09 (95% CI: 0.08-0.10), while the survival probabilities for patients diagnosed in the post- EGFR testing period were 0.45 (95% CI: 0.43-0.46), 0.29 (95% CI: 0.27-0.30), and 0.16 (95% CI: 0.15-0.1 7), respectively. After adjusting for baseline patient and clinical characteristics, OS in the post- EGFR period was significantly improved compared to the pre- EGFR period (HR: 0.81; 95% CI: 0.78-0.85). In the post-EGFR period, among patients who were treated with systemic therapy, those tested for an EGFR mutation had significantly greater survival than patients who were not tested HR of 0.81 (95% CI: 0.70-0.95). Conclusions: These results show the considerable impact of population-based molecular testing and subsequent targeted therapies on survival among advanced NSCLC patients. The estimates here can be used in future studies to evaluate the population-level cost-effectiveness of testing and treatment.

e18776 Background: Adults aged ≥70 years represent approximately half of all patients diagnosed with colon cancer (CC), but undertreatment in this population persists. Recent guidelines have aimed to reduce age-related biases in the treatment of CC and emphasized the importance of personalizing management with comprehensive geriatric assessments (CGAs). Therefore, we hypothesized that age-related disparities in the curative-intent treatment of CC would improve over time. Methods: This was a retrospective, population-based cohort study of adults diagnosed with CC between 2010 and 2018 in Alberta, Canada. The study data included patient demographics and clinical characteristics collected through the Alberta Cancer Registry and electronic medical records. Patients were stratified by age: < 70 and ≥70 years. Cox proportional hazard models (CPHM) were generated to evaluate the associations and interaction between age groups and treatment status on disease-specific survival (DSS), after adjusting for important covariates. Multivariable logistic regression was used to identify time trends and predictors of treatment receipt. Results: A total of 10,838 patients were included, of whom 5,176 (48%) were aged ≥70 years and 2,468 (23%) had stage IV CC at initial diagnosis. Older age was associated with greater comorbidity and less advanced disease ( p < 0.001, standardized mean difference > 0.1 for both). The vast majority (87%) of patients in the overall cohort received surgery while 34% received systemic therapy. In multivariable CPHM, older age was associated with lower DSS (HR 1.42, 95%CI 1.31-1.54, p < 0.001) while surgery and systemic therapy were each associated with higher DSS (HR 0.30, 95%CI 0.27-0.33, p < 0.001; HR 0.40, 95%CI 0.37-0.43, p < 0.001; respectively). However, the interaction between age and treatment status was not statistically significant ( p = 0.78 for surgery; p = 0.17 for systemic therapy). Compared to the younger age group, the odds of receiving surgery and systemic therapy were 3 and 5 times lower, respectively, among older patients (OR 0.27, 95%CI 0.18-0.40, p < 0.001; OR 0.18, 95%CI 0.16-0.20, p < 0.001; respectively). In addition to younger age, predictors of surgery receipt included less comorbidity and stage II/III vs I disease, whereas predictors of systemic therapy receipt included male sex, southern residence, higher neighbourhood income, less comorbidity, and stage III vs IV disease ( p < 0.05 for all). There were no statistically significant correlations between year of diagnosis and treatment receipt ( ptrend = 0.07 for surgery; ptrend = 0.26 for systemic therapy). Conclusions: Surgery and systemic therapy continue to improve CC outcomes regardless of age. However, rates of curative-intent treatment for CC were consistently lower in patients aged ≥70 years, with minimal changes over time. Better integration of CGAs into routine care may be needed to reduce persistent age-related treatment disparities.

