Cancer screening with multicancer detection tests: A translational science review.

Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test.

Predictive Performance of Cell-Free Nucleic Acid-Based Multi-Cancer Early Detection Tests: A Systematic Review.

BACKGROUND: Cancer-screening tests that can detect multiple cancer types, or multi-cancer early detection (MCED) tests, have emerged recently as a potential new tool in decreasing cancer morbidity and mortality. Most MCED assays are based on detecting cell-free tumor DNA (CF-DNA) in the blood. MCEDs offer the potential for screening for cancer organ sites with high mortality, both with and without recommended screening. However, their clinical utility has not been established. Before clinical utility can be established, the clinical validity of MCEDs, i.e., their ability to predict cancer status, must be demonstrated. In this study we performed a systematic review of the predictive ability for cancer of cell-free-nucleic acid-based MCED tests. CONTENT: We searched PubMed for relevant publications from January 2017 to February 2023, using MeSH terms related to multi-cancer detection, circulating DNA, and related concepts. Of 1811 publications assessed, 61 were reviewed in depth and 20 are included in this review. For almost all studies, the cancer cases were assessed at time of diagnosis. Most studies reported specificity (generally 95% or higher) and overall sensitivity (73% median). The median number of cancer types assessed per assay was 5. Many studies also reported sensitivity by stage and/or cancer type. Sensitivity generally increased with stage. SUMMARY: To date, relatively few published studies have assessed the clinical validity of MCED tests. Most used cancer cases assessed at diagnosis, with generally high specificity and variable sensitivity depending on cancer type and stage. The next steps should be testing in the intended-use population, i.e., asymptomatic persons.

Diagnostic follow-up of indeterminate pulmonary nodules in the Medicare population.

BACKGROUND: Management of indeterminate pulmonary nodules (IPNs) is associated with redistribution of lung cancer to earlier stages, but most subjects with IPNs do not have lung cancer. The burden of IPN management in Medicare recipients was assessed. METHODS: Surveillance, Epidemiology, and End Results-Medicare data were analyzed for IPNs, diagnostic procedures, and lung cancer status. IPNs were defined as chest computed tomography (CT) scans with accompanying International Classification of Diseases (ICD) codes of 793.11 (ICD-9) or R91.1 (ICD-10). Two cohorts were defined: persons with IPNs during 2014-2017 comprised the IPN cohort, whereas those with chest CT scans without IPNs during 2014-2017 comprised the control cohort. Excess rates of various procedures due to reported IPNs over 2 years of follow-up (chest CT, positron emission tomography [PET]/PET-CT, bronchoscopy, needle biopsy, and surgical procedures) were estimated using multivariable Poisson regression models comparing the cohorts adjusted for covariates. Prior data on stage redistribution associated with IPN management were then used to define a metric of excess procedures per late-stage case avoided. RESULTS: Totals of 19,009 and 60,985 subjects were included in the IPN and control cohorts, respectively; 3.6% and 0.8% had lung cancer during follow-up. Excess procedures per 100 persons with IPNs over a 2-year follow-up were 63, 8.2, 1.4, 1.9, and 0.9 for chest CT, PET/PET-CT, bronchoscopy, needle biopsy, and surgery, respectively. Corresponding excess procedures per late-stage case avoided were 48, 6.3, 1.1, 1.5, and 0.7 based on an estimated 1.3 late-stage cases avoided per 100 IPN cohort subjects. CONCLUSIONS: The metric of excess procedures per late-stage case avoided can be used to measure the benefits-to-harms tradeoff of IPN management.

MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis.

