Screening Arm Research Articles

Bias-corrected estimates of effects of PSA screening decisions on the risk of prostate cancer diagnosis and death: Analysis of the Finnish randomized study of screening for prostate cancer.

More information is needed about effects of prostate-specific antigen (PSA) screening for informed decision making. The objective of our study is to evaluate the effects of an implemented screening decision on the risk of prostate cancer (PC) diagnosis and PC death. In a randomized trial, 31,867 Finnish men aged 55-67 years were allocated to the screening arm and 48,282 to the control arm during 1996-1999. Two to three screening rounds were offered to the screening arm with a PSA cut-off of 4.0 ng/ml. A counterfactual exclusion method was used to adjust for the effects of screening noncompliance and PSA contamination on risk of PC death and PC incidence by prognostic group at 15 years of follow up. After correcting for noncompliance and contamination, PSA screening led to 32.4 (95% CI 26.4, 38.6) more PC diagnoses per 1,000 men after 15 years and 1.4 (95% CI 0.0, 2.8) fewer PC deaths compared to the control arm. The corresponding results of an intention-to-screen analysis were 16.5 (95% CI 12.3, 20.7) and 0.8 (95% CI 0.5, 2.0), respectively. These results can be used for patient counseling in informed decision making about PC screening. A limitation of the study was the lack of comprehensive data on contamination.

Allopurinol and the risk of prostate cancer in a Finnish population-based cohort.

Allopurinol reduces oxidative stress and may thus have an anti-inflammatory effect. Previous studies suggest that allopurinol use might decrease the risk of prostate cancer (PCa) among gout patients. We studied the association between allopurinol use and PCa incidence. The cohort consists of 76,874 men without prevalent PCa, originally identified for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). The follow-up started at entry to the trial. We excluded men using allopurinol in the year before entry (wash-out). PCa cases detected during 1996-2015 were identified from the Finnish Cancer Registry. Information on tumor Gleason score and TNM stage were obtained from medical files. Information on PSA level was obtained from screening samples for men in the FinRSPC screening arm and from laboratory databases for men in the control arm. Information on BMI was based on a questionnaire sent to men in the FinRSPC screening arm in 2004-2008. Drug purchase information were obtained from the national prescription database. We used Cox regression (adjusted for age, FinRSPC trial arm, PCa family history and use of other medication) to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of PCa risk by allopurinol use. We analyzed medication as a time-dependent variable to minimize immortal time bias. There were 9062 new PCa diagnoses in the cohort. Follow-up time did not differ by allopurinol use (median 17 yr; IQR 11-19 vs median 17 yr; IQR 12.33-19). The risk of PCa did not differ by allopurinol use (multivariable adjusted HR 1.03; 95% CI 0.92-1.16). Allopurinol use did not associate with the risk of high-grade or metastatic cancer. Cumulative duration or average yearly dose of allopurinol use showed no association with PCa risk. No delayed risk associations were observed in the lag-time analyses. We observed no difference in the PCa risk by allopurinol use.

The Number of Screening Cycles Needed to Reduce Prostate Cancer Mortality in the Finnish Section of the European Randomized Study of Prostate Cancer (ERSPC).

The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer mortality by PSA-based screening. The aim of the study is to evaluate screening effect on prostate cancer incidence and mortality in relation to number of screening rounds attended.Experimental Design: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance, then remained among the once-screened until the second screen and similarly for the possible third round. The control arm was the reference. Follow-up started at randomization and ended at death, emigration, or end of 2013. Prostate cancer incidence and mortality, as well lung cancer and overall mortality were evaluated. Prostate cancer incidence was increased among screened men, but was not directly related to the number of screening rounds. Prostate cancer mortality was decreased in men screened twice or three times, but did not materially differ in those who did not attend the screening, and in men screened once compared with the control arm. The largest mortality reduction was in men screened three times [HR 0.17; 95% confidence interval (CI), 0.09-0.33]. However, a reduction was also seen in lung cancer (HR 0.59; 95% CI, 0.47-0.73) and overall mortality (HR 0.56; 95% CI, 0.52-0.60). Assuming a similar relative reduction being due to selection bias and screening in prostate cancer as other causes of death (40% reduction), approximately half of the observed prostate cancer mortality reduction by repeated screening is likely to be noncausal and a real screening effect may account for up to 40% reduction in men screened three times. Prostate cancer mortality reduction can only be achieved by repeated screening cycles.

