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The coronavirus disease (COVID-19) pandemic and its economic consequences may disproportionately impact cancer survivors and their overall health-related quality of life. The objective of this study was to examine whether cancer survivors experienced higher levels of financial strain or food insecurity compared to those without a history of cancer.Kaiser Permanente Research Bank (KPRB) study participants were invited to complete a series of electronic surveys starting April 2020 to assess the impact of the COVID-19 pandemic. Participants who completed the initial survey and one follow-up survey were included. The odds of financial strain and food insecurity in those with and without a history of cancer were estimated using multinomial logistic regression.Cancer survivors (n = 16,231) had lower odds of reporting "somewhat hard" (AOR = 0.77) and "very hard" (AOR = 0.67) financial strain, and food insecurity "sometimes" (AOR = 0.70) and "often" (AOR = 0.55) compared to those with no history of cancer (n = 88,409). Non-Hispanic (NH) Black and Hispanic cancer survivors had higher odds compared to NH Whites of reporting financial strain and food insecurity. Smokers and those with multiple comorbidities had higher odds of reporting financial strain and food insecurity among cancer survivors.While cancer survivors overall did not report greater financial strain or food insecurity than individuals without a history of cancer, subsets of cancer survivors are experiencing greater social risks during the pandemic and should be prioritized for screening for social risk factors.Incorporating screening for social risk factors into care coordination workflows for subsets of cancer survivors should be a priority.

The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

AIM: International studies have shown that most colon cancers are diagnosed among people with symptoms, but research is limited in the United States. We conducted a retrospective study with adults aged 50–85 years diagnosed with stage I-IIIA colon cancer in 1995–2014 in two US healthcare systems. METHOD: Mode of detection (screening or symptomatic) was ascertained from medical records. We estimated unadjusted odds ratios (OR) and 95% confidence intervals (CI) comparing detection mode by patient factors at diagnosis (year, age, sex, race, smoking status, body mass index [BMI], Charlson score), pre-diagnostic primary care utilization, and tumor characteristics (stage, location). RESULTS: Of 1,675 people with colon cancer, 38.4% were screen-detected, while 61.6% were diagnosed following symptomatic presentation. Screen-detected cancer was more common among those diagnosed in 2010–2014 vs. 1995–1999 (OR=1.65, 95%CI=1.19–2.28), and those with a BMI of 25-0 (OR=0.71, 95%CI=0.56–0.91 for score=1, OR=0.34, 95%CI=0.26–0.45 for score=2+), and those with 2+ pre-diagnostic primary care visits (OR=0.53, 95%CI=0.37–0.76) vs. 0 visits. The odds of screen detection were lower among patients diagnosed with stage IIA (OR=0.33, 95%CI=0.27–0.41) or IIB (OR=0.12, 95%CI=0.06–0.24) cancers vs. stage I. CONCLUSION: Most colon cancers among screen-eligible adults were diagnosed following symptomatic presentation. Even with increasing screening rates over time, research is needed to better understand why specific groups are more likely to be diagnosed when symptomatic and identify opportunities for interventions.

BACKGROUND Declines in the prevalence of cigarette smoking, advances in targeted therapies, and implementation of lung cancer screening have changed the clinical landscape for lung cancer. An increasing proportion of lung cancer deaths are in those who have never smoked cigarettes. To better understand contemporary patterns in survival among patients with lung cancer, a comprehensive evaluation of factors associated with survival, including differential associations by smoking status, is needed. METHODS Patients diagnosed with lung cancer between 1/1/2010 and 9/30/2019 were identified. We estimated all-cause and lung cancer-specific median, 5-year, and multivariable restricted mean survival time (RMST) to identify demographic, socioeconomic, and clinical factors associated with survival, overall and stratified by smoking status (never, former, and current). RESULTS Analyses included 6,813 patients with lung cancer: 13.9% never smoked, 54.2% formerly smoked, and 31.9% currently smoked. All-cause RMST through 5-years for those who never, formerly, and currently smoked was 32.1, 25.9, and 23.3 months, respectively. Lung cancer specific RMST was 36.3, 30.3, and 26.0, respectively. Across most models, female sex, younger age, higher SES, first course surgery, histology, and BMI were positively associated, and higher stage was inversely associated with survival. Relative to White patients, Black patients had increased survival among those who formerly smoked. CONCLUSION We identify actionable factors associated with survival between those who never, formerly, and currently smoked cigarettes. These findings illuminate opportunities to address underlying mechanisms driving lung cancer progression, including use of first-course treatment, and enhanced implementation of tailored smoking cessation interventions for individuals diagnosed with cancer.

Background Identifying key determinants is crucial for improving program implementation and achieving long-term sustainment within healthcare organizations. Organizational-level complexity and heterogeneity across multiple stakeholders can complicate our understanding of program implementation. We describe two data visualization methods used to operationalize implementation success and to consolidate and select implementation factors for further analysis. Methods We used a combination of process mapping and matrix heat mapping to systematically synthesize and visualize qualitative data from 66 stakeholder interviews across nine healthcare organizations, to characterize universal tumor screening programs of all newly diagnosed colorectal and endometrial cancers and understand the influence of contextual factors on implementation. We constructed visual representations of protocols to compare processes and score process optimization components. We also used color-coded matrices to systematically code, summarize, and consolidate contextual data using factors from the Consolidated Framework for Implementation Research (CFIR). Combined scores were visualized in a final data matrix heat map. Results Nineteen process maps were created to visually represent each protocol. Process maps identified the following gaps and inefficiencies: inconsistent execution of the protocol, no routine reflex testing, inconsistent referrals after a positive screen, no evidence of data tracking, and a lack of quality assurance measures. These barriers in patient care helped us define five process optimization components and used these to quantify program optimization on a scale from 0 (no program) to 5 (optimized), representing the degree to which a program is implemented and optimally maintained. Combined scores within the final data matrix heat map revealed patterns of contextual factors across optimized programs, non-optimized programs, and organizations with no program. Conclusions Process mapping provided an efficient method to visually compare processes including patient flow, provider interactions, and process gaps and inefficiencies across sites, thereby measuring implementation success via optimization scores. Matrix heat mapping proved useful for data visualization and consolidation, resulting in a summary matrix for cross-site comparisons and selection of relevant CFIR factors. Combining these tools enabled a systematic and transparent approach to understanding complex organizational heterogeneity prior to formal coincidence analysis, introducing a stepwise approach to data consolidation and factor selection.