Approximately 3.5% of deliveries in Canada result in potentially preventable neonatal readmission, often times due to preventable morbidities. With complexities in hospital discharge planning, health care providers may benefit in identifying infants at risk of readmission for additional monitoring. To develop and validate models for predicting 7-day neonatal readmission following vaginal or cesarean births. All liveborn term singleton infants without congenital anomalies in the province of Alberta who were not admitted to the NICU were identified using perinatal and hospitalization databases. A temporal split-sample was used for model development (2012–2014, vaginal n = 63,378; cesarean n = 21,225) and external validation (2014–2015, vaginal n = 21,583, cesarean n = 7,477). Multivariable logistic regression models using backward stepwise selection were used to identify predictors of 7-day readmission. We evaluated predictors of maternal age, Apgar score, length-of-stay, birthweight, gestational age, parity, residence, and sex. Hosmer-Lemeshow test and c-statistics were used to estimate calibration and discrimination. The rate of readmission was 3.3% (95% CI 3.1%, 3.4%) and 2.1% (95% CI 1.9%, 2.3%) following vaginal and cesarean births in the development dataset. Prediction model following vaginal birth, excluding predictors of length-of-stay and birthweight, had sub-optimal performance in development (c-statistics 0.69) and validation data (c-statistics 0.68). Prediction model following cesarean birth, excluding predictors of maternal age, birthweight, and residence, had sub-optimal performance in development (c-statistics 0.62) and validation data (c-statistics 0.64). Readmission was observed in 7.9% (95% CI 7.1%, 8.8%) and 4.9% (95% CI 3.9%, 6.1%) of infants of vaginal and cesarean births, respectively, in the top quintile for the risk of 7-day readmission. Using routinely collected administrative data, we developed and validated prediction models for neonatal readmission following vaginal and cesarean births. Presently the model is sub-optimal for use in risk assessment and planning at discharge, however, additional information may improve the predictive performance.

Objective To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways. Design Systematic review and meta-analysis. Data sources Published studies in Medline from 1 January 2000 to 10 April 2020. Eligibility criteria for selecting studies Curative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models. Results The review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P Conclusions Cancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes.

Objectives Acute exposures to outdoor air pollution have been shown to reduce lung function in children with asthma, but the effect on adults with asthma has not been established in a meta-analysis. The objective of this study was to conduct a systematic literature review and meta-analysis of studies that assessed the relationship of outdoor air pollution and peak expiratory flow (PEF) in adults with asthma. Methods Studies that contained data on outdoor air pollution levels (PM10, PM2.5, or NO2) and PEF in adults with asthma were eligible for inclusion. Effect estimates were quantified for each air pollution measure using random effects models. Heterogeneity was investigated with the Q-test and I2 statistics. Meta-regression and subgroup analyses were conducted to determine differences in effect by air pollution measures and the inclusion of smokers. Results A total of 22 effect estimates from 15 studies were included in this review. A 10 μg/m3 increase in acute PM10 exposure was associated with a −0.19 L/min (95% CI: 0.30, −0.09) change in PEF. For both PM10 and PM2.5, the inclusion of current smokers was a significant source of heterogeneity among studies (meta-regression: p = 0.04 and p = 0.03). Among studies that only included non-smokers, a 10 μg/m3 increase in acute exposure to PM10 and PM2.5 was associated with changes in PEF of −0.25 L/min (95% CI: 0.38, −0.13) and −1.02 L/min (95% CI: 1.79, −0.24), respectively. Conclusions This study provides evidence that acute increases in PM10 and PM2.5 levels are associated with decreases in PEF in adults with asthma, particularly among non-smokers.

Ultraviolet radiation (UVR) is an established cause of non-melanoma skin cancer (NMSC)—basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The aim of this study was to estimate the current burden of BCC and SCC associated with UVR and modifiable UVR behaviours (sunburn, sunbathing, and indoor tanning) in Canada in 2015. The current burden of BCC and SCC associated with UVR was estimated by comparing 2015 incidence rates with rates of less exposed body sites (trunk and lower limbs) after adjusting for estimated surface areas. The burden associated with modifiable UVR behaviours was estimated by using prevalence estimates among Caucasians from the Second National Sun Survey, and relative risks that are generalizable to Canadians from conducting meta-analyses of relevant studies. We estimated that 80.5% of BCCs and 83.0% of SCCs were attributable to UVR. Adult sunburn was associated with relative risks of 1.85 (95% CI 1.15–3.00) for BCC and 1.41 (95% CI 0.91–2.18) for SCC, while adult sunbathing was associated with relative risks of 1.82 (95% CI 1.52–2.17) for BCC and 1.14 (95% CI 0.53–2.46) for SCC. We estimated that 18.6% of BCCs and 9.9% of SCCs were attributable to adult sunburn, while 28.1% of BCCs were attributable to adult sunbathing. We estimated that 46.2% of BCCs and 17.3% of SCCs were attributable to modifiable UVR behaviours combined. Our results provide quantifiable estimates of the potentially avoidable burden of NMSCs among Canadians. These estimates can be used to motivate prevention efforts in Canada.