Results of Prostate Cancer Screening in a Unique Cohort at 19 yr of Follow-up

We assessed the effect of screening in the European Randomized study of Screening for Prostate Cancer (ERSPC) Rotterdam pilot 1 study cohort with men randomized in 1991–1992. A total of 1134 men were randomized on a 1:1 basis to a screening (S) and control (C) arm after prostate-specific antigen (PSA) testing (PSA ≥10.0ng/ml was excluded from randomization). Further PSA testing was offered to all men in the S-arm with 4-yr intervals starting at age 55yr and screened up to the age of 74yr. Overall, a PSA level of ≥3.0ng/ml triggered biopsy. At time of analysis, 63% of men had died. Overall relative risk of metastatic (M+) disease and prostate cancer (PCa) death was 0.46 (95% confidence interval [CI]: 0.19–1.11) and 0.48 (95% CI: 0.17–1.36), respectively, in favor of screening. This ERSPC Rotterdam pilot 1 study cohort, screened in a period without noteworthy contamination, shows that PSA-based screening could result in considerable reductions of M+ disease and mortality which if confirmed in larger datasets should trigger further discussion on pros/cons of PCa screening. Patient summaryIn a cohort with 19yr of follow-up, we found indications for a more substantial reduction in metastatic disease and cancer-specific mortality in favor of prostate cancer screening than previously reported. If confirmed in larger cohorts, these findings should be considered in the ongoing discussion on harms and benefits of prostate cancer screening.

Residential exposure to fine particulate matter air pollution and incident breast cancer in a cohort of Canadian women

Background: Air pollution has been classified as a human carcinogen based largely on epidemiological studies of lung cancer. Recent research suggests that exposure to ambient air pollution increases the risk of breast cancer. Methods: Our aim was to characterize associations between residential exposure to ambient fine particulate matter (PM2.5) and the incidence of breast cancer in a cohort of 89,247 women enrolled in the Canadian National Breast Screening Study between 1980 and 1985. Vital status and incident cancers were determined through record linkage to the national registry data through 2005. Individual-level estimates of exposures to PM2.5 at baseline were derived from satellite observations. Six thousand five hundred three incident breast cancers were identified during follow-up. We classified menopausal status using self-reported information collected at baseline and by attained age (50, 52, and 54 years) as women were followed-up. We computed hazard ratios (HRs) and their 95% confidence intervals (CI) using age as the time axis. Models were adjusted for several individual risk factors, including reproductive history, as well as census-based neighborhood-level characteristics. Results: The median residential concentration of PM2.5 was 9.1 μg/m3. In models adjusted for personal and contextual risk factors, a 10-μg/m3 increase in PM2.5 was associated with an elevated risk of premenopausal (HR = 1.26; 95% CI = 0.99, 1.61) but not postmenopausal breast cancer (HR = 1.01; 95% CI = 0.94, 1.10). The elevated risk of premenopausal breast cancer from PM2.5 was only evident among those randomized to the screening arm of the study. Conclusions: Our findings support the hypothesis that exposure to low concentrations of PM2.5 increase the risk of premenopausal breast cancer.

Abstract 2201: Prostate-specific antigen velocity is associated with future prostate cancer mortality among men in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Abstract Higher prostate-specific antigen (PSA) velocity (change in PSA over time) measured after diagnosis or treatment is associated with poorer prognosis for prostate cancer patients. However, less is known about the association between PSA velocity measured prior to a diagnosis of cancer and future prostate cancer mortality. We evaluated whether PSA velocity is associated with the risk of prostate cancer mortality among men without a history of prostate cancer in the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. As part of the PLCO trial, men in the screening arm were offered PSA screening at baseline in the trial and annually thereafter for five years. From the screening arm, we included 33,961 men who had at least two prediagnostic trial PSA measurements (to allow for PSA velocity calculation), among whom 167 later died of prostate cancer. We estimated PSA velocity and initial PSA concentration for each participant from the random slope and random intercept terms in a mixed effects model based on up to the first three trial PSA measures per person since participants varied in the number of available measures. We defined our study baseline for survival analysis as the time of the last PSA measurement used to calculate PSA velocity. Participants were 55 to 79 years of age at our study baseline, and we followed them for up to 18 years (through Dec. 31, 2012) for prostate cancer mortality, with a median follow-up time of 12.7 years (interquartile range: 10.7-14.4 years). We dichotomized PSA velocity as <0.4 vs. ≥0.4 ng/mL/year for comparison with previous studies. We analyzed the association between PSA velocity and prostate cancer mortality using Cox proportional hazards regression, adjusting for initial PSA concentration, age, race, body mass index, our study baseline year, and past finasteride use. Higher PSA velocity was associated with an increased hazard of prostate cancer mortality compared to lower PSA velocity [Hazard Ratio (HR)=2.5, 95% Confidence Interval (CI): 1.7-3.7]. Additional adjustment for family history of prostate cancer or comorbidities did not appreciably alter findings. When we stratified by age at our study baseline, we observed a stronger association among men who were less than 70 years of age (HR=3.1, 95% CI: 1.9-4.9) than among those who were 70 years of age or older (p-interaction=0.04). In conclusion, in this large prospective study, higher prediagnostic PSA velocity was associated with an increased risk of prostate cancer mortality. Our findings suggest a potential benefit of using longitudinal PSA measures in predicting future prostate cancer mortality. Citation Format: Erik Barr, Sonja I. Berndt, John D. Sorkin, Wen-Yi Huang, Kathryn Hughes Barry. Prostate-specific antigen velocity is associated with future prostate cancer mortality among men in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2201.