PDF file, 73K, BRAF mutation status and survival after colorectal cancer diagnosis by patient and tumor characteristics, excluding cases with unknown MSI status.

Background: To reduce colorectal cancer mortality, positive fecal blood tests must be followed by colonoscopy.Methods: We identified 62,384 individuals ages 50 to 89 years with a positive fecal blood test between January 1, 2011 and December 31, 2012 in four health care systems within the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. We estimated the probability of follow-up colonoscopy and 95% confidence intervals (CI) using the Kaplan–Meier method. Overall differences in cumulative incidence of follow-up across health care systems were assessed with the log-rank test. HRs and 95% CIs were estimated from multivariate Cox proportional hazards models.Results: Most patients who received a colonoscopy did so within 6 months of their positive fecal blood test, although follow-up rates varied across health care systems (P Conclusion: Individual characteristics and health care system were associated with colonoscopy after positive fecal blood tests. Patterns were consistent across health care systems, but proportions of patients receiving follow-up varied. These findings suggest that there is room to improve follow-up of positive colorectal cancer screening tests.Impact: Understanding the timing of colonoscopy after positive fecal blood tests and characteristics associated with lack of follow-up may inform future efforts to improve follow-up. Cancer Epidemiol Biomarkers Prev; 25(2); 344–50. ©2016 AACR.

Table S1. Cohort Development for a Comparison of American Indians / Alaska Natives and non-Hispanic Whites with Metastatic Cancer.

Background:BRAF mutations in colorectal cancer (CRC) are disproportionately observed in tumors exhibiting microsatellite instability (MSI) and are associated with other prognostic factors. The independent association between BRAF mutation status and CRC survival, however, remains unclear.Methods: We evaluated the association between the BRAF c.1799T>A (p.V600E) mutation and survival in individuals with incident invasive CRC diagnosed between 1997 and 2007 in Western Washington State. Tumor specimens were tested for this BRAF mutation and MSI status. We used Cox regression to estimate HRs and 95% confidence intervals (CI) for the association between BRAF mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumor site, stage, and MSI status.Results: Among 1,980 cases tested, 12% were BRAF c.1799T>A (p.V600E) mutation–positive (n = 247). BRAF-mutated CRC was associated with poorer disease-specific survival adjusting for age, sex, time from diagnosis to enrollment, stage, and MSI status (HR, 1.43; 95% CI, 1.05–1.95). This association was limited to cases diagnosed at ages Conclusions: Our results show that the prevalence of BRAF mutations in CRC differs by patient and tumor characteristics and suggest that the association between BRAF status and CRC survival may differ by some of these factors.Impact: The presence of a BRAF c.1799T>A (p.V600E) mutation is associated with significantly poorer prognosis after CRC diagnosis among subgroups of patients. Cancer Epidemiol Biomarkers Prev; 21(10); 1792–8. ©2012 AACR.

Supplementary Table S1. Characteristics of PROSPR participants with a positive fecal occult blood test with no covariate information missing, 2011-2012 (N=47,827). Supplementary Table S2. Associations between patient characteristics and time to colonoscopy follow-up after positive fecal occult blood test in PROSPR healthcare systems, 2011-2012, over different follow-up periods.

PDF file, 60K, Joint BRAF / MSI status and survival after colorectal cancer diagnosis, excluding cases with unknown MSI status.

Supplementary Table 1 - PDF file 74K, Prevalence of serrated lesion subtypes with mutant BRAF, CIMP-high, and methylated MLH1: Group Health Enrollees 1998-2007

Supplemental Material for Demographic, Clinical, and Behavioral Factors Associated With Electronic Nicotine Delivery Systems Use in a Large Cohort in the United States by Shauna Goldberg Scott, MPH, Heather S. Feigelson, PhD, MPH, J. D. Powers, MS, Morgan N. Clennin, PhD, MPH, Jason A. Lyons, MA, Mark T. Gray BS, Anil Vachani, MD, MS, and Andrea N. Burnett-Hartman, PhD, MPH in Tobacco Use Insights.

Additional file 1: Fig. 1. Data Extraction Guide for Universal Tumor Screening (UTS) Protocol Processes. Fig 2. Process and Contextual Differences within Organization 1. Fig 3. Initial Process Map for Organizational Unit 1A. Fig 4. Reconciled Process Map for Organizational Unit 1A. Fig. 5. Process Gap/Inefficiency to Optimization Component Conversion Table. Fig. 6. Matrix of UTS Protocol Optimization Levels by Organizational Unit. Fig. 7. Section of the CFIR Codebook Used for Qualitative Data Analysis. Fig. 8. Data Matrix of Factors Related to Intervention Characteristics from Organizational Unit 7. Fig. 9. Example of a Data Matrix Heat Map for Factors Related to Intervention Characteristics. Fig. 10. Example of Combined Codes for Factors Related to Intervention Characteristics. Fig. 11. Consolidated Data Matrix Heat Map for Characteristics of Intervention by Optimization Score. Fig. 12. Example of Collapsed Code ‘Evidence & Relative Advantage’ for all Organizational Units. Fig. 13. Final Heat Map of Factors Selected for Coincidence Analysis (CNA).

