Modifiable Failures in the Colorectal Cancer Screening Process and Their Association With Risk of Death.

BACKGROUND & AIMS: Colorectal cancer (CRC) deaths occur when patients do not receive screening or have inadequate follow-up of abnormal results or when the screening test fails. We have few data on the contribution of each to CRC-associated deaths or factors associated with these events. METHODS: We performed a retrospective cohort study of patients in the Kaiser Permanente Northern and Southern California systems (55-90 years old) who died of CRC from 2006 through 2012 and had ≥5 years of enrollment before diagnosis. We compared data from patients with those from a matched cohort of cancer-free patients in the same system. Receipt, results, indications, and follow-up of CRC tests in the 10-year period before diagnosis were obtained from electronic databases and chart audits. RESULTS: Of 1750 CRC deaths, 75.9% (n = 1328) occurred in patients who were not up to date in screening and 24.1% (n = 422) occurred in patients who were up to date. Failure to screen was associated with fewer visits to primary care physicians. Of 3486 cancer-free patients, 44.6% were up to date in their screening. Patients who were up to date in their screening had a lower risk of CRC death (odds ratio, 0.38; 95% confidence interval, 0.33-0.44). Failure to screen, or failure to screen at appropriate intervals, occurred in a 67.8% of patients who died of CRC vs 53.2% of cancer-free patients; failure to follow-up on abnormal results occurred in 8.1% of patients who died of CRC vs 2.2% of cancer-free patients. CRC death was associated with higher odds of failure to screen or failure to screen at appropriate intervals (odds ratio, 2.40; 95% confidence interval, 2.07-2.77) and failure to follow-up on abnormal results (odds ratio, 7.26; 95% confidence interval, 5.26-10.03). CONCLUSIONS: Being up to date on screening substantially decreases the risk of CRC death. In 2 health care systems with high rates of screening, most people who died of CRC had failures in the screening process that could be rectified, such as failure to follow-up on abnormal findings; these significantly increased the risk for CRC death.

Effects of Organized Colorectal Cancer Screening on Cancer Incidence and Mortality in a Large Community-Based Population.

BACKGROUND & AIMS: Little information is available on the effectiveness of organized colorectal cancer (CRC) screening on screening uptake, incidence, and mortality in community-based populations. METHODS: We contrasted screening rates, age-adjusted annual CRC incidence, and incidence-based mortality rates before (baseline year 2000) and after (through 2015) implementation of organized screening outreach, from 2007 through 2008 (primarily annual fecal immunochemical testing and colonoscopy), in a large community-based population. Among screening-eligible individuals 51-75 years old, we calculated annual up-to-date status for cancer screening (by fecal test, sigmoidoscopy, or colonoscopy), CRC incidence, cancer stage distributions, and incidence-based mortality. RESULTS: Initiation of organized CRC screening significantly increased the up-to-date status of screening, from 38.9% in 2000 to 82.7% in 2015 (P < .01). Higher rates of screening were associated with a 25.5% reduction in annual CRC incidence between 2000 and 2015, from 95.8 to 71.4 cases/100,000 (P < .01), and a 52.4% reduction in cancer mortality, from 30.9 to 14.7 deaths/100,000 (P < .01). Increased screening was initially associated with increased CRC incidence, due largely to greater detection of early-stage cancers, followed by decreases in cancer incidence. Advanced-stage CRC incidence rates decreased 36.2%, from 45.9 to 29.3 cases/100,000 (P < .01), and early-stage CRC incidence rates decreased 14.5%, from 48.2 to 41.2 cases/100,000 (P < .04). CONCLUSIONS: Implementing an organized CRC screening program in a large community-based population rapidly increased screening participation to the ≥80% target set by national organizations. Screening rates were sustainable and associated with substantial decreases in CRC incidence and mortality within short time intervals, consistent with early detection and cancer prevention.

The Be-Well Study: a prospective cohort study of lifestyle and genetic factors to reduce the risk of recurrence and progression of non-muscle-invasive bladder cancer.

PURPOSE: Bladder cancer is one of the top five cancers diagnosed in the U.S. with a high recurrence rate, and also one of the most expensive cancers to treat over the life-course. However, there are few observational, prospective studies of bladder cancer survivors. METHODS: The Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study) is a National Cancer Institute-funded, multi-center prospective cohort study of non-muscle-invasive bladder cancer (NMIBC) patients (Stage Ta, T1, Tis) enrolled from the Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) health care systems, with genotyping and biomarker assays performed at Roswell Park Comprehensive Cancer Center. The goal is to investigate diet and lifestyle factors in recurrence and progression of NMIBC, with genetic profiles considered, and to build a resource for future NMIBC studies. RESULTS: Recruitment began in February 2015. As of 30 June 2018, 1,281 patients completed the baseline interview (774 KPNC, 511 KPSC) with a recruitment rate of 54%, of whom 77% were male and 23% female, and 80% White, 6% Black, 8% Hispanic, 5% Asian, and 2% other race/ethnicity. Most patients were diagnosed with Ta (69%) or T1 (27%) tumors. Urine and blood specimens were collected from 67% and 73% of consented patients at baseline, respectively. To date, 599 and 261 patients have completed the 12- and 24-month follow-up questionnaires, respectively, with additional urine and saliva collection. CONCLUSIONS: The Be-Well Study will be able to answer novel questions related to diet, other lifestyle, and genetic factors and their relationship to recurrence and progression among early-stage bladder cancer patients.