Effectiveness of Prenatal Vitamin D Deficiency Screening and Treatment Program: A Stratified Randomized Field Trial.

Despite evidence on the association between hypovitaminosis D and adverse pregnancy outcomes and the positive impact of vitamin D supplementation, no evidence exists supporting a universal screening program in pregnancy as part of routine prenatal care. We sought to determine the effectiveness of a prenatal screening program on optimizing 25-hydroxyvitamin D [25(OH)D] levels and preventing pregnancy complications. Also, to identify a safe regimen, we compared several regimens in a subgroup of vitamin D-deficient pregnant women. Two cities of Masjed-Soleyman and Shushtar from Khuzestan province, Iran, were selected as the screening and nonscreening arms, respectively. Within the screening arm, a randomized controlled trial was conducted on 800 pregnant women. Health centers of Masjed-Soleyman and Shushtar cities. Pregnant women aged 18 to 40 years. Women with moderate [25(OH)D, 10 to 20 ng/mL] and severe [25(OH)D, <10 ng/mL] deficiency were randomly divided into four subgroups and received vitamin D3 (D3) until delivery. Maternal concentration of 25(OH)D at delivery and rate of pregnancy complications. After supplementation, only 2% of the women in the nonscreening site met the sufficiency level (>20 ng/mL) vs 53% of the women in the screening site. Adverse pregnancy outcomes, including preeclampsia, gestational diabetes mellitus, and preterm delivery, were decreased by 60%, 50%, and 40%, respectively, in the screening site. A D3 injection in addition to monthly 50,000 IU maintenance therapy contributed the most to achievement of sufficient levels at delivery. A prenatal vitamin D screening and treatment program is an effective approach in detecting deficient women, improving 25(OH)D levels, and decreasing pregnancy adverse outcomes.

Medical Care Costs Were Similar Across the Low-dose Computed Tomography and Chest X-Ray Arms of the National Lung Screening Trial Despite Different Rates of Significant Incidental Findings.

The National Lung Screening Trial (NLST) reported lung cancer and all-cause mortality reductions for low-dose computed tomography (LDCT) versus chest x-ray (CXR) screening. Although LDCT lung screening has received a grade B from the United States Preventive Services Task Force and is a covered service under most health plans, concerns remain on the costs engendered by screening, and the impact of the high rate of significant incidental finding (SIF) detection on those costs. We linked American College of Radiology Imaging Network NLST and Medicare fee-for-service claims data for participants from 23 sites for 2002-2009. We performed participant-level analyses using generalized linear regression models to estimate the adjusted annual mean of the 3-year total medical costs per person in each study arm and within screen outcome categories (ever positive with abnormalities suspicious for lung cancer, always negative for abnormalities suspicious for lung cancer, but with SIFs, and always negative without SIFs). The adjusted annual mean total per person costs were not significantly different between screening arms [LDCT, $11,029 (95% confidence interval, $10,107-$11,951); CXR, $10,905 (95% confidence interval, $10,059-$11,751)], despite higher proportions of individuals with SIFs in the LDCT versus the CXR arm (18% vs. 4%; P<0.0001). We found little difference in total annual per person costs between LDCT-screened and CXR-screened Medicare participants, despite the higher number of SIFs in the LDCT arm of the study.

Incidental Thyroid Nodules in the National Lung Screening Trial: Estimation of Prevalence, Malignancy Rate, and Strategy for Workup