BACKGROUND: The use of 12-core systematic prostate biopsy is associated with diagnostic inaccuracy that contributes to both overdiagnosis and underdiagnosis of prostate cancer. Biopsies performed with magnetic resonance imaging (MRI) targeting may reduce the misclassification of prostate cancer in men with MRI-visible lesions. METHODS: Men with MRI-visible prostate lesions underwent both MRI-targeted and systematic biopsy. The primary outcome was cancer detection according to grade group (i.e., a clustering of Gleason grades). Grade group 1 refers to clinically insignificant disease; grade group 2 or higher, cancer with favorable intermediate risk or worse; and grade group 3 or higher, cancer with unfavorable intermediate risk or worse. Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens were recorded. Secondary outcomes were the detection of cancers of grade group 2 or higher and grade group 3 or higher, cancer detection stratified by previous biopsy status, and grade reclassification between biopsy and radical prostatectomy. RESULTS: A total of 2103 men underwent both biopsy methods; cancer was diagnosed in 1312 (62.4%) by a combination of the two methods (combined biopsy), and 404 (19.2%) underwent radical prostatectomy. Cancer detection rates on MRI-targeted biopsy were significantly lower than on systematic biopsy for grade group 1 cancers and significantly higher for grade groups 3 through 5 (P<0.01 for all comparisons). Combined biopsy led to cancer diagnoses in 208 more men (9.9%) than with either method alone and to upgrading to a higher grade group in 458 men (21.8%). However, if only MRI-target biopsies had been performed, 8.8% of clinically significant cancers (grade group ≥3) would have been misclassified. Among the 404 men who underwent subsequent radical prostatectomy, combined biopsy was associated with the fewest upgrades to grade group 3 or higher on histopathological analysis of surgical specimens (3.5%), as compared with MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%). CONCLUSIONS: Among patients with MRI-visible lesions, combined biopsy led to more detection of all prostate cancers. However, MRI-targeted biopsy alone underestimated the histologic grade of some tumors. After radical prostatectomy, upgrades to grade group 3 or higher on histopathological analysis were substantially lower after combined biopsy. (Funded by the National Institutes of Health and others; Trio Study ClinicalTrials.gov number, NCT00102544.).

Changes in uptake of stool-based colorectal cancer screening during the Covid-19 pandemic.

PURPOSE: Colorectal cancer (CRC) screening is underutilized and endoscopic colon screening includes a number of barriers that were exacerbated by the Covid-19 pandemic. At-home stool-based screening (SBS) increased during the pandemic and potentially reached eligible adults hesitant to be screened by endoscopy. The purpose of this analysis was to examine the change in uptake of SBS during the pandemic among adults not screened within guidelines by endoscopy. METHODS: We used data from the 2019 and 2021 National Health Interview Surveys to estimate uptake of SBS among adults aged 50-75 years, without a previous diagnosis of CRC and without guideline-concordant endoscopic screening. We also examined provider recommendations for screening tests. To examine if changes in uptake differed during the pandemic by demographic and health characteristics, we combined survey years and ran logistic regression models with an interaction term for each factor and survey year. RESULTS: In our study population, SBS increased 74% overall from 2019 to 2021 (8.7% to 15.1%; p < 0.001), with the largest percent increase among those aged 50-52 years (3.5% to 9.9%; p < 0.001). Among those aged 50-52 years, the ratio of endoscopy to SBS changed from 83%/17% in 2019 to 55%/45% in 2021. Cologuard was the only screening test where recommendations by healthcare providers significantly increased from 2019 (10.6% to 16.1%; p = 0.002). CONCLUSIONS: Use and recommendations for SBS increased substantially during the pandemic. Increased awareness among patients could potentially improve future CRC screening rates if uptake of SBS occurs among those unable or unwilling to be screened by endoscopy.

PLCOjs, a FAIR GWAS web SDK for the NCI Prostate, Lung, Colorectal and Ovarian Cancer Genetic Atlas project.

MOTIVATION: The Division of Cancer Epidemiology and Genetics (DCEG) and the Division of Cancer Prevention (DCP) at the National Cancer Institute (NCI) have recently generated genome-wide association study (GWAS) data for multiple traits in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Genomic Atlas project. The GWAS included 110 000 participants. The dissemination of the genetic association data through a data portal called GWAS Explorer, in a manner that addresses the modern expectations of FAIR reusability by data scientists and engineers, is the main motivation for the development of the open-source JavaScript software development kit (SDK) reported here. RESULTS: The PLCO GWAS Explorer resource relies on a public stateless HTTP application programming interface (API) deployed as the sole backend service for both the landing page's web application and third-party analytical workflows. The core PLCOjs SDK is mapped to each of the API methods, and also to each of the reference graphic visualizations in the GWAS Explorer. A few additional visualization methods extend it. As is the norm with web SDKs, no download or installation is needed and modularization supports targeted code injection for web applications, reactive notebooks (Observable) and node-based web services. AVAILABILITY AND IMPLEMENTATION: code at https://github.com/episphere/plco; project page at https://episphere.github.io/plco.