Index colonoscopy-related risk factors for postcolonoscopy colorectal cancers.

BACKGROUND AND AIMS: Postcolonoscopy colorectal cancers (PCCRCs) are defined as those detected ≤10 years after an index colonoscopy negative for cancer, but modifiable risk factors are not well established in large, community-based populations. METHODS: We evaluated risk factors from the index colonoscopy for PCCRCs diagnosed 1 to 10 years after an index colonoscopy using a case-control design. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for potential confounders. RESULTS: A proximal polyp ≥10 mm (OR, 8.18; 95% CI, 4.59-14.60), distal polyp ≥10 mm (OR, 3.30; 95% CI, 1.65-6.58), adenoma with (OR, 3.23; 95% CI, 1.83-5.68) and without advanced histology (OR, 1.87; 95% CI, 1.37-2.55), and an incomplete colonoscopy (OR, 5.52; 95% CI, 2.98-10.21) were associated with PCCRC. Risk factors for early versus late cancers (12-36 months vs >36 months to 10 years after examination) included incomplete polyp excision in the colonic segment of the subsequent cancer (OR, 4.76; 95% CI, 2.35-9.65); failure to examine the segment (OR, 2.42; 95% CI, 1.27-4.60); and a polyp ≥10 mm in the segment (OR, 2.38; 95% CI, 1.53-3.70). A total of 559 of 1206 patients with PCCRC (46.4%) had 1 or more risk factors that were significant for PCCRC (incomplete examination, large polyp, or any adenoma). CONCLUSIONS: In a large community-based study with comprehensive capture of PCCRCs, almost half of PCCRCs had potentially modifiable factors related to polyp surveillance or removal and examination completeness. These represent potential high-yield targets to further increase the effectiveness of colorectal cancer screening.

Statins as a free pass: Body mass index and other cardiovascular risk factors among lipid-lowering medication users and nonusers in the California Men's Health Study.

To lower risk from cardiovascular disease (CVD), national guidelines recommend lifestyle changes followed by use of lipid-lowering medications when appropriate. Previous studies have questioned whether individuals taking these medications are less likely to modify their dietary intake and physical activity, resulting in increased body mass index (BMI). We assessed BMI and CVD clinical risk factors over time between lipid-lowering medication users and nonusers in a diverse cohort of middle-aged and older men. The cohort consisted of 63,357 men who enrolled in the California Men's Health Study between 2002 and 2003 and were not taking lipid-lowering medications at baseline. Lipid-lowering medication use was determined over twelve years of follow-up. BMI and other CVD risk factors were assessed with longitudinal linear mixed effect models adjusting for possible confounders. Overall, lipid-lowering medication users had higher BMI than nonusers (p < .0001); however, there was a decrease over time for both groups (p < .0001). Total cholesterol, LDL-C, and triglycerides decreased for users and nonusers (p < .0001). While HDL-C was higher for nonusers (p < .05), over time this measure increased in both groups (p < .0001). We found no evidence of increases in BMI after initiation of lipid-lowering medication in this cohort. Instead, BMI decreased and several cholesterol-related CVD risk factors improved for lipid-lowering medication users and nonusers. This suggests that men placed on lipid-lowering medications do not view them as a panacea for their increased risk of cardiovascular disease. Instead, they appear to perceive them as one component of a multi-pronged strategy including lifestyle and nutrition as suggested by current guidelines.

Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study.

Background: Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction in transgender persons may be related to hormone use. Objective: To examine the incidence of these events in a cohort of transgender persons. Design: Electronic medical record-based cohort study of transgender members of integrated health care systems who had an index date (first evidence of transgender status) from 2006 through 2014. Ten male and 10 female cisgender enrollees were matched to each transgender participant by year of birth, race/ethnicity, study site, and index date enrollment. Setting: Kaiser Permanente in Georgia and northern and southern California. Patients: 2842 transfeminine and 2118 transmasculine members with a mean follow-up of 4.0 and 3.6 years, respectively, matched to 48 686 cisgender men and 48 775 cisgender women. Measurements: VTE, ischemic stroke, and myocardial infarction events ascertained from diagnostic codes through the end of 2016 in transgender and reference cohorts. Results: Transfeminine participants had a higher incidence of VTE, with 2- and 8-year risk differences of 4.1 (95% CI, 1.6 to 6.7) and 16.7 (CI, 6.4 to 27.5) per 1000 persons relative to cisgender men and 3.4 (CI, 1.1 to 5.6) and 13.7 (CI, 4.1 to 22.7) relative to cisgender women. The overall analyses for ischemic stroke and myocardial infarction demonstrated similar incidence across groups. More pronounced differences for VTE and ischemic stroke were observed among transfeminine participants who initiated hormone therapy during follow-up. The evidence was insufficient to allow conclusions regarding risk among transmasculine participants. Limitation: Inability to determine which transgender members received hormones elsewhere. Conclusion: The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. Primary Funding Source: Patient-Centered Outcomes Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Effectiveness of screening colonoscopy in reducing the risk of death from right and left colon cancer: a large community-based study.

