PRECISION CANCER SCREENING IN HIGH-RISK POPULATIONS: APPLICATIONS IN CERVICAL, ANAL, AND LUNG CANCERS

Cancer screening can prevent mortality and morbidity from cancer, but it also causes harms. Recently, precision (i.e. risk-based, personalized) screening approaches have emerged as a way to better balance these benefits and harms. The purpose of this dissertation was to identify opportunities for precision screening among two U.S. populations at high risk for cancer: people living with HIV and people with a history of heavy smoking. The first aim (Chapter 2) analyzed data from the Women’s Interagency HIV Study to compare cervical precancer risks between women living with HIV (WLHIV) and general population women. We used a risk benchmarking framework to draw conclusions regarding appropriate cervical cancer screening and management strategies for WLHIV. We show that current guidelines are largely appropriate, but that in some instances, considering CD4 cell count (immunosuppression status) could inform risk-tailored strategies. The second aim (Chapter 3) analyzed data from the Multicenter AIDS Cohort Study (MACS) to describe patterns of repeated anal cytology testing among HIV-positive and HIV-negative men who have sex with men (MSM). We show that approximately one-third of HIV-positive MSM have consistently negative anal cytology over 3 years, which may identify men for whom high-resolution anoscopy is unlikely to be beneficial. Following abnormal anal cytology, the next cytology is commonly negative in HIV-negative or immunocompetent HIV-positive MSM, while persistent cytological abnormality is more likely among immunosuppressed HIV-positive MSM. Finally, the third aim (Chapter 4) develops a risk model to describe how individual lung cancer risk evolved based on screening CT findings during the National Lung Screening Trial. We show that those with a negative CT screen and no emphysema or consolidation maintained reduced lung cancer risk at the next annual screen and thus might be candidates for longer screening intervals. In contrast, most false-positives experienced substantially increased lung cancer detection at the next screen, which could be stratified by accounting for specific features of lung nodules. In sum, this dissertation describes three settings in which precision cancer screening could achieve a better balance of benefits and harms for two high-risk populations. Success in implementing these approaches will require interdisciplinary efforts that engage clinicians, patients, and researchers

Comparative performance of lung cancer risk models to define lung screening eligibility in the United Kingdom

Abstract: Background: The National Health Service England (NHS) classifies individuals as eligible for lung cancer screening using two risk prediction models, PLCOm2012 and Liverpool Lung Project-v2 (LLPv2). However, no study has compared the performance of lung cancer risk models in the UK. Methods: We analysed current and former smokers aged 40–80 years in the UK Biobank (N = 217,199), EPIC-UK (N = 30,813), and Generations Study (N = 25,777). We quantified model calibration (ratio of expected to observed cases, E/O) and discrimination (AUC). Results: Risk discrimination in UK Biobank was best for the Lung Cancer Death Risk Assessment Tool (LCDRAT, AUC = 0.82, 95% CI = 0.81–0.84), followed by the LCRAT (AUC = 0.81, 95% CI = 0.79–0.82) and the Bach model (AUC = 0.80, 95% CI = 0.79–0.81). Results were similar in EPIC-UK and the Generations Study. All models overestimated risk in all cohorts, with E/O in UK Biobank ranging from 1.20 for LLPv3 (95% CI = 1.14–1.27) to 2.16 for LLPv2 (95% CI = 2.05–2.28). Overestimation increased with area-level socioeconomic status. In the combined cohorts, USPSTF 2013 criteria classified 50.7% of future cases as screening eligible. The LCDRAT and LCRAT identified 60.9%, followed by PLCOm2012 (58.3%), Bach (58.0%), LLPv3 (56.6%), and LLPv2 (53.7%). Conclusion: In UK cohorts, the ability of risk prediction models to classify future lung cancer cases as eligible for screening was best for LCDRAT/LCRAT, very good for PLCOm2012, and lowest for LLPv2. Our results highlight the importance of validating prediction tools in specific countries

Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers: A retrospective nested case-control study in two prospective cohorts

The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI: 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6-14) and overall specificity was 92% (95% CI: 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts

Population-Based Precision Cancer Screening: A Symposium on Evidence, Epidemiology, and Next Steps.

Precision medicine, an emerging approach for disease treatment that takes into account individual variability in genes, environment, and lifestyle, is under consideration for preventive interventions, including cancer screening. On September 29, 2015, the National Cancer Institute sponsored a symposium entitled "Precision Cancer Screening in the General Population: Evidence, Epidemiology, and Next Steps". The goal was two-fold: to share current information on the evidence, practices, and challenges surrounding precision screening for breast, cervical, colorectal, lung, and prostate cancers, and to allow for in-depth discussion among experts in relevant fields regarding how epidemiology and other population sciences can be used to generate evidence to inform precision screening strategies. Attendees concluded that the strength of evidence for efficacy and effectiveness of precision strategies varies by cancer site, that no one research strategy or methodology would be able or appropriate to address the many knowledge gaps in precision screening, and that issues surrounding implementation must be researched as well. Additional discussion needs to occur to identify the high priority research areas in precision cancer screening for pertinent organs and to gather the necessary evidence to determine whether further implementation of precision cancer screening strategies in the general population would be feasible and beneficial. Cancer Epidemiol Biomarkers Prev; 25(11); 1449-55. ©2016 AACR.U.S. National Cancer InstituteThis is the author accepted manuscript. The final version is available from the American Association for Cancer Research via http://dx.doi.org/10.1158/1055-9965.EPI-16-055

