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Background: Cervical cancer screening with high-risk human papillomavirus (HrHPV) testing is being introduced. Most HrHPV infections are transient, requiring triage tests to identify individuals at highest risk for progression to cervical cancer. Head-to-head comparisons of available strategies for screening and triage are needed. Endometrial and ovarian cancers could be amenable to similar testing. Methods: Between 2016 and 2020, discarded cervical cancer screening specimens from women ages 25 to 65 undergoing screening at Kaiser Permanente Northern California were collected. Specimens were aliquoted, stabilized, and stored frozen. Human papillomavirus (HPV), cytology, and histopathology results as well as demographic and cofactor information were obtained from electronic medical records (EMR). Follow-up collection of specimens was conducted for 2 years, and EMR-based data collection was planned for 5 years. Results: Collection of enrollment and follow-up specimens is complete, and EMR-based follow-up data collection is ongoing. At baseline, specimens were collected from 54,957 HPV-positive, 10,215 HPV-negative/Pap-positive, and 12,748 HPV-negative/Pap-negative women. Clinical history prior to baseline was available for 72.6% of individuals, of which 53.9% were undergoing routine screening, 8.6% recently had an abnormal screen, 30.3% had previous colposcopy, and 7.2% had previous treatment. As of February 2021, 55.7% had one or more colposcopies, yielding 5,563 cervical intraepithelial neoplasia grade 2 (CIN2), 2,756 cervical intraepithelial neoplasia grade 3 (CIN3), and 146 cancer histopathology diagnoses. Conclusions: This robust population-based cohort study represents all stages of cervical cancer screening, management, and posttreatment follow-up. Impact: The IRIS study is a unique and highly relevant resource allowing for natural history studies and rigorous evaluation of candidate HrHPV screening and triage markers, while permitting studies of biomarkers associated with other gynecologic cancers.

Objectives We propose a risk-tailored approach for management of lung cancer screening results. This approach incorporates individual risk factors and low-dose computed tomography (LDCT) image features into calculations of immediate and next-screen (1-y) risks of lung cancer detection, which in turn can recommend short-interval imaging or 1-year or 2-year screening intervals. Methods We first extended the "LCRAT+CT" individualized risk calculator to predict lung cancer risk after either a negative or abnormal LDCT screen result. To develop the abnormal screen portion, we analyzed 18,129 abnormal LDCT results in the National Lung Screening Trial (NLST), including lung cancers detected immediately (n = 649) or at the next screen (n = 235). We estimated the potential impact of this approach among NLST participants with any screen result (negative or abnormal). Results Applying the draft National Health Service (NHS) England protocol for lung screening to NLST participants referred 76% of participants to a 2-year interval, but delayed diagnosis for 40% of detectable cancers. The Lung Cancer Risk Assessment Tool+Computed Tomography (LCRAT+CT) risk model, with a threshold of less than 0.95% cumulative lung cancer risk, would also refer 76% of participants to a 2-year interval, but would delay diagnosis for only 30% of cancers, a 25% reduction versus the NHS protocol. Alternatively, LCRAT+CT, with a threshold of less than 1.7% cumulative lung cancer risk, would also delay diagnosis for 40% of cancers, but would refer 85% of participants for a 2-year interval, a 38% further reduction in the number of required 1-year screens beyond the NHS protocol. Conclusions Using individualized risk models to determine management in lung cancer screening could substantially reduce the number of screens or increase early detection.

Background Low-dose chest CT screening for lung cancer has become a standard of care in the United States, in large part because of the results of the National Lung Screening Trial (NLST). Additional evidence supporting the net benefit of low-dose chest CT screening for lung cancer, and increased experience in minimizing the potential harms, has accumulated since the prior iteration of these guidelines. Here, we update the evidence base for the benefit, harms, and implementation of low-dose chest CT screening. We use the updated evidence base to provide recommendations where the evidence allows, and statements based on experience and expert consensus where it does not. Methods Approved panelists reviewed previously developed key questions using the Population, Intervention, Comparator, Outcome format to address the benefit and harms of low-dose CT screening, and key areas of program implementation. A systematic literature review was conducted using MEDLINE via PubMed, Embase, and the Cochrane Library on a quarterly basis since the time of the previous guideline publication. Reference lists from relevant retrievals were searched, and additional papers were added. Retrieved references were reviewed for relevance by two panel members. The quality of the evidence was assessed for each critical or important outcome of interest using the Grading of Recommendations, Assessment, Development and Evaluation approach. Meta-analyses were performed where appropriate. Important clinical questions were addressed based on the evidence developed from the systematic literature review. Graded recommendations and ungraded statements were drafted, voted on, and revised until consensus was reached. Results The systematic literature review identified 75 additional studies that informed the response to the 12 key questions that were developed. Additional clinical questions were addressed resulting in seven graded recommendations and nine ungraded consensus statements. Conclusions Evidence suggests that low-dose CT screening for lung cancer can result in a favorable balance of benefit and harms. The selection of screen-eligible individuals, the quality of imaging and image interpretation, the management of screen-detected findings, and the effectiveness of smoking cessation interventions can impact this balance.