OBJECTIVE: Screening colonoscopy's effectiveness in reducing colorectal cancer mortality risk in community populations is unclear, particularly for right-colon cancers, leading to recommendations against its use for screening in some countries. This study aimed to determine whether, among average-risk people, receipt of screening colonoscopy reduces the risk of dying from both right-colon and left-colon/rectal cancers. DESIGN: We conducted a nested case-control study with incidence-density matching in screening-eligible Kaiser Permanente members. Patients who were 55-90 years old on their colorectal cancer death date during 2006-2012 were matched on diagnosis (reference) date to controls on age, sex, health plan enrolment duration and geographical region. We excluded patients at increased colorectal cancer risk, or with prior colorectal cancer diagnosis or colectomy. The association between screening colonoscopy receipt in the 10-year period before the reference date and colorectal cancer death risk was evaluated while accounting for other screening exposures. RESULTS: We analysed 1747 patients who died from colorectal cancer and 3460 colorectal cancer-free controls. Compared with no endoscopic screening, receipt of a screening colonoscopy was associated with a 67% reduction in the risk of death from any colorectal cancer (adjusted OR (aOR)=0.33, 95% CI 0.21 to 0.52). By cancer location, screening colonoscopy was associated with a 65% reduction in risk of death for right-colon cancers (aOR=0.35, CI 0.18 to 0.65) and a 75% reduction for left-colon/rectal cancers (aOR=0.25, CI 0.12 to 0.53). CONCLUSIONS: Screening colonoscopy was associated with a substantial and comparably decreased mortality risk for both right-sided and left-sided cancers within a large community-based population.

Patterns and predictors of repeat fecal immunochemical and occult blood test screening in four large health care systems in the United States.

OBJECTIVES: Effectiveness of fecal occult blood test (FOBT) for colorectal cancer (CRC) screening depends on annual testing, but little is known about patterns of repeat stool-based screening within different settings. Our study's objective was to characterize screening patterns and identify factors associated with repeat screening among patients who completed an index guaiac FOBT (gFOBT) or fecal immunochemical test (FIT). METHODS: We performed a multi-center retrospective cohort study among people who completed a FOBT between January 2010 and December 2011 to characterize repeat screening patterns over the subsequent 3 years. We studied at 4 large health care delivery systems in the United States. Logistic regression analyses were used to identify factors associated with repeat screening patterns. We included individuals aged 50-71 years who completed an index FOBT and had at least 3 years of follow-up. We excluded people with a history of CRC, colonoscopy within 10 years or flexible sigmoidoscopy within 5 years before the index test, or positive index stool test. Consistent screening was defined as repeat FOBT within every 15 months and inconsistent screening as repeat testing at least once during follow-up but less than consistent screening. RESULTS: Among 959,857 eligible patients who completed an index FIT or gFOBT, 344,103 had three years of follow-up and met inclusion criteria. Of these, 46.6% had consistent screening, 43.4% inconsistent screening, and 10% had no repeat screening during follow-up. Screening patterns varied substantially across healthcare systems, with consistent screening proportions ranging from 1 to 54.3% and no repeat screening proportions ranging from 6.9 to 42.8%. Higher consistent screening proportions were observed in health systems with screening outreach and in-reach programs, whereas the safety-net health system, which uses opportunistic clinic-based screening, had the lowest consistent screening. Consistent screening increased with older age but was less common among racial/ethnic minorities and patients with more comorbidities. CONCLUSIONS: Adherence with annual FOBT screening is highly variable across healthcare delivery systems. Settings with more organized screening programs performed better than those with opportunistic screening, but evidence-based interventions are needed to improve CRC screening adherence in all settings.

Agreement between medical records and self-reports: Implications for transgender health research.