There is limited research on the prevalence of incidental thyroid nodules (ITNs) in the United States screening population and on the appropriate evaluation of computed tomography (CT)-detected ITNs. The purpose of this study is to determine the prevalence of ITNs in the National Lung Screening Trial (NLST) and develop a workup strategy for ITNs. CT images were obtained for subjects with documented thyroid abnormalities in the CT screening arm of the NLST, subjects diagnosed with thyroid malignancies, and control subjects. Several size thresholds were compared to determine how many nodules would be further evaluated and how many thyroid malignancies would be missed had each threshold been applied at the time of workup. Thyroid nodules were reported in 0.7% (117 of 17,309 subjects). In 663 control subjects without reported thyroid nodules, thyroid nodules were identified in 78 (11.8%). Reported nodules were larger than unreported nodules (21.3 vs 16.9 mm, P = .03). Thyroid malignancies were diagnosed in 0.1% (22 of 17,309). If a 20-mm rather than a 10-mm cutoff were used to determine which nodules should be further evaluated, all malignancies would be detected, but 24 rather than 62 patients would require workup, for a workup reduction rate of 48.7% (38 of 78). Less than 1% of subjects in the NLST had reported ITNs. The true prevalence of ITNs was estimated to be 11.8%, which provides a better approximation of the number of patients who could potentially receive workup. A 20-mm rather than a 10-mm cutoff would reduce the workup rate by almost 50% while still capturing all malignancies.

Costs of screening for prostate cancer: Evidence from the Finnish Randomised Study of Screening for Prostate Cancer after 20-year follow-up using register data

ObjectivesFew empirical analyses of the impact of organised prostate cancer (PCa) screening on healthcare costs exist, despite cost-related information often being considered as a prerequisite to informed screening decisions. Therefore, we estimate the differences in register-based costs of publicly funded healthcare in the two arms of the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC) after 20 years. MethodsWe obtained individual-level register data on prescription medications, as well as inpatient and outpatient care, to estimate healthcare costs for 80,149 men during the first 20 years of the FinRSPC. We compared healthcare costs for the men in each trial arm and performed statistical analysis. ResultsFor all men diagnosed with PCa during the 20-year observation period, mean PCa-related costs appeared to be around 10% lower in the screening arm (SA). Mean all-cause healthcare costs for these men were also lower in the SA, but differences were smaller than for PCa-related costs alone, and no longer statistically significant. For men dying from PCa, although the difference was not statistically significant, mean all-cause healthcare costs were around 10% higher. When analysis included all observations, cumulative costs were slightly higher in the CA; however, after excluding extreme values, cumulative costs were slightly higher in the SA. ConclusionsNo major cost impacts due to screening were apparent, but the FinRSPC's 20-year follow-up period is too short to provide definitive evidence at this stage. Longer term follow-up will be required to be better informed about the costs of, or savings from, introducing mass PCa screening.

Targeted versus non-targeted HIV testing offered via electronic questionnaire in a Swiss emergency department: A randomized controlled study.

BackgroundIn Switzerland, the national HIV testing recommendations propose targeted testing. Although the emergency department (ED) is mentioned specifically as a site where HIV testing should take place, the testing rate in our ED is 1% of patients seen. The aim of this study was to use electronic tablets to offer testing to ED patients and to examine whether non-targeted screening increased testing rates compared to targeted testing.MethodsThis randomised, cross-over design study took place at Lausanne University Hospital, Switzerland, between August and November 2015. Eligible patients were randomised to a targeted testing or a non-targeted screening arm. Using electronic tablets, targeted arm patients completed a risk factor assessment; patients with risk factors were offered free rapid HIV testing. Non-targeted arm patients received information about HIV and HIV testing on their tablet and were then offered testing. In a second step, patients who declined testing were crossed over to the other strategy. The primary endpoint was the HIV testing rate per arm.ResultsEighty patients were recruited to each study arm. In the targeted arm, 17 patients (of 80, 21%) had at least one risk factor and were offered testing, of whom eight (of 17, 47%) accepted. HIV testing rate in the targeted arm was 10% (8/80) compared to 48% (38/80) in the non-targeted arm (P<0.001). Secondary cross–screening, where targeted arm patients without risk factors were offered non-targeted screening, increased the testing rate in the targeted arm to 45% (36/80). Among patients offered testing, the acceptance rate did not differ between targeted and non-targeted arms, at 48% and 53%, respectively (P = 0.9)DiscussionIn our centre, non-targeted HIV screening resulted in a higher testing rate than targeted testing due to more patients being offered a test. The acceptance rate of testing offered did not differ between targeted and non-targeted arms. Electronic tablets were well-received by patients and easy to use. We conclude that non-targeted HIV screening using electronic tablets would increase the HIV testing rate in our ED.Trial registrationClinicalTrials.gov NCT03038724

Management of Patients With High Baseline Hip Fracture Risk by FRAX Reduces Hip Fractures-A Post Hoc Analysis of the SCOOP Study.