Introduction To help target preventive strategies, we estimated US population attributable risks (PARs) of demographic and potentially modifiable risk factors for esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric noncardia adenocarcinoma (GNCA). Methods We prospectively examined the associations for risk factors and these cancers in 490,605 people in the National Institutes of Health-the American Association of Retired Persons Diet and Health cohort Diet and Health Study cohort from 1995 to 2011. Exposures were obtained from the baseline questionnaire. Diagnoses of gastroesophageal reflux disease were extracted for a subset of eligible National Institutes of Health-the American Association of Retired Persons Diet and Health cohort subjects through linkage to Medicare and then multiply imputed for non-Medicare-eligible subjects. Hazard ratios were calculated using multivariable-adjusted Cox proportional hazards regression. Adjusted population attributable risks were calculated for the US population aged 50-71 years by combining the hazard ratios with the estimated joint distribution of risk factor prevalence from the 2015 National Health Interview Survey. Results Smoking remained the most important risk factor for ESCC and was estimated to cause more than 1/3 of EAC and GCA and 1/10 of GNCA. Obesity and gastroesophageal reflux disease were associated with more than 1/2 of EAC and 1/3 of GCA. Compared with each lowest-risk level category, common risk factors were estimated to be associated with 73.7% of ESCC (95% confidence interval [CI]: 62.1%-85.4%), 70.3% of EAC (95% CI: 64.4%-76.2%), 69.3% of GCA (95% CI: 61.0%-77.7%), and 33.6% of GNCA (95% CI: 21.7%-45.5%). Discussion These factors accounted for a large proportion of esophageal and gastric cancers in the United States, highlighting opportunities for education and intervention to reduce the burden of these highly fatal cancers.

BACKGROUND Studying the differential impact of aspirin and other nonsteroidal anti-inflammatory drugs across the stages of colorectal neoplasia from early adenoma to cancer is critical for understanding the benefits of these widely used drugs. METHODS With 13 years of follow-up, the authors prospectively evaluated the association between aspirin and ibuprofen use and incident distal adenoma (1221 cases), recurrent adenoma (862 cases), and incident colorectal cancer (CRC; 2826 cases) among men and women in the population-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. With multivariable-adjusted models, odds ratio (ORs) and 95% confidence intervals (CIs) for adenoma incidence and recurrence and hazard ratios (HRs) and 95% CIs for incident CRC were determined. RESULTS The authors observed a significantly reduced risk of incident adenoma with ibuprofen use (≥30 vs

Background Prior studies have suggested that gastroesophageal reflux disease (GERD) may be associated with risk of squamous cancers of the larynx and esophagus; however, most of these studies have had methodological limitations or insufficient control for potential confounders. Methods We prospectively examined the association between GERD and esophageal adenocarcinoma (EADC), esophageal squamous cell carcinoma (ESCC), and laryngeal squamous cell carcinoma (LSCC) in 490,605 participants of the NIH-AARP Diet and Health Study cohort who were 50-71 years of age at baseline. Exposure to risk factors were obtained from the baseline questionnaire. GERD diagnosis was extracted among eligible participants via linkage to Medicare diagnoses codes and then multiply imputed for non-Medicare-eligible participants. Hazard ratios (HRs) and 95% CIs of GERD were computed using Cox regression. Results From 1995 to 2011, we accrued 931 cases of EADC, 876 cases of LSCC, and 301 cases of ESCC in this cohort and estimated multivariable-adjusted HRs of 2.23 (95% CI, 1.72-2.90), 1.91 (95% CI, 1.24-2.94), and 1.99 (95% CI, 1.39-2.84) for EADC, LSCC, and ESCC, respectively. The associations were independent of sex, smoking status, alcohol intake, and follow-up time periods. We estimated that among the general population in the United States, 22.04% of people aged 50-71 years suffered from GERD. Using risk factor distributions for the United States from national survey data, 16.92% of LSCC cases and 17.32% of ESCC cases among individuals aged 50-71 years were estimated to be associated with GERD. Conclusion GERD is a common gastrointestinal disorder, but future prospective studies are needed to replicate our findings. If replicated, they may inform clinical surveillance of GERD patients and suggest new avenues for prevention of these malignancies.