A key priority of transgender health research is the evaluation of long-term effects of gender affirmation treatment. Thus, accurate assessment of treatment receipt is critical. The data for this analysis came from an electronic medical records (EMR) based cohort of transgender individuals. A subset of cohort members were also asked to complete a self-administered survey. Information from the EMR was compared with survey responses to assess the extent of agreement regarding transmasculine (TM)/transfeminine (TF) status, hormone therapy receipt, and type of surgery performed. Logistic regression models were used to assess whether participant characteristics were associated with disagreement between data sources. Agreement between EMR and survey-derived information was high regarding TM/TF status (99%) and hormone therapy receipt (97%). Lower agreement was observed for chest reconstruction surgery (72%) and genital reconstruction surgery (84%). Using survey responses as the "gold standard", both chest and genital reconstruction surgeries had high specificity (95 and 93%, respectively), but the corresponding sensitivities were low (49 and 68%, respectively). A lower proportion of TM had concordant results for chest reconstruction surgery (64% versus 79% for TF) while genital reconstruction surgery concordance was lower among TF (79% versus 89% for TM). For both surgery types, agreement was highest among the youngest participants. Our findings offer assurance that EMR-based data appropriately classify cohort participants with respect to their TM/TF status or hormone therapy receipt. However, current EMR data may not capture the complete history of gender affirmation surgeries. This information is useful in future studies of outcomes related to gender affirming therapy.

Association Between Gender Confirmation Treatments and Perceived Gender Congruence, Body Image Satisfaction, and Mental Health in a Cohort of Transgender Individuals.

BACKGROUND: Transgender individuals sometimes seek gender confirmation treatments (GCT), including hormone therapy (HT) and/or surgical change of the chest and genitalia ("top" and "bottom" gender confirmation surgeries). These treatments may ameliorate distress resulting from the incongruence between one's physical appearance and gender identity. AIM: The aim was to examine the degree to which individuals' body-gender congruence, body image satisfaction, depression, and anxiety differed by GCT groups in cohorts of transmasculine (TM) and transfeminine (TF) individuals. METHODS: The Study of Transition, Outcomes, and Gender is a cohort study of transgender individuals recruited from 3 health plans located in Georgia, Northern California, and Southern California; cohort members were recruited to complete a survey between 2015-2017. Participants were asked about: history of GCT; body-gender congruence; body image satisfaction; depression; and anxiety. Participants were categorized as having received: (1) no GCT to date; (2) HT only; (3) top surgery; (4) partial bottom surgery; and (5) definitive bottom surgery. OUTCOMES: Outcomes of interest included body-gender congruence, body image satisfaction, depression, and anxiety. RESULTS: Of the 2,136 individuals invited to participate, 697 subjects (33%) completed the survey, including 347 TM and 350 TF individuals. The proportion of participants with low body-gender congruence scores was significantly higher in the "no treatment" group (prevalence ratio [PR] = 3.96, 95% CI 2.72-5.75) compared to the definitive bottom surgery group. The PR for depression comparing participants who reported no treatment relative to those who had definitive surgery was 1.94 (95% CI 1.42-2.66); the corresponding PR for anxiety was 4.33 (95% CI 1.83-10.54). CLINICAL TRANSLATION: Withholding or delaying GCT until depression or anxiety have been treated may not be the optimal treatment course given the benefits of reduced levels of distress after undergoing these interventions. CONCLUSIONS: Strengths include the well-defined sampling frame, which allowed correcting for non-response, a sample with approximately equal numbers of TF and TM participants, and the ability to combine data on HT and gender confirmation surgeries. Limitations include the cross-sectional design and the fact that participants may not be representative of the transgender population in the United States. Body-gender congruence and body image satisfaction were higher, and depression and anxiety were lower among individuals who had more extensive GCT compared to those who received less treatment or no treatment at all. Owen-Smith AA, Gerth J, Sineath RC, et al. Association Between Gender Confirmation Treatments and Perceived Gender Congruence, Body Image Satisfaction and Mental Health in a Cohort Of Transgender Individuals. J Sex Med 2018;15:591-600.

Adenoma detection rate and risk of colorectal cancer and death.

BACKGROUND: The proportion of screening colonoscopic examinations performed by a physician that detect one or more adenomas (the adenoma detection rate) is a recommended quality measure. However, little is known about the association between this rate and patients' risks of a subsequent colorectal cancer (interval cancer) and death. METHODS: Using data from an integrated health care delivery organization, we evaluated the associations between the adenoma detection rate and the risks of colorectal cancer diagnosed 6 months to 10 years after colonoscopy and of cancer-related death. With the use of Cox regression, our estimates of attributable risk were adjusted for the demographic characteristics of the patients, indications for colonoscopy, and coexisting conditions. RESULTS: We evaluated 314,872 colonoscopies performed by 136 gastroenterologists; the adenoma detection rates ranged from 7.4 to 52.5%. During the follow-up period, we identified 712 interval colorectal adenocarcinomas, including 255 advanced-stage cancers, and 147 deaths from interval colorectal cancer. The unadjusted risks of interval cancer according to quintiles of adenoma detection rates, from lowest to highest, were 9.8, 8.6, 8.0, 7.0, and 4.8 cases per 10,000 person-years of follow-up, respectively. Among patients of physicians with adenoma detection rates in the highest quintile, as compared with patients of physicians with detection rates in the lowest quintile, the adjusted hazard ratio for any interval cancer was 0.52 (95% confidence interval [CI], 0.39 to 0.69), for advanced-stage interval cancer, 0.43 (95% CI, 0.29 to 0.64), and for fatal interval cancer, 0.38 (95% CI, 0.22 to 0.65). Each 1.0% increase in the adenoma detection rate was associated with a 3.0% decrease in the risk of cancer (hazard ratio, 0.97; 95% CI, 0.96 to 0.98). CONCLUSIONS: The adenoma detection rate was inversely associated with the risks of interval colorectal cancer, advanced-stage interval cancer, and fatal interval cancer. (Funded by the Kaiser Permanente Community Benefit program and the National Cancer Institute.).