The extent to which physical activity reduces breast cancer risk through changes in global DNA methylation is unknown. We systematically identified studies that investigated the association between: (i) physical activity and global DNA methylation; or (ii) global DNA methylation and breast cancer risk. Associations were quantified using random-effects models. Heterogeneity was investigated through subgroup analyses and the Q-test and I2 statistics. Twenty-four studies were reviewed. We observed a trend between higher levels of physical activity and higher levels of global DNA methylation [pooled standardized mean difference = 0.19; 95% confidence interval (CI), −0.03–0.40; P = 0.09] which, in turn, had a suggestive association with a reduced breast cancer risk (pooled relative risk = 0.70; 95% CI, 0.49–1.02; P = 0.06). In subgroup analyses, a positive association between physical activity and global DNA methylation was observed among studies assessing physical activity over long periods of time (P = 0.02). Similarly, the association between global DNA methylation and breast cancer was statistically significant for prospective cohort studies (P = 0.007). Despite the heterogeneous evidence base, the literature suggests that physical activity reduces the risk of breast cancer through increased global DNA methylation. This study is the first to systematically overview the complete biologic pathway between physical activity, global DNA methylation, and breast cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1320–31. ©2018 AACR.

The incidence of early-onset (50) colorectal cancer (eoCRC) has been increasing in Canada. Little is known about treatment patterns and outcomes among this patient population in Canada.We conducted a retrospective population-based cohort study of CRC patients in Alberta (2010-2018) using electronic medical records and administrative claims data. Treatment patterns and CRC-specific mortality were compared between early-onset age groups (40 and 40-49) and average age-at-onset (60-70) (aoCRC) patients with multivariable logistic regression and cox proportional hazard models.There were 334 and 935 patients in the early-onset groups and 4606 in the aoCRC group. Compared with aoCRC, patients40 were more likely to receive chemotherapy in stage II colon (OR 3.41, CI 1.75-6.47) and stage III rectal (OR 3.01, CI 1.18-10.21), and to receive systemic therapy (OR 2.40, CI 1.46-4.12) and radiation in stage IV CRC (OR 2.70, CI 1.48-4.92). The 40-49 age group was more likely to receive chemotherapy in stage II colon (OR 2.13, CI 1.25-3.56), and chemoradiation in stage II rectal (OR 2.16, CI 1.25-3.80) and stage III rectal (OR 1.63, CI 1.13-2.40), as well as systemic therapy in stage IV CRC (OR 2.46, CI 1.75-3.52). Survival did not differ between40 and 60-70 age groups. Survival was significantly higher for the 40-49 age group, but only in stage IV (HR 0.79, CI 0.67-0.94).EoCRC patients tended to receive more therapy than average age CRC patients with minimal survival gains. Additional research to identify optimal treatment strategies for eoCRC patients is required.

Genetic and epigenetic alterations are required for carcinogenesis and the mutation burden across tumor types has been investigated. Here, we investigate epigenetic alterations with a novel measure of global DNA methylation dysregulation, the methylation dysregulation index (MDI), across 14 cancer types in The Cancer Genome Atlas (TCGA) database. DNA methylation data—obtained using Illumina HumanMethylation450 BeadChip—was accessed from TCGA. We calculated the MDI in 14 tumor types (n = 5,592 tumors), using adjacent normal tissues (n = 701) from each tumor site. Copy number alteration, and mutation burden were retrieved from cBioportal (n = 5,152). We tested the relation of subject MDI across tumors and with age, gender, tumor stage, estimated tumor purity, and copy number alterations for both overall MDI and genomic-context-specific MDI. We also investigated the top most dysregulated loci shared across tumor types. There was a broad range of extent in methylation dysregulation across tumor types (P < 2.2E-16). However, a consistent pattern of methylation dysregulation stratified by genomic context was observed across tumor types where the highest dysregulation occurred at non-CpG island regions. Considering other summary measures of somatic alteration, MDI was correlated with copy number alterations but not with mutation burden. Using the top dysregulated CpG sites in common across tumors, 4 classes of cancer types were observed, and the functional consequences of these alterations to gene expression were confirmed. This work identified the global DNA methylation dysregulation patterns across 14 cancer types showing a higher impact for the non-CpG island areas. The most dysregulated loci across cancer types identified common clusters across cancer types that may have implications for future treatment and prevention measures.