We examined whether draft 2020 United States Preventive Services Task Force (USPSTF) lung cancer screening recommendations “partially ameliorate racial disparities in screening eligibility” compared with the 2013 guidelines, as claimed. Using data from the 2015 National Health Interview Survey, USPSTF-2020 increased eligibility by similar proportions for minorities (97.1%) and Whites (78.3%). Contrary to the intent of USPSTF-2020, the relative disparity (differences in percentages of model-estimated gainable life-years from National Lung Screening Trial–like screening by eligible Whites vs minorities) actually increased from USPSTF-2013 to USPSTF-2020 (African Americans: 48.3%–33.4% = 15.0% to 64.5%–48.5% = 16.0%; Asian Americans: 48.3%–35.6% = 12.7% to 64.5%–45.2% = 19.3%; Hispanic Americans: 48.3%–24.8% = 23.5% to 64.5%–37.0% = 27.5%). However, augmenting USPSTF-2020 with high-benefit individuals selected by the Life-Years From Screening with Computed Tomography (LYFS-CT) model nearly eliminated disparities for African Americans (76.8%–75.5% = 1.2%) and improved screening efficiency for Asian and Hispanic Americans, although disparities were reduced only slightly (Hispanic Americans) or unchanged (Asian Americans). The draft USPSTF-2020 guidelines increased the number of eligible minorities vs USPSTF-2013 but may inadvertently increase racial and ethnic disparities. LYFS-CT could reduce disparities in screening eligibility by identifying ineligible people with high predicted benefit regardless of race and ethnicity.

Summary Background The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. Methods We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. Findings We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23–2·10; p=0·0005 in the discovery dataset; 1·22, 1·05–1·40; p=0·0072 in the validation dataset; and 1·27, 1·12–1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02–1·51; p=0·034 in the discovery dataset; 1·10, 0·98–1·20; p=0·10 in the validation dataset; and 1·11, 1·02–1·22; p=0·018 in the combined dataset. Interpretation Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. Funding The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.

Ghrelin is a hormone produced in the oxyntic glands of the stomach. Previous work by our group has suggested that serum ghrelin concentrations are inversely associated with gastric and esophageal cancer risk. We measured ghrelin concentrations in the Linxian General Population Nutrition Intervention Trial (NIT), and the Shanghai Women's Health Study (SWHS). In NIT, we analyzed serum samples from 298 esophageal squamous cell carcinoma (ESCC) cases, 518 gastric cardia adenocarcinoma (GCA) cases, 258 gastric noncardia adenocarcinoma (GNCA) cases and 770 subcohort controls (case–cohort). In SWHS, we measured ghrelin in plasma samples from 249 GNCA cases and 498 matched controls (nested case–control). Ghrelin was measured using radioimmunoassay. In NIT and SWHS, low ghrelin concentrations were associated with an increased risk of developing GNCA and GCA. The hazard ratio (HR Q1:Q4) for GNCA in NIT was 1.35 (95% CI: 0.89–2.05; p-trend = 0.02); the odds ratio in SWHS was 1.66 (95% CI: 1.02–2.70; p-trend = 0.06). Low ghrelin was associated with a twofold increase of GCA (HR Q1:Q4 = 2.00, 95% CI: 1.45–2.77; p-trend

Supplemental digital content is available in the text., Objective To manage cervical screening abnormalities, the 2019 ASCCP management consensus guidelines will recommend clinical action on the basis of risk of cervical precancer and cancer. This article details the methods used to estimate risk, to determine the risk-based management, and to validate that the risk-based recommendations are of general use in different settings. Methods Based on 1.5 million patients undergoing triennial cervical screening by cotesting at the Kaiser Permanente Northern California from 2003 to 2017, we estimated risk profiles for different clinical scenarios and combinations of past and current human papillomavirus and cytology test results. We validated the recommended management by comparing with the estimated risks in several external data sources. Results Risk and management tables are presented separately by Egemen et al.1 and Demarco et al.2 Risk-based management derived from the Kaiser Permanente Northern California largely agreed with the management implied from the estimated risks of the other data sources. Conclusions The new risk-based guidelines present management of abnormal cervical screening results. By describing the steps used to develop these guidelines, the methods presented in this article can provide a basis for future extensions of the risk-based guidelines.