To evaluate whether limited participation in life activities is associated with quality of life (QOL) in rectal cancer survivors, and if so, whether this association is independent of bowel function difficulties. We surveyed rectal cancer survivors from four healthcare systems about their QOL, bowel function, and participation in life activities. Additional demographic and clinical variables were extracted from the electronic health record. We examined independent associations between bowel function, participation in life activities, and QOL, controlling for potential confounders. We also identified factors, including ostomy status, that correlate with participation in life activities. Of the 527 respondents, 52% were male, 80% were non-Hispanic white, and the mean age was 63. In fully adjusted models for all rectal cancer survivors, participation in life activities was positively associated with QOL, while bowel function was not. Bowel function retained an independent association with QOL for those who previously had an ostomy and were therefore more likely to have a low rectal anastomosis. Lower participation in life activities was correlated with lower self-reported physical and cognitive function, younger age, financial difficulty, and being non-Hispanic white. Rectal cancer survivors’ participation in life activities was strongly associated with QOL, even when controlling for numerous confounders, including bowel function. Identifying ways to improve participation in life activities may be critical to developing rehabilitative and other supportive interventions that optimize QOL among rectal cancer survivors.

Purpose: Although studies have evaluated the mental health impacts in those recently diagnosed with cancer during the pandemic, few studies focused on cancer survivors who are past their primary cancer treatment. The objective of this study was to assess the impact of the COVID-19 pandemic on depression, anxiety, and loneliness between those with and without a history of cancer.Methods: Kaiser Permanente Research Bank participants were invited to complete a series of surveys from May to December 2020. The difference in score of depression, anxiety, and loneliness were estimated using linear mixed regression. All models adjusted for age group, sex, race/ethnicity, Kaiser Permanente region, smoking status, and Charlson comorbidity score.Results: Among cancer survivors, 21% and 19% met the thresholds for increased risk of depression and anxiety. Among those without a history of cancer, 24% met the thresholds for increased risk of depression and anxiety. Both groups reported decreases in mean depression, anxiety, and loneliness scores between May and July 2020, however, scores increased from August to December 2020. Cancer survivors had decreased depression, anxiety, and loneliness scores compared to those without a history of cancer. Among cancer survivors, younger age groups and females reported increased depression, anxiety, and loneliness scores, while non-Hispanic Black and Asian participants reported decreased depression, anxiety, and loneliness scores.Conclusion: The results of this study highlight the continued necessity of addressing mental health needs and social support in cancer survivors, especially those who are younger and female, during and after a public health emergency.

Rising trends in the incidence and mortality of early-onset colorectal cancer (CRC) in those who are younger than 50 years have been well established. These trends have spurred intense investigation focused on elucidating the epidemiology and characteristics of early-onset CRC, as well as on identifying strategies for early detection and prevention. In this review, we provide a contemporary update on early-onset CRC with a particular focus on epidemiology, molecular characterization, red flag signs and symptoms, and screening for early-onset CRC.

Background: Most genetics studies lack the diversity necessary to ensure that all groups benefit from genetic research. Objectives: To explore facilitators and barriers to genetic research participation. Methods: We conducted a survey on genetics in research and healthcare from November 15, 2017 to February 28, 2018 among adult Kaiser Permanente (KP) members who had been invited to participate in the KP biobank (KP Research Bank). We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the willingness to participate in genetic research under different return of results scenarios and genetic discrimination concerns between groups, according to their demographic characteristics. Results: A total of 57,331 KP members were invited to participate, and 10,369 completed the survey (18% response rate). Respondents were 65% female, 44% non-Hispanic White (NH White), 22% Asian/Native Hawaiian or other Pacific Islander (Asian/PI), 19% non-Hispanic Black (NH Black), and 16% Hispanic. Respondents willing to participate in genetic research ranged from 22% with no results returned to 87% if health-related genetic results were returned. We also found variation by race/ethnicity; when no results were to be returned, Asian/PIs, Hispanics, and NH Blacks were less likely to want to participate than NH Whites (p < 0.05). However, when results were returned, disparities in the willingness to participate disappeared for NH Blacks and Hispanics. Genetic discrimination concerns were more prevalent in Asian/PIs, Hispanics, and NH Blacks than in NH Whites (p < 0.05). Conclusions: Policies that prohibit the return of results and do not address genetic discrimination concerns may contribute to a greater underrepresentation of diverse groups in genetic research.

The effectiveness and efficiency of cancer screening in real-world settings depend on many factors, including test sensitivity and specificity. Outside of select experimental studies, not everyone receives a gold standard test that can serve as a comparator in estimating screening test accuracy. Thus, many studies of screening test accuracy use the passage of time to infer whether or not cancer was present at the time of the screening test, particularly for patients with a negative screening test. We define the accuracy assessment interval as the period of time after a screening test that is used to estimate the test's accuracy. We describe how the length of this interval may bias sensitivity and specificity estimates. We call for future research to quantify bias and uncertainty in accuracy estimates and to provide guidance on setting accuracy assessment interval lengths for different cancers and screening modalities.

Introduction Our primary purpose is to understand comorbidities and health outcomes associated with electronic nicotine delivery systems (ENDS) use. Methods Study participants were Kaiser Permanente (KP) members from eight US regions who joined the Kaiser Permanente Research Bank (KPRB) from September 2015 through December 2019 and completed a questionnaire assessing demographic and behavioral factors, including ENDS and traditional cigarette use. Medical history and health outcomes were obtained from electronic health records. We used multinomial logistic regression to estimate odd ratios (ORs) and 95% confidence intervals (CIs) of current and former ENDS use according to member characteristics, behavioral factors, and clinical history. We used Cox regression to estimate hazard ratios (HRs) and 95% CIs comparing risk of health outcomes according to ENDS use. Results Of 119 593 participants, 1594 (1%) reported current ENDS use and 5603 (5%) reported past ENDS use. ENDS users were more likely to be younger, male, gay or lesbian, and American Indian / Alaskan Native or Asian. After adjustment for confounding, current ENDS use was associated with current traditional cigarette use (OR = 39.55; CI:33.44-46.77), current marijuana use (OR = 6.72; CI:5.61-8.05), history of lung cancer (OR = 2.64; CI:1.42-4.92), non-stroke cerebral vascular disease (OR = 1.55; CI:1.21-1.99), and chronic obstructive pulmonary disease (OR = 2.16; CI:1.77-2.63). Current ENDS use was also associated with increased risk of emergency room (ER) visits (HR = 1.17; CI: 1.05-1.30) and death (HR = 1.84; CI:1.02-3.32). Conclusions Concurrent traditional cigarette use, marijuana use, and comorbidities were prevalent among those who used ENDS, and current ENDS use was associated with an increased risk of ER visits and death. Additional research focused on health risks associated with concurrent ENDS and traditional cigarette use in those with underlying comorbidities is needed.