Background: A protective relationship has been hypothesized between exposure to solar ultraviolet radiation (UVR) and the development of breast cancer. Objective: The objective of this study was to conduct a systematic literature review and meta-analysis of studies examining the association of exposure to solar UVR and breast cancer risk. Methods: We searched Medline, EMBASE, and Web of Science for all studies investigating exposure to solar UVR and breast cancer risk. Separate analyses were performed using estimates of time spent in the sun, and ambient UVR. Associations were estimated using DerSimonian and Laird random-effect models. Heterogeneity was investigated through subgroup analyses and I2 statistics. Results: Fourteen studies were included in the review and 13 in the meta-analysis, with the majority (n=8) conducted in North America. We observed a decreased risk of breast cancer for individuals spending ≥1h/d in the sun during summer months over a lifetime or usual adulthood compared with

ObjectiveGermline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.DesignWhole exome sequencing of formalin-fixed paraffin embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers.ResultsThe combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC’s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10−5), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99), however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls.ConclusionAssessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.SIGNIFICANCE OF THE STUDYWhat is already known about this subject?Identifying carriers of pathogenic variants (PVs) in moderate/high-risk colorectal cancer (CRC) and polyposis susceptibility genes has clinical relevance for diagnosis, targeted screening and prevention strategies, prognosis, and treatment options. However, challenges still remain in the identification of carriers and the classification of rare variants in these genes.Previous studies have identified tumour mutational signatures that result from defective DNA repair including DNA mismatch repair (MMR) deficiency and base excision repair defects, DNA repair mechanisms that underlie the common hereditary CRC and polyposis syndromes but their diagnostic utility in CRC is unknown.What are the new findings?Single base substitution (SBS)-related mutational signatures derived from whole exome sequencing of formalin-fixed paraffin embedded (FFPE)-derived CRC tissue DNA can effectively discriminate CRCs that developed in biallelic MUTYH PV carriers from CRC-affected non-carriers.CRCs that develop in MMR PV carriers (Lynch syndrome) can be effectively differentiated from sporadic MMR-proficient CRC by a combination of indel (ID) signatures, but the SBS and ID tumour mutational signatures are less effective at discriminating Lynch syndrome-related CRC from sporadic MMR-deficient CRC resulting from MLH1 gene promoter hypermethylation.The SBS and ID mutational signatures associated with biallelic MUTYH PV carriers and MMR PV carriers are robust to changes in experimental settings.We demonstrate the optimal experimental settings for calculating mutational signatures and define thresholds that optimise sensitivity and specificity for classifying CRC aetiology as hereditary or non-hereditary.How might it impact on clinical practice in the foreseeable future?Deriving SBS- and ID-related mutational signatures from CRCs can identify carriers of PVs in hereditary CRC and polyposis susceptibility genes.The application of mutational signatures has the potential to improve the diagnosis of hereditary CRC and aid in variant classification, leading to improved clinical management and CRC prevention.

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.

BACKGROUND: Although cancer incidence over time is well documented in Canada, trends by birth cohort and age group are less well known. We analyzed age- and sex-standardized incidence trends in Canada for 16 major cancer sites and all cancers combined. METHODS: We obtained nationally representative population-based cancer incidence data in Canada between 1971 and 2015 from the National Cancer Incidence Reporting System (1969–1992) and the Canadian Cancer Registry (1992–2015). We analyzed cancer-incidence trends, reported as annual percent change (APC) for each 10-year group from age 20 to 89 years. We also estimated age-adjusted incidence rate ratios from fitted birth cohort models. RESULTS: Across most age categories, the most recent trends show significant decreases in the incidence of cervical (APC −8.8% to −0.33%), lung (men: −7.42% to −0.36%; women: −6.27% to 1.07%), bladder (women: −4.12% to −0.07%; men: −5.13% to −0.38%) and prostate cancer (−11.11% to −1.11%). Significant increasing trends were observed for kidney, thyroid and uterine cancers. Overall incidence has increased among both sexes younger than 50 years of age, with recent increases in pancreatic cancer among men, breast cancer among women and colorectal cancer among both sexes. From the birth cohort analysis, we observed increasing trends in colorectal, liver and prostate cancers among men; kidney cancer and melanoma among women; and thyroid cancer among both sexes. We observed decreasing trends in cervical and ovarian cancers, and in bladder and lung cancers among men. INTERPRETATION: Cancer incidence is decreasing at many sites targeted by primary-prevention efforts, such as smoking cessation and screening programs. Substantial increases in incidence among younger populations are driven by cancers possibly associated with obesity.