Background: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria. Methods: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case–control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2). Results: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660–0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95–5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04–36.28) had risk higher than 0.0151. Conclusions: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention. Impact: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.

To improve risk stratification and treatment decisions for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We used SNP-array data from the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT peripheral blood (collected 2–4 weeks before the administration of conditioning regimen) from 1974 AML patients who received HCT between 2000 and 2011. All aberrations detected in ≥ 10 patients were tested for their association with overall survival (OS), separately by remission status, using the Kaplan–Meier estimator. Cox regression models were used for multivariable analyses. Follow-up was through January 2019. We identified 701 unique chromosomal aberrations in 285 patients (7% of 1438 in complete remission (CR) and 36% of 536 not in CR). Copy-neutral loss-of-heterozygosity (CNLOH) in chr17p in CR patients (3-year OS = 20% vs. 50%, with and without chr17p CNLOH, p = 0.0002), and chr13q in patients not in CR (3-year OS = 4% vs. 26%, with and without chr13q CNLOH, p

Background Lifetime use of bituminous (‘smoky’) coal is associated with nearly a 100-fold higher risk of lung cancer mortality compared with anthracite (‘smokeless’) coal use in rural Xuanwei, China, among women. Risk of mortality from ischaemic heart disease (IHD) and stroke for these coal types has not been evaluated. Methods A cohort of 16 323 non-smoking women in Xuanwei, who were lifetime users of either smoky or smokeless coal, were followed up from 1976 to 2011. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) to evaluate lifetime use of coal types and stoves in the home in relation to risk of IHD and stroke mortality. Results Among lifetime users of smokeless coal, higher average exposure intensity (≥4 tons/year vs 64 ton-years vs ≤28 ton-years, HR = 6.5, 95% CI = 1.5–28.3; Ptrend =0.003) during follow-up and over their lifetime was associated with increased IHD mortality, and ventilated stove use dramatically reduced this risk (HR = 0.2, 95% CI 0.1–0.5). Higher cumulative exposure to smoky coal during follow-up showed positive associations with IHD mortality, but the evidence for other metrics was less consistent compared with associations with smokeless coal use. Conclusions Higher use of smokeless coal, which is burned throughout China and is generally regarded to be a cleaner fuel type, is associated with IHD mortality. Use of cleaner fuels or stove interventions may be effective in reducing the increasing burden of IHD in developing regions that currently rely on smokeless coal for cooking and heating.

Lengthening the annual low-dose computed tomography (CT) screening interval for individuals at lowest risk of lung cancer could reduce harms and improve efficiency. We analyzed 23 328 participants in the National Lung Screening Trial who had a negative CT screen (no ≥4-mm nodules) to develop an individualized model for lung cancer risk after a negative CT. The Lung Cancer Risk Assessment Tool + CT (LCRAT+CT) updates “prescreening risk” (calculated using traditional risk factors) with selected CT features. At the next annual screen following a negative CT, risk of cancer detection was reduced among the 70% of participants with neither CT-detected emphysema nor consolidation (median risk = 0.2%, interquartile range [IQR] = 0.1%–0.3%). However, risk increased for the 30% with CT emphysema (median risk = 0.5%, IQR = 0.3%–0.8%) and the 0.6% with consolidation (median = 1.6%, IQR = 1.0%–2.5%). As one example, a threshold of next-screen risk lower than 0.3% would lengthen the interval for 57.8% of screen-negatives, thus averting 49.8% of next-screen false-positives among screen-negatives but delaying diagnosis for 23.9% of cancers. Our results support that many, but not all, screen-negatives might reasonably lengthen their CT screening interval.