Background Black people experience excess cervical and colorectal (CRC) cancer burden. Racial residential segregation, one measure of exposure to racism, is a potential driver of these inequities. To achieve cancer equity, it is crucial to better understand the role of racism and cancer prevention and early detection behaviors, including cancer screening. We assessed the association of exposure to Black residential segregation and cancer screening among Black and White adults. Methods This was a retrospective cohort study using electronic medical record data from patients who were members of the Population-based Research to Optimize the Screening Process (PROSPR) cohort. The sample included non-Hispanic (NH) Black or NH White average-risk urban adults at five U.S. healthcare settings who were eligible and due for cervical cancer screening (women aged 21-65 years) or CRC screening (50-75 years) when they had a primary care appointment (cohort entry) from 2010-2012. Black residential segregation was measured using sample-based quartiles of the local exposure and isolation (LEx/Is) metric comprising census-tract level data from 2008-2012 American Community Survey. The outcome was receipt of cervical cancer screening (completion of Pap or Pap/human papillomavirus [HPV] co-test) or CRC screening (completion of FIT/gFOBT, sigmoidoscopy, or colonoscopy) within 3 years of cohort entry. Multilevel logistic regression was used to calculate association of segregation and screening while adjusting for patient- and census-travel level covariates (age, race, sex, year of cohort entry, comorbidities, healthcare system, and census tract level poverty rate.) Results Of 164,238 and 652,719 patients eligible and due for cervical cancer or CRC screening respectively, 106,753 (65.0%) and 465,042 (71.2%) received timely screening. Black patients (6.4% of cervical screening and 15.7% of CRC screening sample), compared to White patients, were more likely to live in neighborhoods in the highest quartile of Black segregation (cervical sample: 44.1% vs. 17.6%; CRC sample: 51.8% vs. 19.4%). Greater exposure to segregation was associated with lower odds of cervical cancer screening (Quartile [Q]4 vs. Q1 odds ratio [OR]=0.92; 95% CI 0.89-0.94) and CRC screening (Q4 vs. Q1 OR=0.91; 95% CI 0.89-0.92) in unadjusted models; these associations were attenuated in adjusted models for cervical (Q4 vs. Q1 adjusted OR[aOR]=0.99; 95%CI=0.95-1.03) and CRC screening (Q4 vs. Q1 aOR=1.0; 95% CI 0.97-1.02). Notably, in adjusted models for both screening types, higher census tract level neighborhood poverty rate was associated with lower odds of screening, and Black (vs. White) race was associated with higher odds of cervical cancer screening but lower odds of CRC screening. Discussion In this study within five healthcare systems, Black residential segregation was not associated with screening after adjustment for other variables. Additional analyses will assess potential for effect measure modification by patient race, healthcare system, and other factors. Citation Format: Sandi L. Pruitt, Lynn N. Ibekwe, Kaitlin Todd, Erica S. Breslau, Andrea N. Burnett-Hartman, Cheryl R. Clark, Natalie J. Del Vecchio, Jennifer S. Haas, Stacey Honda, Christopher I. Li, Rachel L. Winer, Christine Neslund-Dudas, Rachel Issaka. Association of racial residential segregation and screening uptake for cervical and colorectal cancer among Black and White patients in five diverse U.S. healthcare systems [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A114.

To examine whether quantitative pathologic analysis of digitized hematoxylin and eosin slides of colorectal carcinoma (CRC) correlates with clinicopathologic features, molecular alterations, and prognosis.A quantitative segmentation algorithm (QuantCRC) was applied to 6468 digitized hematoxylin and eosin slides of CRCs. Fifteen parameters were recorded from each image and tested for associations with clinicopathologic features and molecular alterations. A prognostic model was developed to predict recurrence-free survival using data from the internal cohort (n = 1928) and validated on an internal test (n = 483) and external cohort (n = 938).There were significant differences in QuantCRC according to stage, histologic subtype, grade, venous/lymphatic/perineural invasion, tumor budding, CD8 immunohistochemistry, mismatch repair status, KRAS mutation, BRAF mutation, and CpG methylation. A prognostic model incorporating stage, mismatch repair, and QuantCRC resulted in a Harrell's concordance (c)-index of 0.714 (95% confidence interval [CI], 0.702-0.724) in the internal test and 0.744 (95% CI, 0.741-0.754) in the external cohort. Removing QuantCRC from the model reduced the c-index to 0.679 (95% CI, 0.673-0.694) in the external cohort. Prognostic risk groups were identified, which provided a hazard ratio of 2.24 (95% CI, 1.33-3.87, P = .004) for low vs high-risk stage III CRCs and 2.36 (95% CI, 1.07-5.20, P = .03) for low vs high-risk stage II CRCs, in the external cohort after adjusting for established risk factors. The predicted median 36-month recurrence rate for high-risk stage III CRCs was 32.7% vs 13.4% for low-risk stage III and 15.8% for high-risk stage II vs 5.4% for low-risk stage II CRCs.QuantCRC provides a powerful adjunct to routine pathologic reporting of CRC. A prognostic model using QuantCRC improves prediction of recurrence-free survival.