Endoscopist fatigue estimates and colonoscopic adenoma detection in a large community-based setting.

BACKGROUND AND AIMS: Endoscopist fatigue may impact colonoscopy quality, but prior studies conflict, and minimal data exist from community-based practices where most colonoscopies are performed. METHODS: Within a large, community-based integrated healthcare system, we evaluated the associations among 4 measures of endoscopist fatigue and colonoscopic adenoma detection from 2010 to 2013. Fatigue measures included afternoon versus morning colonoscopy and the number of GI procedures performed before a given colonoscopy, including consideration of prior procedure complexity. Analyses were adjusted for potential confounders using multivariate logistic regression. RESULTS: We identified 126 gastroenterologists who performed 259,064 total GI procedures (median, 6 per day; range, 1-24), including 76,445 screening and surveillance colonoscopies. Compared with morning examinations, colonoscopies in the afternoon were not associated with lower adenoma detection for screening examinations, surveillance examinations, or their combination (OR for combination, .99; 95% CI, .96-1.03). The number of procedures performed before a given colonoscopy, with or without consideration of prior procedure complexity, was also not inversely associated with adenoma detection (OR for adenoma detection for colonoscopies in the fourth quartile of fatigue based on the number of prior procedures performed vs colonoscopies performed as the first procedure of the day, .99; 95% CI, .94-1.04). CONCLUSIONS: In a large community-based setting, adenoma detection for screening and surveillance colonoscopies were not associated with either time of day or the number of prior procedures performed by the endoscopist, within the range of procedure volumes evaluated. The lack of association persisted after accounting for prior procedure complexity.

Human papillomavirus vaccination and subsequent cervical cancer screening in a large integrated healthcare system.

BACKGROUND: Human papillomavirus vaccination may result in lowered intention to be screened for cervical cancer, potentially leading to gaps in screening coverage and avoidable cervical cancer diagnoses. OBJECTIVE: The purpose of this study was to examine the association between human papillomavirus vaccination and subsequent cervical cancer screening initiation and adherence to recommended screening intervals to detect gaps in screening coverage and inform future prevention efforts. STUDY DESIGN: A retrospective cohort study was conducted in 2 distinct cohorts of female members of Kaiser Permanente Southern California, which is a large integrated healthcare delivery system. Papanicolaou screening initiation was evaluated in women who reached 21 years from 2010-2013. Adherence to recommended screening intervals was evaluated in women who were 25-30 years old in 2010. All women were observed to the end of 2013 for the evaluation of their screening behaviors. History of human papillomavirus vaccination and Papanicolaou screening were obtained from electronic medical records. Adherence to recommended screening intervals was measured as ≥85% vs <85% of the observed "screening up-to-date" person-time. Multivariable Cox and logistic regression models were used to examine associations between vaccination history and screening initiation and interval adherence. Demographic characteristics, gynecologic health history, healthcare use, and characteristics of women's primary care providers were included as potential confounders in the analyses. RESULTS: There were 27,352 and 41,328 women included in the screening initiation and screening interval adherence analyses, respectively. In comparison with unvaccinated women, adjusted hazard ratios (95% confidence intervals [CIs]) for screening initiation among women who had been vaccinated against human papillomavirus were 1.19 (95% CI, 1.11-1.28), 1.44 (95% CI, 1.34-1.53), and 1.57 (95% CI, 1.50-1.65) for 1, 2, and ≥3 doses, respectively. Adjusted odds ratios for screening interval adherence were 0.93 (95% CI, 0.83-1.04), 1.73 (95% CI, 1.52-1.97), and 2.29 (95% CI, 2.05-2.56), for 1, 2, and ≥3 doses, respectively. CONCLUSION: Women who had been vaccinated against human papillomavirus in this community-based, integrated healthcare setting were more likely to be screened for cervical cancer than were unvaccinated women. Our findings underscore the need for targeted interventions among unvaccinated women who may be disproportionally affected by cervical cancer, despite the presence of population-based screening programs.

Genetic Biomarker Prevalence Is Similar in Fecal Immunochemical Test Positive and Negative Colorectal Cancer Tissue.