15-Year Benefits of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality : A Pooled Analysis of Randomized Trials.

BACKGROUND: The effectiveness of screening for colorectal cancer (CRC) by sex and age in randomized trials is uncertain. OBJECTIVE: To evaluate the 15-year effect of sigmoidoscopy screening on CRC incidence and mortality. DESIGN: Pooled analysis of 4 large-scale randomized trials of sigmoidoscopy screening. SETTING: Norway, the United States, the United Kingdom, and Italy. PARTICIPANTS: Women and men aged 55 to 64 years at enrollment. INTERVENTION: Sigmoidoscopy screening. MEASUREMENTS: Primary end points were cumulative incidence rate ratio (IRR) and mortality rate ratio (MRR) and rate differences after 15 years of follow-up comparing screening versus usual care in intention-to-treat analyses. Stratified analyses were done by sex, cancer site, and age at screening. RESULTS: Analyses comprised 274 952 persons (50.7% women), 137 493 in the screening and 137 459 in the usual care group. Screening attendance was 58% to 84%. After 15 years, the rate difference for CRC incidence was 0.51 cases (95% CI, 0.40 to 0.63 cases) per 100 persons and the IRR was 0.79 (CI, 0.75 to 0.83). The rate difference for CRC mortality was 0.13 deaths (CI, 0.07 to 0.19 deaths) per 100 persons, and the MRR was 0.80 (CI, 0.72 to 0.88). Women had less benefit from screening than men for CRC incidence (IRR for women, 0.84 [CI, 0.77 to 0.91]; IRR for men, 0.75 [CI, 0.70 to 0.81]; P = 0.032 for difference) and mortality (MRR for women, 0.91 [CI, 0.77 to 1.17]; MRR for men, 0.73 [CI, 0.64 to 0.83]; P = 0.025 for difference). There was no statistically significant difference in screening effect between persons aged 55 to 59 years and those aged 60 to 64 years. LIMITATION: Data from the U.K. trial were less granular because of privacy regulations. CONCLUSION: This pooled analysis of all large randomized trials of sigmoidoscopy screening demonstrates a significant and sustained effect of sigmoidoscopy on CRC incidence and mortality for 15 years. PRIMARY FUNDING SOURCE: Health Fund of South-East Norway.

Cervical cancer screening and predictors of screening by diabetes status.

PURPOSE: Women with diabetes have lower survival rates after a cervical cancer diagnosis compared to women without diabetes. Pap smears and human papilloma virus (HPV) testing are highly effective screening tests for cervical cancer, therefore, it is important to know the prevalence of guideline-concordant screening among women with diabetes and understand if their predictors of screening differ. The purpose of this analysis was to assess guideline-concordant cervical cancer screening and predictors by diabetes status. METHODS: We used the 2019 National Health Interview Survey data, limited to women aged 21-65 years without a previous diagnosis of cancer, a hysterectomy, or diagnosed with diabetes in the year prior to the survey. We considered the Pap and HPV tests together and concordance as being tested within the past 3 years as part of a routine exam. We calculated weighted, adjusted prevalence, and prevalence ratios (PRs) of screening concordance comparing women with diabetes to those without. RESULTS: The unadjusted prevalence of concordant screening was 66.5% for women with diabetes compared to 73.3% for women without diabetes (PR = 0.91 95% CI 0.84-0.98). In the fully adjusted model adjusting for factors known to be associated with diabetes and access to healthcare, the association was attenuated and no longer statistically significant (PR = 0.96 95% CI 0.89-1.04). CONCLUSION: Cervical cancer screening concordance was lower in women with diabetes compared to those without overall but the deficit appears to be due primarily to underlying differences in sociodemographic characteristics and access to healthcare and not diabetes independently.

Why Does Magnetic Resonance Imaging-Targeted Biopsy Miss Clinically Significant Cancer?