ABSTRACTThe Screening for Osteoporosis in Older Women for the Prevention of Fracture (SCOOP) study was a community‐based screening intervention in women aged 70 to 85 years in the United Kingdom. In the screening arm, licensed osteoporosis treatments were recommended in women identified to be at high risk of hip fracture using the FRAX risk assessment tool (including bone mineral density measurement). In the control arm, standard care was provided. Screening led to a 28% reduction in hip fractures over 5 years. In this planned post hoc analysis, we wished to examine for interactions between screening effectiveness on fracture outcome (any, osteoporotic, and hip fractures) on the one hand and baseline FRAX 10‐year probability of hip fracture on the other. All analyses were conducted on an intention‐to‐treat basis, based on the group to which women were randomized, irrespective of whether screening was completed. Of 12,483 eligible participants, 6233 women were randomized to screening, with treatment recommended in 898 (14.4%). No evidence of an effect or interaction was observed for the outcomes of any fracture or osteoporotic fracture. In the screening arm, 54 fewer hip fractures were observed than in the control arm (164 versus 218, 2.6% versus 3.5%), and commensurate with treatment being targeted to those at highest hip fracture risk, the effect on hip fracture increased with baseline FRAX hip fracture probability (p = 0.021 for interaction); for example, at the 10th percentile of baseline FRAX hip probability (2.6%), there was no evidence that hip fractures were reduced (hazard ratio [HR] = 0.93; 95% confidence interval [CI] 0.71 to 1.23), but at the 90th percentile (16.6%), there was a 33% reduction (HR = 0.67; 95% CI 0.53 to 0.84). Prior fracture and parental history of hip fracture positively influenced screening effectiveness on hip fracture risk. We conclude that women at high risk of hip fracture based on FRAX probability are responsive to appropriate osteoporosis management. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

The Cost-Effectiveness of Screening in the Community to Reduce Osteoporotic Fractures in Older Women in the UK: Economic Evaluation of the SCOOP Study.

The SCOOP study was a two-arm randomized controlled trial conducted in the UK in 12,483 eligible women aged 70 to 85 years. It compared a screening program using the FRAX® risk assessment tool in addition to bone mineral density (BMD) measures versus usual management. The SCOOP study found a reduction in the incidence of hip fractures in the screening arm, but there was no evidence of a reduction in the incidence of all osteoporosis-related fractures. To make decisions about whether to implement any screening program, we should also consider whether the program is likely to be a good use of health care resources, ie, is it cost-effective? The cost per gained quality adjusted life year of screening for fracture risk has not previously been demonstrated in an economic evaluation alongside a clinical trial. We conducted a "within trial" economic analysis alongside the SCOOP study from the perspective of a national health payer, the UK National Health Service (NHS). The main outcome measure in the economic analysis was the cost per quality adjusted life year (QALY) gained over a 5-year time period. We also estimated cost per osteoporosis-related fracture prevented and the cost per hip fracture prevented. The screening arm had an average incremental QALY gain of 0.0237 (95% confidence interval -0.0034 to 0.0508) for the 5-year follow-up. The incremental cost per QALY gained was £2772 compared with the control arm. Cost-effectiveness acceptability curves indicated a 93% probability of the intervention being cost-effective at values of a QALY greater than £20,000. The intervention arm prevented fractures at a cost of £4478 and £7694 per fracture for osteoporosis-related and hip fractures, respectively. The current study demonstrates that a systematic, community-based screening program of fracture risk in older women in the UK represents a highly cost-effective intervention. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Development of prostate-specific antigen (PSA) screening nomograms for 15-year prediction of prostate cancer diagnosis (PCDx), mortality (PCM), and all-cause mortality (ACM).

110 Background: Recommendations for PSA screening encourage shared decision making between patients and providers, rather than population-based screening. Nomograms provide individualized risk predictions potentially enhancing informed decisions to undergo screening. Our objective was to develop PSA screening nomograms using demographic and follow-up data from two large randomized screening trials: the Göteborg Screening Trial ( Lancet Oncol. 2010;11:725-32) and Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial ( N Engl J Med. 2009;360:1310-9). The endpoints of the models were PCDx, PCM, and ACM at 15 years. Methods: Patients with screening prior to trial entry were excluded, leaving 59,951 total subjects: 19,899 and 40,052 from Göteborg and PLCO, respectively. Demographic information including age, family history of PCDx, ethnicity, Charlson Comorbidity Index, marital status, education, and control vs. screening arm were used as predictive variables. If screened, baseline PSA was used as an additional continuous variable. Models for ACM were first developed, then models predicting PCDx and PCM using competing risk analysis. Predictive accuracy was assessed using the concordance index (c-index) and calibration plots. Results: On multivariable analysis, all variables were significant (P &lt; 0.05) for predicting at least one outcome. Nomograms predicting PCDx, PCM, and ACM demonstrated reasonable discrimination: c-index 0.60, 0.65, 0.70, respectively. When a single baseline PSA was included, discriminative accuracy improved for PCDx and PCM, but remained the same for ACM: c-index 0.78, 0.74, 0.69, respectively. Estimates were well-calibrated for all endpoints. Conclusions: Using demographic information, we developed PSA screening nomograms, with good discrimination and calibration in predicting all three outcomes. A single baseline PSA improved nomogram discrimination substantially for PCDx and PCM. We will study the implementation of these nomograms into clinic practice to aid decisions for previously unscreened patients, or whether to continue PSA screening for patients with a known prior PSA.