US guidelines recommend that most women older than 65 years cease cervical screening after two consecutive negative cotests (concurrent HPV and cytology tests) in the previous 10 years, with one in the last 5 years. However, this recommendation was based on expert opinion and modeling rather than empirical data on cancer risk. We therefore estimated the 5‐year risks of cervical precancer (cervical intraepithelial neoplasia grade 3 or adenocarcinoma in situ [CIN3]) after one, two and three negative cotests among 346,760 women aged 55–64 years undergoing routine cotesting at Kaiser Permanente Northern California (2003–2015). Women with a history of excisional treatment or CIN2+ were excluded. No woman with one or more negative cotests was diagnosed with cancer during follow‐up. Five‐year risks of CIN3 after one, two, and three consecutive negative cotests were 0.034% (95% CI: 0.023%–0.046%), 0.041% (95% CI: 0.007%–0.076%) and 0.016% (95% CI: 0.000%–0.052%), respectively (p trend < 0.001). These risks did not appreciably differ by a positive cotest result prior to the one, two or three negative cotest(s). Since CIN3 risks after one or more negative cotests were significantly below a proposed 0.12% CIN3+ risk threshold for a 5‐year screening interval, a longer screening interval in these women is justified. However, the choice of how many negative cotests provide sufficient safety against invasive cancer over a woman's remaining life represents a value judgment based on the harms versus benefits of continued screening. Ideally, this guideline should be informed by longer‐term follow‐up given that exiting is a long‐term decision., What's new? US guidelines recommend that women older than 65 years cease screening for cervical cancer following two consecutive negative cotests (HPV and cytology) in the previous ten years. However, these guidelines are based on modelling and expert opinion, rather than empirical data. In this large epidemiological study, the authors estimated the risks of cervical precancer following one, two, or three negative cotests among women aged 55‐64 years. They caution that the optimal time for women to exit screening represents a value judgment, based on the harms versus benefits of continued screening. Further data are needed.

Inflammation is a driver of colorectal neoplasia; however, what particular inflammatory processes play a role in early carcinogenesis are unclear. We compared serum levels of 78 inflammation markers between 171 pathologically confirmed colorectal adenoma cases (including 48 incident cases) and 344 controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We used weighted multivariable logistic regression to compute odds ratio (OR) and 95% confidence interval (CI). We found 14 markers associated with risk of adenoma overall; three of these were also associated with incident adenoma: CC-chemokine cysteine motif chemokine ligand 20 (CCL20) [overall adenoma fourth versus first quartile: OR 4.8, 95% CI 2.0–12, Ptrend 0.0007; incident adenoma third versus first tertile: OR 4.6, 95% CI 1.0–22, Ptrend 0.03], growth-related gene oncogene products (GRO) [OR 3.8, 95% CI 1.6–9.3, Ptrend 0.006 and OR 3.6, 95% CI 1.1–12, Ptrend 0.04, respectively] and insulin [OR 2.9, 95% CI 0.8–10, Ptrend 0.05 and OR 7.8, 95% CI 1.3–46, Ptrend 0.03, respectively]. All statistical tests were two-sided. These results provide important new evidence implicating CCL20- and GRO-related pathways in early colorectal carcinogenesis and further support a role for insulin.

Background: Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation screening. A key property of eligibility criteria is the tradeoff between the number of mutation carriers identified versus population members tested. We assess the fractions of mutation carriers identified, versus women undergoing mutation testing, for BRCA1/2 founder mutation screening in U.S. Ashkenazi-Jewish women. Methods: BRCA1/2 carrier probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0% and 10%, we compared the percentage of founder mutations detected versus the percentage of women requiring mutation testing. PCR mutation testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in BRCA1, and 6174delT in BRCA2). Results: Identifying 90% of BRCA1/2 founder mutations required testing the 60% of Ashkenazi-Jewish women with carrier probabilities exceeding 0.56%, potentially avoiding mutation testing for approximately 0.7 to 1.1 million U.S. Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier probability exceeded 0.78% identified 80% of mutation carriers, increasing to 89% of mutation carriers when accounting for cascade testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds, e.g., a 5% threshold identified 46% of mutation carriers while testing 10% of women. Conclusions: Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation carriers versus women tested. Low carrier-probability thresholds identified 90% of BRCA1/2 founder mutation carriers, without testing approximately 1 million U.S. Ashkenazi-Jewish women with lowest carrier probabilities. Impact: In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation screening.