PURPOSE: Multiple studies demonstrate magnetic resonance imaging (MRI)-targeted biopsy detects more clinically significant cancer than systematic biopsy; however, some clinically significant cancers are detected by systematic biopsy only. While these events are rare, we sought to perform a retrospective analysis of these cases to ascertain the reasons that MRI-targeted biopsy missed clinically significant cancer which was subsequently detected on systematic prostate biopsy. MATERIALS AND METHODS: Patients were enrolled in a prospective study comparing cancer detection rates by transrectal MRI-targeted fusion biopsy and systematic 12-core biopsy. Patients with an elevated prostate specific antigen (PSA), abnormal digital rectal examination, or imaging findings concerning for prostate cancer underwent prostate MRI and subsequent MRI-targeted and systematic biopsy in the same setting. The subset of patients with grade group (GG) ≥3 cancer found on systematic biopsy and GG ≤2 cancer (or no cancer) on MRI-targeted biopsy was classified as MRI-targeted biopsy misses. A retrospective analysis of the MRI and MRI-targeted biopsy real-time screen captures determined the cause of MRI-targeted biopsy miss. Multivariable logistic regression analysis compared baseline characteristics of patients with MRI-targeted biopsy misses to GG-matched patients whose clinically significant cancer was detected by MRI-targeted biopsy. RESULTS: Over the study period of 2007 to 2019, 2,103 patients met study inclusion criteria and underwent combined MRI-targeted and systematic prostate biopsies. A total of 41 (1.9%) men were classified as MRI-targeted biopsy misses. Most MRI-targeted biopsy misses were due to errors in lesion targeting (21, 51.2%), followed by MRI-invisible lesions (17, 40.5%) and MRI lesions missed by the radiologist (3, 7.1%). On logistic regression analysis, lower Prostate Imaging-Reporting and Data System (PI-RADSTM) score was associated with having clinically significant cancer missed on MRI-targeted biopsy. CONCLUSIONS: While uncommon, most MRI-targeted biopsy misses are due to errors in lesion targeting, which highlights the importance of accurate co-registration and targeting when using software-based fusion platforms. Additionally, some patients will harbor MRI-invisible lesions which are untargetable by MRI-targeted platforms. The presence of a low PI-RADS score despite a high PSA is suggestive of harboring an MRI-invisible lesion.

Differences in the relationship between diabetes and prostate cancer among Black and White non-Hispanic men.

PURPOSE: Studies finding lower incidence rates of prostate cancer among men with diabetes have been primarily conducted in White non-Hispanic (WNH) populations. The purpose of this analysis is to compare the relationship between diabetes and prostate cancer among Black (BNH) and White non-Hispanic men. METHODS: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2011 to 2015 to compare incidence rates and tumor characteristics between BNH and WNH men by diabetes status. Age-adjusted incidence rates and corresponding rate ratios (RR) by diabetes status were calculated overall and by tumor grade, stage, and PSA level separately for BNH and WNH men. We used multivariable logistic regression to compare tumor characteristics among men with prostate cancer in the numerator, both within and across race/ethnic groups. RESULTS: Overall age-adjusted incidence rates were significantly lower in men with diabetes compared to those without among WNH men [RR = 0.88 95% Confidence Interval (CI) 0.86-0.90] but there was no difference in rates by diabetes status among BNH men (RR = 1.01 95% CI 0.96-1.07). Men with diabetes were less likely to be diagnosed with distant-staged tumors compared to those without diabetes in both race/ethnic groups but the magnitude of difference by diabetes status was greater in BNH [Odds Ratio (OR) = 0.52 95% CI 0.42-0.64] than WNH (OR = 0.88 95% CI 0.81-0.95) men (p-value for interaction < 0.001). CONCLUSION: The relationship between diabetes and prostate cancer differed between BNH and WNH men. The differences could have implications in evaluating the effectiveness of prostate cancer screening in men with diabetes across racial/ethnic subgroups.

Other and All-Cause Mortality among Men Diagnosed with Prostate Cancer in the PLCO Trial.