Abstract OT3-03-01: Preference-Tolerant randomized trial of risk-based vs. annual breast cancer screening: WISDOM study in progress

Abstract Purpose: Women Informed to Screen Depending on Measures of risk (WISDOM) trial is a pragmatic study comparing two real world approaches to clinical care for breast screening: annual screening versus personalized screening. The novelty of the personalized arm of the study is that we are combining known risk factors (age, family history, history of breast disease, ethnicity, BIRADS breast density, and genetics) into a single risk assessment model. All components of the model have been tested and established, but have never been used jointly. The goal of the WISDOM study is to examine the effectiveness of personalized breast cancer screening and to bring objective recommendations to the current mammography screening debate. Methods: The WISDOM trial will enroll 100,000 women with a preference-tolerant design that will determine if risk-based screening vs. annual screening, is as safe, less morbid, enables prevention, and is preferred by women. Women 40 - 74 years of age with no history of breast cancer or DCIS, and no previous double mastectomy can join the study from the WISDOM Study website (wisdomstudy.org). All participants sign up, elect randomization or self-select the study arm, provide electronic consent using DocuSign (eConsent), and sign a Medical Release Form. For all participants, 5-year risk of developing breast cancer is calculated according to the Breast Cancer Screening Consortium (BCSC) model. For participants in the personalized arm, the overall 5-year risk BCSC score is combined with a Polygenic Risk Score, based on a genetic test including mutations in 9 genes (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, ATM, PALB2, and CHEK2) and a panel of 75 common single nucleotide polymorphisms known to increase breast cancer risk. Risk stratification will determine frequency of screening. The study is registered on ClinicalTrials.gov as NCT02620852. Results: As of June 12th 2017, the WISDOM study is live at all UC medical centers and recruitment is open to all eligible women in California. Up to date 4,769 eligible women registered at all sites. 2,823 women have consented in the trial. 64% were randomized and 36% chose their screening arm. A pilot was conducted to test the logistics of online participation and examine the acceptance of the study design and approach. We are partnering with health insurance companies and self-insured companies to reach our recruitment goal. Conclusions: Enrollment will be completed by end of 2018. Acknowledgment: support by the Patient-Centered Outcomes Research Institute (PCORI), PCS-1402-10749 to L.J.E. (*) Authors equally contributed to this work. Citation Format: Acerbi I, Abihider K, Ling J, Layton T, DeRosa D, Madlensky L, Tice J, Shieh Y, Ziv E, Sarrafan S, Firouzian R, Tong B, Blanco A, Lee V, Heditsian D, Brain S, Kaplan C, Borowsky A, Anton-Culver H, Naeim A, Cink T, Stover Fiscalini A, Parker B, van 't Veer L, Wisdom Study and Athena Breast Health Network Investigators and Advocate Partners, LaCroix A, Esserman L. Preference-Tolerant randomized trial of risk-based vs. annual breast cancer screening: WISDOM study in progress [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-03-01.

Abstract PD2-14: Participation in a personalized breast cancer screening trial does not increase anxiety at baseline