Background: Multi-cancer tests offer screening for multiple cancers with one blood draw, but the potential population impact is poorly understood. Methods: We formulate mathematical expressions for expected numbers of: (i) individuals exposed to unnecessary confirmation tests ( ${\rm{EUC}}$ ), (ii) cancers detected ( ${\rm{CD}}$ ), and (iii) lives saved ( ${\rm{LS}}$ ) given test performance, disease incidence and mortality, and mortality reduction. We add colorectal, liver, lung, ovary, and pancreatic cancer to a test for breast cancer, approximating prevalence at ages 50, 60, or 70 using incidence over the next 5 years and mortality using corresponding probabilities of cancer death over 15 years in the Surveillance, Epidemiology, and End Results registry. Results: ${\rm{EUC}}$ is overwhelmingly determined by specificity. For a given specificity, ${\rm{EUC}}/{\rm{CD}}$ is most favorable for higher prevalence cancers. Under 99% specificity and sensitivities as published for a 50-cancer test, ${\rm{EUC}}/{\rm{CD}}$ is 1.1 for breast + lung versus 1.3 for breast + liver at age 50. Under a common mortality reduction associated with screening, ${\rm{EUC}}/{\rm{LS}}$ is most favorable when the test includes higher mortality cancers (e.g., 19.9 for breast + lung vs. 30.4 for breast + liver at age 50 assuming a common 10% mortality reduction). Conclusions: Published multi-cancer test performance suggests a favorable tradeoff of ${\rm{EUC}}$ to ${\rm{CD}}$, yet the full burden of unnecessary confirmations will depend on the posttest work-up protocol. Harm–benefit tradeoffs will be improved if tests prioritize more prevalent and/or lethal cancers for which curative treatments exist. Impact: The population impact of multi-cancer testing will depend not only on test performance but also on disease characteristics and efficacy of early treatment. See related commentary by Duffy and Sasieni, p. 3

Researchers at the NCI have developed the Risk-Based NLST Outcomes Tool (RNOT), an online tool that calculates risk of lung cancer diagnosis and death with and without lung cancer screening, and false-positive risk estimates. This tool has the potential to facilitate shared decision making for screening. The objective of this study was to examine how current heavy and former smokers understand and respond to personalized risk estimates from the RNOT. Individuals who were eligible for lung cancer screening and were visiting Walter Reed National Military Medical Center were invited to participate in a semi-structured interview to assess their experiences with and perceptions of the RNOT. Results were analyzed using template analysis. Participants found their risk of lung cancer death to be lower than anticipated and were confused by changes in risk for lung cancer diagnosis with and without screening. Most participants indicated that the RNOT would be helpful in making screening decisions, despite reporting that there was no maximum risk for a false positive that would lead them to forgo lung cancer screening. Participants provided actionable needs and recommendations to optimize this tool. Risk-based screening tools may enhance shared decision making. The RNOT is being updated to incorporate these findings.

Background: There are well-documented disparities in lung cancer outcomes across populations. Lung cancer screening (LCS) has the potential to reduce lung cancer mortality, but for this benefit to be realized by all high-risk groups, there must be careful attention to ensuring equitable access to this lifesaving preventive health measure.Objectives: To outline current knowledge on disparities in eligibility criteria for, access to, and implementation of LCS, and to develop an official American Thoracic Society statement to propose strategies to optimize current screening guidelines and resource allocation for equitable LCS implementation and dissemination.Methods: A multidisciplinary panel with expertise in LCS, implementation science, primary care, pulmonology, health behavior, smoking cessation, epidemiology, and disparities research was convened. Participants reviewed available literature on historical disparities in cancer screening and emerging evidence of disparities in LCS.Results: Existing LCS guidelines do not consider racial, ethnic, socioeconomic, and sex-based differences in smoking behaviors or lung cancer risk. Multiple barriers, including access to screening and cost, further contribute to the inequities in implementation and dissemination of LCS.Conclusions: This statement identifies the impact of LCS eligibility criteria on vulnerable populations who are at increased risk of lung cancer but do not meet eligibility criteria for screening, as well as multiple barriers that contribute to disparities in LCS implementation. Strategies to improve the selection and dissemination of LCS in vulnerable groups are described.

Early detection of clinical outcomes such as cancer may be predicted using longitudinal biomarker measurements. Tracking longitudinal biomarkers as a way to identify early disease onset may help to reduce mortality from diseases like ovarian cancer that are more treatable if detected early. Two disease risk prediction frameworks, the shared random effects model (SREM) and the pattern mixture model (PMM) could be used to assess longitudinal biomarkers on disease early detection. In this article, we studied the discrimination and calibration performances of SREM and PMM on disease early detection through an application to ovarian cancer, where early detection using the risk of ovarian cancer algorithm (ROCA) has been evaluated. Comparisons of the above three approaches were performed via analyses of the ovarian cancer data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Discrimination was evaluated by the time-dependent receiver operating characteristic curve and its area, while calibration was assessed using calibration plot and the ratio of observed to expected number of diseased subjects. The out-of-sample performances were calculated via using leave-one-out cross-validation, aiming to minimize potential model overfitting. A careful analysis of using the biomarker cancer antigen 125 for ovarian cancer early detection showed significantly improved discrimination performance of PMM as compared with SREM and ROCA, nevertheless all approaches were generally well calibrated. Robustness of all approaches was further investigated in extensive simulation studies. The improved performance of PMM relative to ROCA is in part due to the fact that the biomarker measurements were taken at a yearly interval, which is not frequent enough to reliably estimate the changepoint or the slope after changepoint in cases under ROCA.