BACKGROUND: Fecal immunochemical test (FIT) screening detects most asymptomatic colorectal cancers. Combining FIT screening with stool-based genetic biomarkers increases sensitivity for cancer, but whether DNA biomarkers (biomarkers) differ for cancers detected versus missed by FIT screening has not been evaluated in a community-based population. AIMS: To evaluate tissue biomarkers among Kaiser Permanente Northern California patients diagnosed with colorectal cancer within 2 years after FIT screening. METHODS: FIT-negative and FIT-positive colorectal cancer patients 50-77 years of age were matched on age, sex, and cancer stage. Adequate DNA was isolated from paraffin-embedded specimens in 210 FIT-negative and 211 FIT-positive patients. Quantitative allele-specific real-time target and signal amplification assays were performed for 7 K-ras mutations and 10 aberrantly methylated DNA biomarkers (NDRG4, BMP3, SFMBT2_895, SFMBT2_896, SFMBT2_897, CHST2_7890, PDGFD, VAV3, DTX1, CHST2_7889). RESULTS: One or more biomarkers were found in 414 of 421 CRCs (98.3%). Biomarker expression was not associated with FIT status, with the exception of higher SFMBT2_897 expression in FIT-negative (194 of 210; 92.4%) than in FIT-positive cancers (180 of 211; 85.3%; p = 0.02). There were no consistent differences in biomarker expression by FIT status within age, sex, stage, and cancer location subgroups. CONCLUSIONS: The biomarkers of a currently in-use multi-target stool DNA test (K-ras, NDRG4, and BMP3) and eight newly characterized methylated biomarkers were commonly expressed in tumor tissue specimens, independent of FIT result. Additional study using stool-based testing with these new biomarkers will allow assessment of sensitivity, specificity, and clinical utility.

Fecal Immunochemical Test Program Performance Over 4 Rounds of Annual Screening: A Retrospective Cohort Study.

BACKGROUND: The fecal immunochemical test (FIT) is a common method for colorectal cancer (CRC) screening, yet its acceptability and performance over several rounds of annual testing are largely unknown. OBJECTIVE: To assess FIT performance characteristics over 4 rounds of annual screening. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Northern and Southern California. PATIENTS: 323 349 health plan members aged 50 to 70 years on their FIT mailing date in 2007 or 2008 who completed the first round of FIT and were followed for up to 4 screening rounds. MEASUREMENTS: Screening participation, FIT positivity (≥20 µg of hemoglobin/g), positive predictive values for adenoma and CRC, and FIT sensitivity for detecting CRC obtained from Kaiser Permanente electronic databases and cancer registries. RESULTS: Of the patients invited for screening, 48.2% participated in round 1. Of those who remained eligible, 75.3% to 86.1% participated in subsequent rounds. Median follow-up was 4.0 years, and 32% of round 1 participants crossed over to endoscopy over 4 screening rounds-7.0% due to a positive FIT result. The FIT positivity rate (5.0%) and positive predictive values (adenoma, 51.5%; CRC, 3.4%) were highest in round 1. Overall, programmatic FIT screening detected 80.4% of patients with CRC diagnosed within 1 year of testing, including 84.5% in round 1 and 73.4% to 78.0% in subsequent rounds. LIMITATION: Screening detection, rather than long-term cancer prevention, was evaluated. CONCLUSION: Annual FIT screening was associated with high sensitivity for CRC, with high adherence to annual follow-up screening among initial participants. The findings indicate that annual programmatic FIT screening is feasible and effective for population-level CRC screening. PRIMARY FUNDING SOURCE: National Institutes of Health.

Association Between Time to Colonoscopy After a Positive Fecal Test Result and Risk of Colorectal Cancer and Cancer Stage at Diagnosis.