Introductory sentence indicating purpose of the study: Over the last three decades, incidence of colorectal cancer (CRC) has risen steadily among people younger than age 50 (early-onset) in many developed countries, including the United States. More information is needed about the causes of early-onset CRC and novel, pragmatic interventions are needed to ensure rapid identification of early-onset CRC cases through timely screening and symptoms detection. Brief description of pertinent experimental procedures: The Consortium for Research on Early-Onset Colorectal Cancer (CREO) is a partnership among scientists and clinicians at four data-contributing health systems: Kaiser Permanente Northwest, Kaiser Permanente Northern California, and Kaiser Permanente Colorado, and Henry Ford Health. CREO plans to assemble a novel cohort of 8 million adults (including 3,200 early-onset CRC cases diagnosed from 2010 through 2025) encompassing electronic health record, survey, and biospecimen data to conduct research that will identify and estimate the impact of approaches to rapidly detect early-onset CRC through screening and clinical practice. Using electronic health record data from our participating health systems, we identified individuals diagnosed with CRC between 2010 and 2020. Here, we describe demographic and tumor characteristics of individuals with CRC in this cohort, and compare those to national data obtained from the Surveillance, Epidemiology, and End-Results program for the years 2012 – 2016. Summary of the new, unpublished data: We identified 15,884 adults with CRC (1,932 with early-onset CRC and 13,912 with late-onset CRC) in the four participating CREO health systems. Individuals with early-onset CRC in the CREO cohort were non-Hispanic White (54%), Hispanic (18%), Asian-American (14%), and African American/Black (9%). The proportion of CREO cohort adults with early-onset CRC was 12%; this matched the proportion in the population-based SEER data. The proportion of diagnosed CRC cases located in the rectum was 29% in both the CREO cohort and in SEER data. Anatomic location for the remaining tumors varied slightly between the CREO cohort and SEER data: in CREO data, 22% were proximal colon cancers, and 31% were distal colon cancers; in SEER data, and 29% were proximal and 22% were distal. Statement of the conclusions: Our findings show that CREO’s assembled cohort of electronic health record data from multiple large health systems matches several key aspects of population-based data from SEER. Through CREO, we plan to create a comprehensive, multi-level dataset of a new, racially and ethnically diverse cohort of 8 million adults in order to elucidate factors associated with the alarming rise in early-onset CRC and identify interventions to ensure rapid identification and secondary prevention of early-onset CRC. Citation Format: Gloria D. Coronado, Andrea Burnett-Hartman, Jeffrey Lee, Carmit McMullen, Carolyn Rutter, Mary Ann McBurnie, Christine Neslund-Dudas, John Carethers. Building a data resource to advance research on early-onset colorectal cancer: The consortium for research on early-onset colorectal cancer (CREO) [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A011.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76OAS1variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay ofOAS1. We suggest that genetically-regulated loss ofOAS1expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of theOAS1risk haplotypes.

Background: Relatively little is known about factors associated with long-term survival (LTS) following a diagnosis of ovarian cancer. Methods: We conducted a retrospective study of high-grade serous ovarian cancer (HGSOC) to explore predictors of LTS (defined as ≥7 years of survival) using electronic medical record data from a network of integrated health care systems. Multivariable logistic regression with forward selection was used to compare characteristics of women who survived ≥7 years after diagnosis (n = 148) to those who died within 7 years of diagnosis (n = 494). Results: Our final model included study site, age, stage at diagnosis, CA-125, comorbidity score, receipt of chemotherapy, BMI, and four separate comorbid conditions: weight loss, depression, hypothyroidism, and liver disease. Of these, only younger age, lower stage, and depression were statistically significantly associated with LTS. Conclusions: We did not identify any new characteristics associated with HGSOC survival. Impact: Prognosis of ovarian cancer generally remains poor. Large, pooled studies of ovarian cancer are needed to identify characteristics that may improve survival.

To evaluate whether limited participation in life activities is associated with quality of life (QOL) in rectal cancer survivors, and if so, whether this association is independent of bowel function difficulties.We surveyed rectal cancer survivors from four healthcare systems about their QOL, bowel function, and participation in life activities. Additional demographic and clinical variables were extracted from the electronic health record. We examined independent associations between bowel function, participation in life activities, and QOL, controlling for potential confounders. We also identified factors, including ostomy status, that correlate with participation in life activities.Of the 527 respondents, 52% were male, 80% were non-Hispanic white, and the mean age was 63. In fully adjusted models for all rectal cancer survivors, participation in life activities was positively associated with QOL, while bowel function was not. Bowel function retained an independent association with QOL for those who previously had an ostomy and were therefore more likely to have a low rectal anastomosis. Lower participation in life activities was correlated with lower self-reported physical and cognitive function, younger age, financial difficulty, and being non-Hispanic white.Rectal cancer survivors' participation in life activities was strongly associated with QOL, even when controlling for numerous confounders, including bowel function. Identifying ways to improve participation in life activities may be critical to developing rehabilitative and other supportive interventions that optimize QOL among rectal cancer survivors.

PurposeThis study aimed to characterize patient and clinical factors associated with cannabis(marijuana) use among patients diagnosed with colorectal cancer (CRC).MethodsWe identified CRC patients, diagnosed from 2016-2018, using the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. CRC patients were recruited via mail and telephone, and participants completed a questionnaire eliciting information on medical history, demographics, and lifestyle factors, including cannabis use. Cancer stage was obtained from SEER registry data.ResultsOf 1,433 survey respondents, 339 (24%) were current cannabis users. Current cannabis use was associated with younger age at diagnosis, lower BMI, and a higher prevalence of cigarette smoking and alcohol consumption (P-value

Rising trends in the incidence and mortality of early-onset colorectal cancer (CRC) in those who are younger than 50 years have been well established. These trends have spurred intense investigation focused on elucidating the epidemiology and characteristics of early-onset CRC, as well as on identifying strategies for early detection and prevention. In this review, we provide a contemporary update on early-onset CRC with a particular focus on epidemiology, molecular characterization, red flag signs and symptoms, and screening for early-onset CRC.