PURPOSE: Men with prostate cancer have high cause-specific survival, and most deaths are from other causes. This study aimed to investigate other and all-cause mortality in a large cancer screening cohort. MATERIALS AND METHODS: From the PLCO (Prostate, Lung, Colorectal and Ovarian) Cancer Screening Trial cohort, we selected men diagnosed with prostate cancer from 1994-2014. We examined other and all-cause survival by prostate cancer risk level, defined as the D'Amico categories for localized disease (low, intermediate and high risk) plus nonlocalized disease. We developed 3 Cox proportional hazards models to assess the relationship between risk level and survival. Model I controlled for age, race, study arm and diagnosis year. Model II additionally controlled for other demographic and medical history factors. Model III additionally controlled for initial treatment. RESULTS: Of 76,672 men in PLCO and 10,859 prostate cancer cases, 9,248 (85.2%) had known prostate cancer risk level (mean±SD age 70.4±6.2 years). Median followup time from diagnosis was 10.8 years (IQR 6.8-15.0). Of 3,318 deaths 81% were from other causes. Compared to the low risk group, other-cause mortality HRs were 1.13 (95% CI 1.04-1.23), 1.35 (95% CI 1.21-1.50) and 1.63 (95% CI 1.35-1.97) for intermediate risk, high risk and advanced disease, respectively, in model II. Model III HRs were similar to model II except for advanced disease, where the HR decreased to 1.35. CONCLUSIONS: Other-cause survival was greater in lower vs higher risk disease, even after controlling for lifestyle characteristics and comorbidities. Further research is needed to identify factors contributing to this higher other-cause mortality to help mitigate the risk.

Adherence with protocol medication use and mortality from unrelated causes in a prevention trial.

Several studies have shown that non-adherence to medication use is associated with lower use of preventive services and increased mortality. We aimed to study the relationship between initial adherence to medication use and mortality in the Prostate Cancer Prevention Trial (PCPT). The PCPT randomized men age 55 and over to a finasteride or placebo arm. Duration of treatment was seven years, followed by end-of-study prostate biopsy. Extended follow-up for mortality was performed by linkage to the National Death Index. Non-adherence was defined as taking under 80% of required pills during the first or second 6-month trial period. Proportional hazards models were used to assess the relationship between adherence and all-cause mortality (excluding prostate cancer deaths). Three models were developed as follows: Model I (controlling for demographics and trial arm), Model II (Model I factors plus specific medical conditions), Model III (Model II factors plus lifestyle factors). Of 18,667 men included in the analysis, 3082 (16.5%) were non-adherent. The most common reasons for non-adherence were side effects (33.9%) and forgetting to take pills (22%). Through 5 and 10 years of follow-up, 178 (5.9%) and 483 (15.7%) non-adherent men died versus 581 (3.7%) and 1887 (12.1%) adherent men. Hazard ratios (HRs) at 5 years were 1.62 (95% CI: 1.37-1.91), 1.55 (95% CI: 1.30-1.83) and 1.49 (95% CI: 1.25-1.76) for Models I-III. HRs at ten years were lower but still statistically significant. Non-adherence to taking protocol medications was associated with increased mortality from unrelated conditions.

Opioid and Other Medication Use and General Health Status in a Cohort of Older Adults.

OBJECTIVE: The aim of this study was to determine whether the use of opioids and other medications in a cohort of older adults was associated with self-reported health status. METHODS: Among participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial linked to Medicare Part D claims data and answering a quality-of-life questionnaire, we examined the relationship between medication use over a 5-year period and various self-reported health status variables assessed several years later, including overall health status (STATUS) and trouble with activities of daily living (TADL). Multivariable logistic regression was used to estimate odds ratios (ORs) for the health status variables and metrics of medication use, including >60-day use, and for opiates, chronic use, with models controlling for demographics (model I), additionally for chronic conditions (model II), and additionally for other medication use (model III). RESULTS: The study cohort included 22,844 PLCO participants (56% women, 90% non-Hispanic whites); 4.2% had chronic opioid use and 12.5% used for >60 days. Fair-poor STATUS was reported in 37.9% of participants with chronic opioid use versus 15.0% of participants without (p < 0.001). ORs for chronic opioid use for fair-poor STATUS (compared to good-excellent) were significantly elevated in all models but decreased from model I (OR = 3.6; 95% CI :3.1-4.1) to model II (OR = 2.7; 95% CI :2.3-3.1) to model III (OR = 2.1; 95% CI :1.8-2.5). ORs for TADL were generally similar to those for STATUS. Other drug classes also had significantly elevated model III ORs for fair-poor versus good-excellent STATUS (range 1.1-1.6). CONCLUSION: Frequent use of various medication classes correlated with measures of future health status in an elderly population, with opioids having the strongest association. The magnitude of the association decreased after controlling for concurrent chronic conditions but remained elevated. Future research should consider how the use of opioids and other medications impact measures of health-related quality of life.