Abstract Introduction: The purpose of this study is to examine whether participation in a personalized screening trial is associated with anxiety or breast cancer worry. The Patient Centered Outcomes Research Institute recently funded WISDOM (Women Informed to Screen Depending On Measures of risk), which is a randomized trial that tests the safety and efficacy of basing starting age, stopping age, frequency and modality of breast cancer screening on individual risk (Clinical Trials Identifier NCT02620852). Methods: In WISDOM, participants can be randomized to annual screening or personalized screening arm, or self-select an arm an observational cohort. This interim analysis examined the first 1817 participants to determine if the personalized risk arm is acceptable and to explore whether baseline anxiety was associated with study arm. For acceptability our target was to have &amp;gt;60% of participants agree to randomization. Participants completed questions about their Risk Perception, the PROMIS Anxiety short form 8a (total scores 8-40 with higher scores indicating more anxiety), and Breast Cancer Risk Worry (BCRW) survey (total scores 5-20) with higher scores indicating more worry) at baseline and before they were given information on their personal risk or study assignment. For the purposes of these analyses, we defined high anxiety to be the percentage of participants scoring =&amp;gt;22 on the PROMIS and &amp;gt;8 on the BCRW. Results: The participants were recruited from three sites (UCSD, UCSF, Sanford Health). Of the 1817 initial participants, 1643 completed the baseline questionnaire. Participants has a mean age of 57 years (SD 9). 15.8% felt their chances of developing breast cancer was high, 19.5% felt their chance of developing breast cancer was greater than the average women, and 56.6% felt their lifetime risk of developing breast cancer was &amp;gt;25. Risk perception was not significantly different between women who opted to be randomized versus the observational arm. The majority of participants were willing to be randomly assigned to an arm (1071/1643, 65.1%). Of those who joined the observational cohort, the majority selected personalized risk arm (474/572, 82.9%). Overall, PROMIS anxiety scores were low at baseline (14.0 MEAN (SD 4.6)) as were the Breast Cancer Risk Worry scores (5.7 MEAN (SD 1.05)). Less than 8% of participants had PROMIS scores &amp;gt;22 and that did not vary across the randomized or observational groups (P=0.2)). About 2% of participants had a BCRW scores &amp;gt;8. Women who worried with breast cancer were more likely to select to be in the observational (3.5%) than randomized (1.7%) arm of the study (P=0.02). Conclusions: For the women approached to participate in Wisdom, personalized screening was acceptable alternative to annual mammography. Participants in general overestimated their lifetime risk of breast cancer, had very low anxiety and low breast cancer worry. Those who were worried about breast cancer opted more often for the observational arm of the study to allow them to choose between the personalized versus annual arm. Future analyses will follow participants prospectively to determine adherence to assigned or selected arm, and whether anxiety changes after receipt of their personalized risk information. Citation Format: Naeim A, Sepucha K, Wenger N, Eklund M, Annette S, Madlensky L, van't Veer L, Parker B, Yau C, Cink T, Anton-Culver H, Borowsky A, Petruse A, Sarrafan S, Stover-Fiscalini A, LaCroix A, Adduci K, Wisdom Advocate Partners, Laura E. Participation in a personalized breast cancer screening trial does not increase anxiety at baseline [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD2-14.

Abstract P3-09-02: Risk stratification using clinical risk factors and genetic variants in a personalized screening trial

Abstract Introduction: Tailoring breast cancer screening according to individual risk may represent an improvement over the current practice of age-based screening. WISDOM (Women Informed to Screen Depending on Measures of Risk) is an ongoing randomized trial comparing the safety, efficacy, cost, and patient acceptability of personalized versus annual screening. Women in the personalized arm receive screening recommendations based on sequencing of 9 genes associated with hereditary breast cancer and a 5-year risk estimate from the Breast Cancer Surveillance Consortium (BCSC) risk model modified by a polygenic risk score (PRS) comprised of 75 single nucleotide polymorphisms. WISDOM represents the first-ever use of a PRS to prospectively modify risk estimates and allows comparison of risk model performance in a population-based setting. Thus, we evaluated the risk estimates generated by: 1) the Breast Cancer Risk Assessment Tool (BCRAT) based on the Gail model, 2) the BCSC model, and 3) the BCSC model modified by the PRS (BCSC-PRS). Methods: We analyzed participants in the personalized screening arm of the WISDOM Study (NCT02620852). The trial opened in October 2016 and is enrolling participants aged 40-74 years. Participants' self-reported demographic and risk factor information were collected through an online portal. Genotyping of participants in the personalized arm was done using a custom panel from Color Genomics. 5-year risk estimates were generated using the BCRAT (2011 version), BCSC, and BCSC-PRS models. In the latter, the PRS was used as a Bayesian likelihood ratio to modify the BCSC 5-year risk estimate. We compared the distributions of BCRAT, BCSC, and BCSC-PRS risk estimates around a low-risk (&amp;lt;1%) and moderately high-risk (≥3%) threshold using a paired statistical test (McNemar). Results: To date, WISDOM has enrolled 2,065 participants, of whom 1,157 are in the personalized arm and 830 have completed risk assessment. The median age was 57 years (interquartile range, IQR 49-64). 83% were Caucasian, 2% African-American, and 7% Asian. 8% self-reported as Hispanic. The median 5-year risk was 1.7% (IQR 1.1-2.3%) using the BCRAT, 1.6% (IQR 1.1-2.3%) using the BCSC model, and 1.5% (IQR 0.9-2.7%) using the BCSC-PRS model. The BCSC-PRS model classified more women into the low (&amp;lt;1%) and moderately high (≥3%) risk categories compared with the BCRAT (p &amp;lt; 0.001) and BCSC model (p &amp;lt; 0.001), Table. 5-year risk classification according to the BCRAT, BCSC and BCSC-PRS models &amp;lt;1%1-3%≥3% n (%)n (%)n (%)Gail161 (19)556 (67)113 (14)BCSC159 (19)568 (68)103 (12)BCSC-PRS275 (33)379 (46)176 (21) Discussion: Adding a PRS to the BCSC model categorized significantly more women below the low-risk threshold and above the moderately high-risk threshold compared with the BCSC model and BCRAT. Furthermore, the BCSC and BCRAT generated similar distributions of risk estimates. Follow-up with incident breast cancer data is needed to determine whether the reclassification provided by the PRS improves risk stratification and clinical outcomes. However, our preliminary findings suggest that incorporating genetic variants into a validated clinical model is feasible and could enhance risk prediction. Citation Format: Shieh Y, Ziv E, Eklund M, Sabacan L, Firouzian R, Madlensky L, Anton-Culver H, Borowsky A, LaCroix A, Naeim A, Parker B, van't Veer L, Esserman L, Tice J, WISDOM Study and Athena Network Investigators WS. Risk stratification using clinical risk factors and genetic variants in a personalized screening trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-09-02.