ObjectiveAn understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for sporadic CRC differs by anatomical subsite of the primary tumor has not been examined.DesignTo identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48,214 CRC cases and 64,159 controls of European ancestry. We characterized effect heterogeneity at CRC risk loci using multinomial modeling.ResultsWe identified 13 loci that reached genome-wide significance (P−8) and that were not reported by previous GWAS for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.ConclusionGenetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumor.Significance of this studyWhat is already known about this subject?Heterogeneity among colorectal cancer (CRC) tumors originating at different locations of the colorectum has been revealed in somatic genomes, epigenomes, and transcriptomes, and in some established environmental risk factors for CRC.Genome-wide association studies (GWAS) have identified over 100 genetic variants for overall CRC risk; however, a comprehensive analysis of the extent to which genetic risk factors differ by the anatomical sublocation of the primary tumor is lacking.What are the new findings?In this large consortium-based study, we analyzed clinical and genome-wide genotype data of 112,373 CRC cases and controls of European ancestry to comprehensively examine whether CRC case subgroups defined by anatomical sublocation have distinct germline genetic etiologies.We discovered 13 new loci at genome-wide significance (P−8) that were specific to certain anatomical sublocations and that were not reported by previous GWAS for overall CRC risk; multiple lines of evidence support strong candidate target genes at several of these loci, including PTGER3, LCT, MLH1, CDX1, KLF14, PYGL, BCL11B, and BMP7.Systematic heterogeneity analysis of genetic risk variants for CRC identified thus far, revealed that the genetic architectures of proximal and distal CRC are partly distinct.Taken together, our results further support the idea that tumors arising in different anatomical sublocations of the colorectum may have distinct etiologies.How might it impact on clinical practice in the foreseeable future?Our results provide an informative resource for understanding the differential role that genes and pathways may play in the mechanisms of proximal and distal CRC carcinogenesis.The new insights into the etiologies of proximal and distal CRC may inform the development of new precision prevention strategies, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention.Our findings suggest that future studies of etiological risk factors for CRC and molecular mechanisms of carcinogenesis should take into consideration the anatomical sublocation of the colorectal tumor.

Background: Understanding the impact of precision medicine on medical practice, patient care, and clinical outcomes is a priority for advancing cancer care. With the recent dramatic increase in the use of tumor genomic testing (TGT), records within EHRs are a rich data source for evaluating the impact of TGT results in real-world clinical practice of care and on patient outcomes. However, extracting TGT results from electronic health records (EHR) is challenging due to a lack of standards to communicate genomic information and an inability to store such information in commonly available EHR systems. Moreover, TGT results are delivered to clinicians in unstructured formats and image-based files (PDFs). We initiated a pilot study to assess the ability of natural language processing (NLP) algorithms to convert EHR unstructured clinical text and PDF-formatted TGT results into research-quality data. Methods: One author (RY) drew a sample of approximately 800 clinical text records from 21 breast cancer patients treated at University of Washington. Sources used for data extraction included medical record notes and PDF reports for two breast cancer gene expression tests: 21-gene Recurrence Score (RS, OncotypeDx) and/or the 70-gene signature (MMP, Mammaprint). A team redacted all PHI and provided records to a commercial collaborator (Pangaeadata.AI, UK), along with definitions of variables to be extracted, but without annotated target answers. Existing NLP algorithms that leverage pre-training, fine-tuning and rules were adapted to extract 26 variables specified by the research team (e.g., age at diagnosis, histology, and RS or MMP dates and scores). The output placed variables into relevant, standardized formats and produced a research quality data set. The extraction strategy depended on the feature and variable characteristics. For example, cancer stage, an ordinal numerical variable, was determined with a rule-based extraction method from outpatient clinic notes and pathology reports, whereas the RS score, a continuous variable, came from OncotypeDx PDF and OCR semi-structured retrieval produced the output. Results/Conclusions: The Pangaea tool obtained an average accuracy of 97.3% with a standard deviation of 3.5% across all 26 variables. The approach is developed based on rules designed and validated by clinical experts, using a model that does not require training, making overfitting likely minimal. Qualitative analysis showed that: 1] algorithms used to electronically extract TGT results provided the same data as manual abstraction by physicians, and 2] context matters, namely, the capability of preliminary semantic understanding in the Pangaea model using contextual words and phrases contributed to high accuracy and can be generalized further with larger datasets. Expansion to other health care data systems is needed to assess scalability of these technologies to create research-quality data fit for use. Citation Format: Rachel Yung, Kari A. Stephens, Meliha Yetisgen, Andrea Burnett-Hartman, Ashwani Tanwar, Guilherme Freire, Atri Sharma, Jingqing Zhang, Vibhor Gupta, Yike Guo, VK Gadi, Larry Kessler. Creating research quality cancer genomic data from electronic health records [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4090.

e13628 Background: Precision medicine has changed treatment practices for patients with cancer. Clinical guidelines recommend tumor marker testing for many types of cancer given its benefits. Studies have demonstrated that tumor marker testing increases use of appropriate targeted therapies which is associated with improved survival, particularly among patients with advanced or metastatic cancer. In March 2018, Medicare issued a national coverage determination (NCD) for next-generation sequencing to facilitate tumor marker testing. Methods: We conducted a retrospective study to assess tumor marker testing among Medicare beneficiaries with cancer from 03/01/2016 through 02/28/2020. Data were obtained from the Virtual Data Warehouses of 6 United States (US) healthcare systems in the Cancer Research Network, a well-established distributed data network for cancer research. Together these systems provide care to a diverse population of over 5.5 million people in the US. The index date was the first observed cancer diagnosis date recorded in the tumor registry during the study period. Subgroup analyses included those with lung, breast, colorectal, or prostate cancers, or those with advanced, metastatic or recurrent cancer. This is part of a larger project that aims to advance methods for scalable and rigorous evaluation of outcomes of coverage policies for genetic tests. Results: We report results from one health system (03/01/2016-3/31/2018) including Medicare beneficiaries ≥65 years and ≥ 90 enrollment days after the index date. Among 2,277 Medicare beneficiaries with cancer, mean (SD) age was 74 (6.8) years, 1,065 (46.8%) were women, 199 (9.9%) had a tumor marker test within 90 days of the index date, and 1072 (47.1%) started a cancer drug therapy within 90 days of the index date. Among Medicare beneficiaries with lung (n=352), breast (n=361) colorectal (n=135) and prostate (n=326) cancers, proportions of patients having tumor marker tests ranged from 2.2% to 12.8% within 90 days of the index date. Among 572 Medicare beneficiaries with advanced, metastatic or recurrent cancer, 59 (10.3%) had a tumor marker test within 90 days of the index date. Conclusions: The relatively low tumor marker testing rate among Medicare beneficiaries with cancer in this health system is consistent with the literature. Analyses are underway to examine changes in tumor marker testing among Medicare beneficiaries after the implementation of the 2018 Medicare NCD.