Key Points Pre-HCT mosaicism is related to increased relapse risk and lower survival after unrelated HCT, independent of cytogenetics at diagnosis. Pre-HCT mosaicism could be a useful clinical tool to guide risk stratification in acute lymphoblastic leukemia patients.

BackgroundThe optimal clinical management of oral precancer remains uncertain. We investigated the natural history of oral leukoplakia, the most common oral precancerous lesion, to estimate the relative and absolute risks of progression to cancer, the predictive accuracy of a clinician’s decision to biopsy a leukoplakia vis-à-vis progression, and histopathologic predictors of progression.MethodsWe conducted a retrospective cohort study (1996–2012) of patients with oral leukoplakia (n = 4886), identified using electronic medical records within Kaiser Permanente Northern California. Among patients with leukoplakia who received a biopsy (n = 1888), we conducted a case-cohort study to investigate histopathologic predictors of progression. Analyses included indirect standardization and unweighted or weighted Cox regression.ResultsCompared with the overall Kaiser Permanente Northern California population, oral cancer incidence was substantially elevated in oral leukoplakia patients (standardized incidence ratio = 40.8, 95% confidence interval [CI] = 34.8 to 47.6; n = 161 cancers over 22 582 person-years). Biopsied leukoplakias had a higher oral cancer risk compared with those that were not biopsied (adjusted hazard ratio = 2.38, 95% CI = 1.73 to 3.28). However, to identify a prevalent or incident oral cancer, the biopsy decision had low sensitivity (59.6%), low specificity (62.1%), and moderate positive–predictive value (5.1%). Risk of progression to oral cancer statistically significantly increased with the grade of dysplasia; 5-year competing risk-adjusted absolute risks were: leukoplakia overall = 3.3%, 95% CI = 2.7% to 3.9%; no dysplasia = 2.2%, 95% CI = 1.5% to 3.1%; mild-dysplasia = 11.9%, 95% CI = 7.1% to 18.1%; moderate-dysplasia = 8.7%, 95% CI = 3.2% to 17.9%; and severe dysplasia = 32.2%, 95% CI = 8.1%–60.0%. Yet 39.6% of cancers arose from biopsied leukoplakias without dysplasia.ConclusionsThe modest accuracy of the decision to biopsy a leukoplakia vis-à-vis presence or eventual development of oral cancer highlights the need for routine biopsy of all leukoplakias regardless of visual or clinical impression. Leukoplakia patients, particularly those with dysplasia, need to be closely monitored for signs of early cancer.

Objective The 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines for the management of cervical cancer screening abnormalities recommend 1 of 6 clinical actions (treatment, optional treatment or colposcopy/biopsy, colposcopy/biopsy, 1-year surveillance, 3-year surveillance, 5-year return to regular screening) based on the risk of cervical intraepithelial neoplasia grade 3, adenocarcinoma in situ, or cancer (CIN 3+) for the many different combinations of current and recent past screening results. This article supports the main guidelines presentation1 by presenting and explaining the risk estimates that supported the guidelines. Methods From 2003 to 2017 at Kaiser Permanente Northern California (KPNC), 1.5 million individuals aged 25 to 65 years were screened with human papillomavirus (HPV) and cytology cotesting scheduled every 3 years. We estimated immediate and 5-year risks of CIN 3+ for combinations of current test results paired with history of screening test and colposcopy/biopsy results. Results Risk tables are presented for different clinical scenarios. Examples of important results are highlighted; for example, the risk posed by most current abnormalities is greatly reduced if the prior screening round was HPV-negative. The immediate and 5-year risks of CIN 3+ used to decide clinical management are shown. Conclusions The new risk-based guidelines present recommendations for the management of abnormal screening test and histology results; the key risk estimates supporting guidelines are presented in this article. Comprehensive risk estimates are freely available online at https://CervixCa.nlm.nih.gov/RiskTables.