Stopping screening, when and how?

Screening for prostate cancer (PC) is still controversial despite randomized trials has found that PC mortality is decreased. The major concern is the high rate of over-diagnosis and subsequent harms that may follow in many men who never would have had any symptoms during life-time if not screened. The high rate of over-diagnosis is driven by the large reservoir of small non-significant cancers that increases with age and found in more than half of men over 70 years, the low specificity of prostate specific antigen (PSA) but also by current “blind” biopsy technique that risk accidentally to hit these small non-significant cancers. The risk of over-diagnosis is increasing with age and the trade-off by screening men in high age is probably higher. At what age harms exceeds benefits is not established but modelling studies has demonstrated that after 65–70 years the quality adjusted life-years (QALYs) gained are decreasing but still on the positive side if screening is continued up to 75 years. A dilemma is that most PC deaths occur in men after the age 80 and the effect of screening seems not to last as long as was thought, already 10 years after termination of screening PC mortality has caught up in the screening arm to a level similar to that in the control group. In the European Randomised Study of Screening for Prostate Cancer (ERSPC) screening was terminated between 71 and 75 years and the first effect of screening on mortality was discernible after 7 years and has been relatively stable around 20% since 9 years after study start. It seems questionable from any standpoint to invite men for screening with an expected life length below 10 years, which is the expected life-length of an averaged 78-year-old man in 2018. However, the balance between harms and benefits specifically in the age 70–80 need more attention as also costs need. Permanent side-effects from (unnecessary) treatments and their impact on quality of life must be evaluated better and related to age and individual variations. In future better screening methods with more specific markers and introduction of imaging will hopefully decrease the present large risk of over-diagnosis in elderly men and thereby expand efficient screening to men in the age group >70 who actually is the high risk group of dying from PC.

Efficacy of endoscopic screening for esophageal cancer in China (ESECC): design and preliminary results of a population-based randomised controlled trial

ObjectiveDescription of the design and preliminary results of baseline recruitment and screening in the endoscopic screening for esophageal cancer in China (ESECC), the first randomised controlled trial (RCT) assessing efficacy...

Simulating results from trials of sigmoidoscopy screening using the OncoSim microsimulation model

IntroductionProjection of the effect of cancer screening interventions are frequently conducted using complex simulation models. It is important that such models demonstrate their ability to replicate observational results on the effect of screening. We present results using the OncoSim-CRC microsimulation model to replicate results from four randomized trials (RCTs) of sigmoidoscopy screening for colorectal cancer (CRC). MethodsThe published results of four RCTs of sigmoidoscopy were reviewed. Two key outcomes were identified: the intention-to-treat hazard ratios (HR) for CRC incidence and CRC mortality for the screening versus control arms. Each RCT study arm was simulated within OncoSim-CRC using the study specific entry criteria, follow-up and observed participation and compliance rates. The ratio of predicted cases (deaths) between intervention arm and control arm was used to estimate the HRs. ResultsThe RCTs differed in the implementation of sigmoidoscopy screening and only one (PLCO) used more than one cycle. All four RCTs found significant reductions, HR <1, in CRC incidence (range 0.77–0.82) and three for CRC mortality (range 0.69–0.78). The four study cohorts were successfully simulated to match the age and sex structure and length of follow-up of the study cohorts. Each OncoSim-CRC trial-specific predicted reduction fell within the confidence intervals for the observed HR for CRC incidence and CRC mortality for the corresponding trial. The predicted ranges of HRs for incidence was 0.74–0.82 and for mortality was 0.66–0.76 for the four trials. ConclusionsOncoSim-CRC predicted reductions in CRC incidence and mortality agreed well with observed in RCTs of sigmoidoscopy screening.