Healthcare Access, Utilization, and Preventive Health Behaviors by Eligibility for Lung Cancer Screening.

In 2013, the US Preventive Services Task Force recommended low-dose computed tomography screening for smokers at high risk of lung cancer; however, use remains low. Efforts to promote lung cancer screening need to consider how receptive this population is to preventive healthcare and cancer screening. In addition, because of demonstrated heterogeneity in behaviors by smoking status, interventions may need to differ among eligible high-risk subgroups. To assess the engagement of high-risk smokers in other preventive healthcare behaviors, we examined healthcare use, including non-lung cancer screening, and healthcare provider discussions regarding screening by eligibility for lung cancer screening. We used the 2015 National Health Interview Survey to assess smoking history, healthcare use, cancer screening, vaccinations, and healthcare provider discussions regarding non-lung cancer screening. We calculated weighted prevalence estimates and prevalence ratios comparing eligible and ineligible current and former smokers to never smokers. Eligible current and former smokers had significantly different healthcare utilization and screening concordance compared to never smokers and to each other. Compared to never smokers, eligible current smokers were significantly less likely to be concordant with breast, colorectal, and cervical cancer screening while eligible former smokers were only less likely to be concordant with breast cancer screening. Eligible current smokers were less likely to report physician discussions about non-lung screening tests. Provider discussions about screening and engagement in preventive healthcare differed among current and former smokers eligible for lung cancer screening. Intervention efforts to increase lung cancer screening levels will likely need to differ as well.

Thyroid Incidentalomas in Association With Low-Dose Computed Tomography in the National Lung Screening Trial.

Advances in cancer screening methods have opened avenues for incidental findings and cancer overdiagnosis. We performed a secondary analysis of the National Lung Screening Trial (enrollment from 2002-2004), a randomized controlled trial comparing low-dose computed tomography (LDCT; n = 26,722) with chest radiography (CXR; n = 26,732) for lung cancer detection, to examine incidental findings related to thyroid cancer (ThCa). Three screening rounds were included, and median follow-up was 6.6 years for LDCT and 6.5 years for CXR. Radiologists reported lung and non-lung-related abnormalities. In the LDCT arm, 5.7%, 4.7%, and 4.5% of participants had abnormalities above the diaphragm (AADs) detected at baseline, year 1, and year 2, respectively, compared with 2.3%, 1.5%, and 1.3% in the CXR arm. In the LDCT arm, 205 AADs (7.0%) were thyroid-related. Overall, 60 ThCas were reported, 35 in the LDCT arm and 25 in the CXR arm (P = 0.2). In the LDCT arm, participants with a prior AAD had a 7.8-fold increased risk (95% confidence interval: 4.0, 15.1) of ThCa compared with those who did not have an AAD. Early and persistent excess of ThCas diagnosed earlier in the LDCT arm suggests overdiagnosis. The use of sensitive screening modalities for early detection of lung cancer might result in the discovery of thyroid incidentalomas.

Contribution of Surveillance Colonoscopy to Colorectal Cancer Prevention.