IMPORTANCE: The fecal immunochemical test (FIT) is commonly used for colorectal cancer screening and positive test results require follow-up colonoscopy. However, follow-up intervals vary, which may result in neoplastic progression. OBJECTIVE: To evaluate time to colonoscopy after a positive FIT result and its association with risk of colorectal cancer and advanced-stage disease at diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study (January 1, 2010-December 31, 2014) within Kaiser Permanente Northern and Southern California. Participants were 70 124 patients aged 50 through 70 years eligible for colorectal cancer screening with a positive FIT result who had a follow-up colonoscopy. EXPOSURES: Time (days) to colonoscopy after a positive FIT result. MAIN OUTCOMES AND MEASURES: Risk of any colorectal cancer and advanced-stage disease (defined as stage III and IV cancer). Odds ratios (ORs) and 95% CIs were adjusted for patient demographics and baseline risk factors. RESULTS: Of the 70 124 patients with positive FIT results (median age, 61 years [IQR, 55-67 years]; men, 52.7%), there were 2191 cases of any colorectal cancer and 601 cases of advanced-stage disease diagnosed. Compared with colonoscopy follow-up within 8 to 30 days (n = 27 176), there were no significant differences between follow-up at 2 months (n = 24 644), 3 months (n = 8666), 4 to 6 months (n = 5251), or 7 to 9 months (n = 1335) for risk of any colorectal cancer (cases per 1000 patients: 8-30 days, 30; 2 months, 28; 3 months, 31; 4-6 months, 31; and 7-9 months, 43) or advanced-stage disease (cases per 1000 patients: 8-30 days, 8; 2 months, 7; 3 months, 7; 4-6 months, 9; and 7-9 months, 13). Risks were significantly higher for examinations at 10 to 12 months (n = 748) for any colorectal cancer (OR, 1.48 [95% CI, 1.05-2.08]; 49 cases per 1000 patients) and advanced-stage disease (OR, 1.97 [95% CI, 1.14-3.42]; 19 cases per 1000 patients) and more than 12 months (n = 747) for any colorectal cancer (OR, 2.25 [95% CI, 1.89-2.68]; 76 cases per 1000 patients) and advanced-stage disease (OR, 3.22 [95% CI, 2.44-4.25]; 31 cases per 1000 patients). CONCLUSIONS AND RELEVANCE: Among patients with a positive fecal immunochemical test result, compared with follow-up colonoscopy at 8 to 30 days, follow-up after 10 months was associated with a higher risk of colorectal cancer and more advanced-stage disease at the time of diagnosis. Further research is needed to assess whether this relationship is causal.

Consequences of Increasing Time to Colonoscopy Examination After Positive Result From Fecal Colorectal Cancer Screening Test.

BACKGROUND & AIMS: Delays in diagnostic testing after a positive result from a screening test can undermine the benefits of colorectal cancer (CRC) screening, but there are few empirical data on the effects of such delays. We used microsimulation modeling to estimate the consequences of time to colonoscopy after a positive result from a fecal immunochemical test (FIT). METHODS: We used an established microsimulation model to simulate an average-risk United States population cohort that underwent annual FIT screening (from ages 50 to 75 years), with follow-up colonoscopy examinations for individuals with positive results (cutoff, 20 µg/g) at different time points in the following 12 months. Main evaluated outcomes were CRC incidence and mortality; additional outcomes were total life-years lost and net costs of screening. RESULTS: For individuals who underwent diagnostic colonoscopy within 2 weeks of a positive result from an FIT, the estimated lifetime risk of CRC incidence was 35.5/1000 persons, and mortality was 7.8/1000 persons. Every month added until colonoscopy was associated with a 0.1/1000 person increase in cancer incidence risk (an increase of 0.3%/month, compared with individuals who received colonoscopies within 2 weeks) and mortality risk (increase of 1.4%/month). Among individuals who received colonoscopy examinations 12 months after a positive result from an FIT, the incidence of CRC was 37.0/1000 persons (increase of 4%, compared with 2 weeks), and mortality was 9.1/1000 persons (increase of 16%). Total years of life gained for the entire screening cohort decreased from an estimated 93.7/1000 persons with an almost immediate follow-up colonoscopy (cost savings of $208 per patient, compared with no colonoscopy) to 84.8/1000 persons with follow-up colonoscopies at 12 months (decrease of 9%; cost savings of $100/patient, compared with no colonoscopy). CONCLUSIONS: By using a microsimulation model of an average-risk United States screening cohort, we estimated that delays of up to 12 months after a positive result from an FIT can produce proportional losses of up to nearly 10% in overall screening benefits. These findings indicate the importance of timely follow-up colonoscopy examinations of patients with positive results from FITs.

Breast cancer screening initiation after turning 40 years of age within the PROSPR consortium.

PURPOSE: Although United States clinical guidelines differ, the earliest recommended age for average risk breast cancer screening is 40 years. Little is known about factors influencing screening initiation. METHODS: We conducted a cohort study within the National Cancer Institute-funded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. We identified 3413 women on their 40th birthday in primary care networks at Geisel School of Medicine at Dartmouth (DH) and Brigham and Women's Hospital (BWH) during 2011-2013 with no prior breast imaging or breast cancer. Cumulative incidence curves and Cox modeling were used to determine time from the 40th birthday to first breast cancer screening, cohort exit, or 42nd birthday. We calculated hazards ratios and 95 % confidence intervals from multivariable Cox proportional hazards models. RESULTS: Breast cancer screening cumulative incidence by the 42nd birthday was 62.9 % (BWH) and 39.8 % (DH). Factors associated with screening initiation were: a primary care visit within a year (HR 4.99, 95 % CI 4.23-5.89), an increasing number of primary care visits within a year (p for trend <0.0001), ZIP code of residence annual median household income ≤$52,000 (HR 0.79, 95 % CI 0.68-0.92), and health insurance type (Medicaid HR 0.72, 95 % CI 0.58-0.88; Medicare HR 0.55, 95 % CI 0.39-0.77; uninsured HR 0.37, 95 % CI 0.25-0.57). CONCLUSIONS: Breast cancer screening uptake after the 40th birthday varies by health system, primary care visits, median household income, and health insurance type, suggesting the need for further exploration. Future research should evaluate screening performance metrics after initiation and consider cumulative benefits and risks associated with breast cancer screening over time.