Double-blind, 12 month follow-up, placebo-controlled trial of mifepristone on cognition in alcoholics: the MIFCOG trial protocol

Background: Increased levels of cortisol during acute alcohol withdrawal have been linked to cognitive deficits and depression. Preclinical research found that the glucocorticoid Type II receptor antagonist, mifepristone, prevented some of the neurotoxic effects of withdrawal and memory loss. Clinical trials have shown mifepristone effective in the treatment of depression. This study aims to examine the extent to which the glucocorticoid Type II receptor antagonist, mifepristone, when given to alcohol dependent males during the acute phase of alcohol withdrawal, will protect against the subsequent memory loss and depressive symptoms during abstinence from alcohol. Methods/Design: The study is a Phase 4 therapeutic use, “Proof of Concept” trial. The trial is a double-blind randomised controlled clinical trial of mifepristone versus inactive placebo. The trial aims to recruit 120 participants referred for an inpatient alcohol detoxification from community alcohol teams, who meet the inclusion criteria; 1) Male, 2) Aged 18–60 inclusive, 3) alcohol dependent for 5 or more years. A screening appointment will take place prior to admission to inpatient alcohol treatment units to ensure that the individual is suitable for inclusion in the trial in accordance with the inclusion and exclusion criteria. On admission participants are randomised to receive 600 mg a day of mifepristone (200 mg morning, afternoon and evening) for 7 days and 400 mg for the subsequent 7 days (200 mg morning and evening) or the equivalent number of placebo tablets for 14 days. Participants will remain in the trial for 4 weeks (at least 2 weeks as an inpatient) and will be followed up at 3, 6 and 12 months post randomisation. Primary outcome measures are cognitive function at week 3 and 4 after cessation of drinking and symptoms of depression over the 4 weeks after cession of drinking, measured using the Cambridge Neuropsychological Test Automated battery and Beck Depression Inventory, respectively. Secondary outcome measures are severity of the acute phase of alcohol withdrawal, alcohol craving, symptoms of protracted withdrawal and maintenance of abstinence and levels of relapse drinking at follow-up. Discussion: The current trial will provide evidence concerning the role of glucocorticoid Type II receptor activation in cognitive function and depression during acute alcohol withdrawal and the efficacy of treatment with mifepristone

State of the science and future directions for research on HIV and cancer : Summary of a joint workshop sponsored by IARC and NCI

An estimated 38 million people live with human immunodeficiency virus (HIV) worldwide and are at excess risk for multiple cancer types. Elevated cancer risks in people living with HIV (PLWH) are driven primarily by increased exposure to carcinogens, most notably oncogenic viruses acquired through shared transmission routes, plus acceleration of viral carcinogenesis by HIV-related immunosuppression. In the era of widespread antiretroviral therapy (ART), life expectancy of PLWH has increased, with cancer now a leading cause of co-morbidity and death. Furthermore, the types of cancers occurring among PLWH are shifting over time and vary in their relative burden in different parts of the world. In this context, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) convened a meeting in September 2022 of multinational and multidisciplinary experts to focus on cancer in PLWH. This report summarizes the proceedings, including a review of the state of the science of cancer descriptive epidemiology, etiology, molecular tumor characterization, primary and secondary prevention, treatment disparities and survival in PLWH around the world. A consensus of key research priorities and recommendations in these domains is also presented

PRECISION CANCER SCREENING IN HIGH-RISK POPULATIONS: APPLICATIONS IN CERVICAL, ANAL, AND LUNG CANCERS

Cancer screening can prevent mortality and morbidity from cancer, but it also causes harms. Recently, precision (i.e. risk-based, personalized) screening approaches have emerged as a way to better balance these benefits and harms. The purpose of this dissertation was to identify opportunities for precision screening among two U.S. populations at high risk for cancer: people living with HIV and people with a history of heavy smoking. The first aim (Chapter 2) analyzed data from the Women’s Interagency HIV Study to compare cervical precancer risks between women living with HIV (WLHIV) and general population women. We used a risk benchmarking framework to draw conclusions regarding appropriate cervical cancer screening and management strategies for WLHIV. We show that current guidelines are largely appropriate, but that in some instances, considering CD4 cell count (immunosuppression status) could inform risk-tailored strategies. The second aim (Chapter 3) analyzed data from the Multicenter AIDS Cohort Study (MACS) to describe patterns of repeated anal cytology testing among HIV-positive and HIV-negative men who have sex with men (MSM). We show that approximately one-third of HIV-positive MSM have consistently negative anal cytology over 3 years, which may identify men for whom high-resolution anoscopy is unlikely to be beneficial. Following abnormal anal cytology, the next cytology is commonly negative in HIV-negative or immunocompetent HIV-positive MSM, while persistent cytological abnormality is more likely among immunosuppressed HIV-positive MSM. Finally, the third aim (Chapter 4) develops a risk model to describe how individual lung cancer risk evolved based on screening CT findings during the National Lung Screening Trial. We show that those with a negative CT screen and no emphysema or consolidation maintained reduced lung cancer risk at the next annual screen and thus might be candidates for longer screening intervals. In contrast, most false-positives experienced substantially increased lung cancer detection at the next screen, which could be stratified by accounting for specific features of lung nodules. In sum, this dissertation describes three settings in which precision cancer screening could achieve a better balance of benefits and harms for two high-risk populations. Success in implementing these approaches will require interdisciplinary efforts that engage clinicians, patients, and researchers