BACKGROUND & AIMS: The contribution of surveillance colonoscopy, as opposed to that of initial colonoscopy examination, to prevention of colorectal cancer (CRC) is uncertain. We estimated the preventive effect of surveillance colonoscopy by applying the recently developed metric of adenoma dwell time avoided needed to prevent 1 CRC case (DTA). METHODS: We followed subjects in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial who underwent colonoscopies following positive findings from sigmoidoscopies (colonoscopy cohort, n = 15,935) for CRC incidence for 10 years. The number and timing of adenomas removed during surveillance were measured in a subset (n = 3492) of patients and extrapolated to the entire cohort to estimate the total avoided adenoma dwell time. A previously determined DTA value of 612 dwell years was applied to estimate the number of CRC cases prevented by surveillance. Proportional reduction in CRC was computed as CP/(CO+CP), where CO and CP are observed and estimated prevented cases, respectively. RESULTS: In the colonoscopy cohort of the PLCO, 2882 subjects had advanced adenomas (AAs), 572 had 3 or more non-advanced adenomas (NAA3+), 4496 had 1-2 non-advanced adenomas (NAA1-2), and 7985 had no adenoma (NA). The mean number of subsequent colonoscopy examinations over 10 years were 1.80 for subjects with AAs, 1.63 for subjects with NAA3+, and 1.46 for subjects with NAA1-2. Average years of avoided adenoma dwell time per subject were 4.0 for subjects with AAs, 5.5 for subjects with NAA3+, and 2.4 for subjects with NAA1-2. There were 56 cases of CRC in subjects with AAs, 4 cases of CRC in subjects with NAA3+, and 33 cases of CRC in subjects with NAA1-2. Estimated proportional reductions in CRC incidence were 25.0% in subjects with AAs (95% CI, 16%-34%), 34.4% in subjects with NAA1-2 (95% CI, 25%-40%), and 30.4% overall (in subjects with AAs, NAA3+, or NAA1-2; 95% CI, 25%-40%). Absolute CRC incidence reductions were 7.1 per 10,000 PY in subjects with AAs and 4.1 per 10,000 PY in subjects with NAA1-2. CONCLUSIONS: Using the recently developed metric of DTA, we estimated that surveillance colonoscopy in the PLCO colonoscopy cohort during 10 years of follow up prevented 30% of CRC cases. Because the methodology for estimation is indirect, the true effect is uncertain.

Examining the relationship between diabetes and prostate cancer through changes in screening guidelines.

PURPOSE: Previous studies have found that men with diabetes are at reduced risk of prostate cancer compared to men without diabetes. The lower risk could be due to biologic differences and/or a diagnosis bias from use of the prostate-specific antigen (PSA) test as a screening and diagnostic tool. We sought to further examine the relationship between diabetes and incidence of prostate cancer and examine the potential impact of changes in PSA screening guidelines in 2008 and 2012. METHODS: We used 2004-2015 Surveillance, Epidemiology and End Results (SEER)-Medicare data and limited the study population to men aged 67-74 with at least 2 years of continuous enrollment. Using the 5% Medicare sample as the denominator and prostate cancer cases as the numerator, we calculated age-adjusted rate ratios (RR) in 2006-2011 and 2012-2015 by diabetes status, overall and by tumor grade. We used multivariable logistic regression to compare tumor characteristics by diabetes status. RESULTS: Men with diabetes had lower incidence rates of prostate cancer compared to men without diabetes in 2006-2011 [RR = 0.89 95% confidence interval (CI) 0.87-0.91] and 2012-2015 (RR = 0.92 95% CI 0.89-0.95) but the slight attenuation toward the null in 2012-2015 was primarily due to the change in RRs for low-grade tumors. CONCLUSION: We found differences in the risk and characteristics of prostate cancer by diabetes status and that some risks have changed over time as guidelines have changed. With lower PSA use in the more recent time-period, rates of low-grade tumors have become more similar by diabetes status.

Aspirin use and ovarian cancer risk using extended follow-up of the PLCO Cancer Screening Trial.

OBJECTIVE: Frequent use of aspirin has been associated with reduced ovarian cancer risk in observational studies, but it is unclear if only daily, low-dose aspirin confers a protective benefit. We examined associations between patterns of aspirin use and ovarian cancer risk among postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. METHODS: Participants were enrolled in PLCO between 1993 and 2001 and followed for cancer outcomes through 2014. Detailed data on aspirin use (e.g., dose, frequency and duration) were ascertained via the supplemental questionnaire (SQX) administered in 2006-2007. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between aspirin use (defined as use ≥once/week) and incident ovarian cancer. We conducted analyses among all women in the study sample and stratified by age at the time of the SQX. RESULTS: There were 41,633 women included in this analysis, of whom 223 developed incident ovarian cancer. Overall, aspirin use was not significantly associated with ovarian cancer risk (HR: 0.93, 95% CI: 0.72-1.21). Among women <70 years, there was suggestion of an inverse association for daily use of aspirin (HR: 0.65, 95% CI: 0.40-1.05), low-dose aspirin (HR: 0.79, 95% CI: 0.51-1.24) and daily use of low-dose aspirin (HR: 0.64, 95% CI: 0.38-1.09). CONCLUSIONS: These findings suggest a potential modest effect of daily, low-dose aspirin in reducing ovarian cancer risk. However, effect estimates were imprecise given the small number of events, and further research will be needed to confirm and extend these findings.