Race/Ethnicity and Adoption of a Population Health Management Approach to Colorectal Cancer Screening in a Community-Based Healthcare System.

BACKGROUND: Screening outreach programs using population health management principles offer services uniformly to all eligible persons, but racial/ethnic colorectal cancer (CRC) screening patterns in such programs are not well known. OBJECTIVE: To examine the association between race/ethnicity and the receipt of CRC screening and timely follow-up of positive results before and after implementation of a screening program. DESIGN: Retrospective cohort study of screen-eligible individuals at the Kaiser Permanente Northern California community-based integrated healthcare delivery system (2004-2013). SUBJECTS: A total of 868,934 screen-eligible individuals 51-74 years of age at cohort entry, which included 662,872 persons in the period before program implementation (2004-2006), 654,633 during the first 3 years after implementation (2007-2009), and 665,268 in the period from 4 to 7 years (2010-2013) after program implementation. INTERVENTION: A comprehensive system-wide long-term effort to increase CRC that included leadership alignment, goal-setting, and quality assurance through a PHM approach, using mailed fecal immunochemical testing (FIT) along with offering screening at office visits. MAIN MEASURES: Differences over time and by race/ethnicity in up-to-date CRC screening (overall and by test type) and timely follow-up of a positive screen. Race/ethnicity categories included non-Hispanic white, non-Hispanic black, Hispanic/Latino, Asian/Pacific Islander, Native American, and multiple races. KEY RESULTS: From 2004 to 2013, age/sex-adjusted CRC screening rates increased in all groups, including 35.2 to 81.1 % among whites and 35.6 to 78.0 % among blacks. Screening rates among Hispanics (33.1 to 78.3 %) and Native Americans (29.4 to 74.5 %) remained lower than those for whites both before and after program implementation. Blacks, who had slightly higher rates before program implementation (adjusted rate ratio [RR] = 1.04, 99 % CI: 1.02-1.05), had lower rates after program implementation (RR for period from 4 to 7 years = 0.97, 99 % CI: 0.96-0.97). There were also substantial improvements in timely follow-up of positive screening results. CONCLUSIONS: In this screening program using core PHM principles, CRC screening increased markedly in all racial/ethnic groups, but disparities persisted for some groups and developed in others, which correlated with levels of adoption of mailed FIT.

Variation in Screening Abnormality Rates and Follow-Up of Breast, Cervical and Colorectal Cancer Screening within the PROSPR Consortium.

BACKGROUND: Primary care providers and health systems have prominent roles in guiding effective cancer screening. OBJECTIVE: To characterize variation in screening abnormality rates and timely initial follow-up for common cancer screening tests. DESIGN: Population-based cohort undergoing screening in 2011, 2012, or 2013 at seven research centers comprising the National Cancer Institute-sponsored Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. PARTICIPANTS: Adults undergoing mammography with or without digital breast tomosynthesis (n = 97,683 ages 40-75 years), fecal occult blood or fecal immunochemical tests (n = 759,553 ages 50-75 years), or Papanicolaou with or without human papillomavirus tests (n = 167,330 ages 21-65 years). INTERVENTION: Breast, colorectal, or cervical cancer screening. MAIN MEASURES: Abnormality rates per 1000 screens; percentage with timely initial follow-up (within 90 days, except 9-month window for BI-RADS 3). Primary care clinic-level variation in percentage with screening abnormality and percentage with timely initial follow-up. KEY RESULTS: There were 10,248/97,683 (104.9 per 1000) abnormal breast cancer screens, 35,847/759,553 (47.2 per 1000) FOBT/FIT-positive colorectal cancer screens, and 13,266/167,330 (79.3 per 1000) abnormal cervical cancer screens. The percentage with timely follow-up was 93.2 to 96.7 % for breast centers, 46.8 to 68.7  % for colorectal centers, and 46.6 % for the cervical cancer screening center (low-grade squamous intraepithelial lesions or higher). The primary care clinic variation (25th to 75th percentile) was smaller for the percentage with an abnormal screen (breast, 8.5-10.3 %; colorectal, 3.0-4.8 %; cervical, 6.3-9.9 %) than for the percentage with follow-up within 90 days (breast, 90.2-95.8 %; colorectal, 43.4-52.0 %; cervical, 29.6-61.4 %). CONCLUSIONS: Variation in both the rate of screening abnormalities and their initial follow-up was evident across organ sites and primary care clinics. This highlights an opportunity for improving the delivery of cancer screening through focused study of patient, provider, clinic, and health system characteristics associated with timely follow-up of screening abnormalities.