Background: Broad participation in genetic research is needed to promote equitable advances in disease treatment and prevention. Objectives: The objective of the study was to assess motivations for, and concerns about, genetic research participation. Methods: The Genetics in Research and Health Care Survey was sent in winter 2017–2018 to 57,331 adult Kaiser Permanente (KP) members from 7 US regions to assess attitudes about genetic testing in health care and research. The survey included an open-ended question on why members would or would not participate in genetic research. Open text responses to this question were coded in the qualitative analysis software Dedoose and analyzed using a thematic analysis approach. Code summaries were organized by major themes, subthemes, and exemplary quotes. Results: Of the 10,369 participants who completed the survey, 2,645 (25%) provided a comment describing reasons they would or would not participate in research involving genetic testing. Respondents who provided a text comment were 64% female, 49% non-Hispanic (NH) White, 17% Asian/Pacific Islander, 20% Hispanic, and 14% NH Black. The primary themes identified were (1) altruism; (2) decision-making and planning; (3) data use; and (4) data security. These major themes were consistent across each race and ethnic group. Conclusions: To promote broad participation in genetic research, it is important that recruitment materials address the primary motivators for genetic research participation, including altruism and the potential use of results for personal decision-making. Study materials should also address concerns about possible misuse of genetic information and fears over potential data breaches.

Background: As more states legalize cannabis for medical and recreational use, people increasingly use cannabis to treat medical conditions and associated symptoms. The prevalence and utility of cannabis for cancer-related symptoms may be clarified by examining cannabis use among patients with a common cancer diagnosis. We aimed to determine the prevalence of cannabis use among colorectal cancer (CRC) survivors and its associations with quality of life (QoL) and cancer-related symptomatology. Methods: A cross-sectional survey of patient-reported QoL outcomes and behaviors, including cannabis use, was conducted within the Patient Outcomes To Advance Learning network’s (PORTAL) CRC Cohort. The cohort included a population-based sample of healthcare system members ≥ 18 years old diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2016. We assessed the association between cannabis use and QoL using the European Organization for Research and Treatment of Cancer QLQ-C30 summary score. Results: Of the 1,784 respondents, 293 (16.4%) reported cannabis use following CRC diagnosis. Current tobacco smokers were more likely to use cannabis compared to former or never tobacco smokers (adjusted odds ratio [aOR] 2.71, 95% CI 1.56 to 4.70). Greater alcohol use (> 4 drinks per month versus ≤ 4 drinks per month) was associated with cannabis use (aOR 2.17, 95% CI 1.65 to 2.85). There was an association between cannabis use and cancer stage at diagnosis, with stage 3 or 4 CRC patients more likely to use cannabis than stage 1 or 2 CRC patients (aOR 1.68, 95% CI 1.25 to 2.25). After adjusting for demographics, medical comorbidities, stage and site of CRC diagnosis, and prescription opioid use, people who used cannabis had significantly lower QoL than people who did not use cannabis (difference of -6.14, 95% CI -8.07 to -4.20). Conclusion: Among CRC survivors, cannabis use was common, associated with more advanced stages of disease, associated with tobacco and alcohol use, and not associated with better QoL. Clinicians should inquire about cannabis use among their patients and provide evidence-based recommendations for cancer-related symptoms.

BACKGROUND Although combustible cigarette use is an established risk factor for severe COVID-19 disease, there is conflicting evidence for the association of electronic cigarette use with SARS-CoV-2 infection and COVID-19 disease severity. METHODS Study participants were from the Kaiser Permanente Research Bank (KPRB), a biorepository that includes adult Kaiser Permanente members from across the United States. Starting in April 2020, electronic surveys were sent to KPRB members to assess the impact of the COVID-19 pandemic. These surveys collected information on self-report of SARS-CoV-2 infection and COVID-related risk factors, including electronic cigarette and combustible cigarette smoking history. We also used electronic health records data to assess COVID-19 diagnoses, positive PCR lab tests, hospitalizations, and death. We used multivariable Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the risk of SARS-CoV-2 infection between individuals by e-cigarette use categories (never, former, and current). Among those with SARS-CoV-2 infection, we used multivariable logistic regression to estimate adjusted odds ratios (ORs) and 95% CIs comparing the odds of hospitalization or death within 30 days of infection between individuals by e-cigarette use categories. RESULTS There were 126,475 individuals who responded to the survey and completed questions on e-cigarette and combustible cigarette use (48% response rate). Among survey respondents, 819 (1%) currently used e-cigarettes, 3,691 (3%) formerly used e-cigarettes, and 121,965 (96%) had never used e-cigarettes. After adjustment for demographic, behavioral, and clinical factors, there was no association with SARS-CoV-2 infection and former e-cigarette use (hazard ratio (HR) = 0.99; CI: 0.83–1.18) or current e-cigarette use (HR = 1.08; CI: 0.76–1.52). Among those with SARS-CoV-2 infection, there was no association with hospitalization or death within 30 days of infection and former e-cigarette use (odds ratio (OR) = 1.19; CI: 0.59–2.43) or current e-cigarette use (OR = 1.02; CI: 0.22–4.74). CONCLUSIONS Our results suggest that e-cigarette use is not associated with an increased risk of SARS-CoV-2 infection or severe COVID-19 illness.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P, Reporting Summary. Further information on experimental design is available in the Life Sciences Reporting Summary linked to this article.

Importance The US Preventive Services Task Force (USPSTF) released updated lung cancer screening recommendations in 2021, lowering the screening age from 55 to 50 years and smoking history from 30 to 20 pack-years. These changes are expected to expand screening access to women and racial and ethnic minority groups. Objective To estimate the population-level changes associated with the 2021 USPSTF expansion of lung cancer screening eligibility by sex, race and ethnicity, sociodemographic factors, and comorbidities in 5 community-based health care systems. Design, setting, and participants This cohort study analyzed data of patients who received care from any of 5 community-based health care systems (which are members of the Population-based Research to Optimize the Screening Process Lung Consortium, a collaboration that conducts research to better understand how to improve the cancer screening processes in community health care settings) from January 1, 2010, through September 30, 2019. Individuals who had complete smoking history and were engaged with the health care system for 12 or more continuous months were included. Those who had never smoked or who had unknown smoking history were excluded. Exposures Electronic health record-derived age, sex, race and ethnicity, socioeconomic status (SES), comorbidities, and smoking history. Main outcomes and measures Differences in the proportion of the newly eligible population by age, sex, race and ethnicity, Charlson Comorbidity Index, chronic obstructive pulmonary disease diagnosis, and SES as well as lung cancer diagnoses under the 2013 recommendations vs the expected cases under the 2021 recommendations were evaluated using χ2 tests. Results As of September 2019, there were 341 163 individuals aged 50 to 80 years who currently or previously smoked. Among these, 34 528 had electronic health record data that captured pack-year and quit-date information and were eligible for lung cancer screening according to the 2013 USPSTF recommendations. The 2021 USPSTF recommendations expanded screening eligibility to 18 533 individuals, representing a 53.7% increase. Compared with the 2013 cohort, the newly eligible 2021 population included 5833 individuals (31.5%) aged 50 to 54 years, a larger proportion of women (52.0% [n = 9631]), and more racial or ethnic minority groups. The relative increases in the proportion of newly eligible individuals were 60.6% for Asian, Native Hawaiian, or Pacific Islander; 67.4% for Hispanic; 69.7% for non-Hispanic Black; and 49.0% for non-Hispanic White groups. The relative increase for women was 13.8% higher than for men (61.2% vs 47.4%), and those with a lower comorbidity burden and lower SES had higher relative increases (eg, 68.7% for a Charlson Comorbidity Index score of 0; 61.1% for lowest SES). The 2021 recommendations were associated with an estimated 30% increase in incident lung cancer diagnoses compared with the 2013 recommendations. Conclusions and relevance This cohort study suggests that, in diverse health care systems, adopting the 2021 USPSTF recommendations will increase the number of women, racial and ethnic minority groups, and individuals with lower SES who are eligible for lung cancer screening, thus helping to minimize the barriers to screening access for individuals with high risk for lung cancer.

Colorectal cancer (CRC) is a leading cause of cancer death, yet many CRC deaths are preventable via CRC screening. Currently only age and family history are used to define screening eligibility. However, CRC risk varies substantially in the population. In recent years polygenic risk scores (PRS) have gained attention as powerful risk prediction tool to personalize interventions. PRS provides a quantitative measure of an individual's inherited risk based on the cumulative effect of many genetic risk variants. Here, we benchmark several genome wide PRS techniques to select the best performing models in CRC risk prediction. We built CRC risk prediction models that incorporate genome-wide genotype data from large-scale research studies (55,105 cases and 65,079 controls, European ancestries) with the imputed genetic data on over 40 million variants. The risk prediction models were externally evaluated in the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, including 101,987 genotyped individuals within the Kaiser Permanente Northern California (KPNC) integrated healthcare delivery system. We built genome-wide PRS using various methods including known CRC risk variants, thresholding and pruning followed by machine learning approaches (ML), LDpred, improved LDpred2, SBayesR, PRS-CS, Lassosum and empirical Bayes. Among 55,033 individuals of European ancestry in the GERA cohort, we evaluated the performance of models in terms of the age and sex-adjusted AUC. We showed that LDpred, LDpred2, LDpred2-sparse, SBayesR and PRS-CS perform equally well in terms of discriminatory accuracy (AUC=0.65). In addition, the PRS developed using the above-mentioned techniques identified the top 30% of the GERA European population has a hazard ratio estimate of ~2.2 on CRC risk, which is comparable to that for having an affected first-degree relative. The developed CRC PRSs will provide way for risk-stratified CRC screening and other targeted interventions. PRS derivation methodsNo. of variantsAUC(1,311 cases and 53,722 controls)Hazard ratio estimates (CI)Top 30% of population vs. remainingKnown variants1400.631.92 (1.75-2.23)PT Clumping + ML (Ridge)10,0000.631.94 (1.72-2.19)LDpred1.2M0.652.20 (1.94-2.47)LDPred21.2M0.652.20 (1.93-2.45)LDpred2 Sparse530K0.652.20 (1.90-2.41)SBayesR1.2M0.652.20 (1.88-2.38)PRS-CS1.2M0.652.20 (1.91-2.43)Lassosum1.2M0.621.76 (1.56-2.58)EBPRS1.2M0.621.81 (1.66-2.11)AUC based on family history in GERA cohort is 0.54 Citation Format: Minta Thomas, Lori C Sakoda, Jeffrey K Lee, Mark A Jenkins, Andrea Burnett-Hartman, Heather Hampel, Elisabeth A Rosenthal, Hermann Brenner, Jenny Chang-Claude, Marc J Gunter, Polly A Newcomb, Steven Gallinger, Tabitha A Harrison, Graham Casey, Victor Moreno, Gail P Jarvik, Stephen B Gruber, Robert E Schoen, Andrew T Chan, Richard B Hayes, Douglas A Corley, Ulrike Peters, Li Hsu. Benchmarking genome-wide polygenic risk score development techniques in colorectal cancer risk prediction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 881.