Timing of breast development (or thelarche) and its endogenous and exogenous determinants may underlie global variation in breast cancer incidence. The study objectives were to characterize endogenous estrogen levels and bisphenol A (BPA) exposure using a migrant study of adolescent girls and test whether concentrations explained differences in thelarche by birthplace and growth environment. Estrogen metabolites (EM) and BPA-glucuronide (BPA-G) were quantified in urine spot samples using liquid chromatography tandem mass spectrometry (LC-MS/MS) from a cross-sectional study of Bangladeshi, first- and second-generation Bangladeshi migrants to the UK, and white British girls aged 5&ndash, 16 years (n = 348). Thelarche status at the time of interview was self-reported and defined equivalent to Tanner Stage &ge, 2. We compared geometric means (and 95% confidence interval (CIs)) of EM and BPA-G using linear regression and assessed whether EM and BPA-G explained any of the association between exposure to the UK and the age at thelarche using hazard ratios and 95% confidence intervals. Average EM decreased with exposure to the UK, whereas BPA-G increased and was significantly higher among white British (0.007 ng/mL, 95% CI: 0.0024&ndash, 0.0217) and second-generation British-Bangladeshi girls (0.009 ng/mL, 95% CI: 0.0040&ndash, 0.0187) compared to Bangladeshi girls (0.002 ng/mL, 95% CI: 0.0018&ndash, 0.0034). Two of four EM ratios (16-pathway/parent and parent/all pathways) were significantly associated with thelarche. The relationship between exposure to the UK and thelarche did not change appreciably after adding EM and BPA-G to the models. While BPA-G is often considered a ubiquitous exposure, our findings suggest it can vary based on birthplace and growth environment, with increasing levels for girls who were born in or moved to the UK. Our study did not provide statistically significant evidence that BPA-G or EM concentrations explained earlier thelarche among girls who were born or raised in the UK.

Risk stratification is the ability of a test or model to separate those at high vs. low risk of disease. There is no risk stratification metric that is in terms of the number of people requiring testing, which would help with considering the benefits, harms, and costs associated with the test and interventions. We introduce the expected number needed to test (NNtest) to identify one more disease case than by randomly selecting people for disease ascertainment. We show that NNtest measures risk stratification, allowing us to decompose NNtest into components that contrast the increase in risk upon testing positive (‘concern’) versus the decrease in risk upon testing negative (‘reassurance’). A graph of the reciprocals of concern vs. reassurance have linear contours of constant NNtest, visualizing the relative importance and tradeoff of each component to better understand the properties of risk thresholds with equal NNtest. We apply NNtest to the controversy over the risk threshold for who should get testing for BRCA1/2 mutations that cause high risks of breast and ovarian cancers. We show that risk thresholds between 0.78% and 5% optimize NNtest. At these thresholds, NNtest≈120 people will require risk-model evaluation to find one more mutation-carrier. However, these thresholds of equal NNtest provide very different concern and reassurance, with 0.78% providing much more reassurance (and thus much less concern) than 5%. Given that genetic testing costs are declining rapidly, the greater reassurance provided by the 0.78% threshold might be deemed more important than the greater concern provided by the 5% threshold.

Background Experimental and clinical studies have implicated certain chemokines and angiogenic cytokines in multiple myeloma (MM) pathogenesis. To investigate whether systemic concentrations of these markers are associated with future MM risk and progression from its precursor, monoclonal gammopathy of undetermined significance (MGUS), we conducted a prospective study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Methods We measured concentrations of 45 immunologic and pro-angiogenic markers in sera from 241 MM case patients, 441 participants with nonprogressing MGUS, and 258 MGUS-free control participants using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. We also evaluated absolute risk of progression using weighted Kaplan-Meier estimates. All statistical tests were two-sided. Results Prediagnostic levels of six markers were statistically significantly elevated among MM case patients compared with MGUS-free control participants using a false discovery rate of 10% (EGF, HGF, Ang-2, CXCL12, CCL8, and BMP-9). Of these, three angiogenesis markers were associated with future progression from MGUS to MM: EGF (fourth vs first quartile: OR = 3.01, 95% CI = 1.61 to 5.63, Ptrend = .00028), HGF (OR = 2.59, 95% CI = 1.33 to 5.03, Ptrend = .015), and Ang-2 (OR = 2.14, 95% CI = 1.15 to 3.98, Ptrend = .07). A composite angiogenesis biomarker score substantially stratified risk of MGUS progression to MM beyond established risk factors for progression, particularly during the first 5 years of follow-up (areas under the curve of 0.71 and 0.64 with and without the angiogenesis marker score, respectively). Conclusions Our prospective findings provide new insights into mechanisms involved in MM development and suggest that systemic angiogenesis markers could potentially improve risk stratification models for MGUS patients.

BACKGROUND: Although risk-based selection of ever-smokers for lung-cancer screening could improve efficiency over US Preventive Services Task Force (USPSTF) guidelines, it preferentially selects older ever-smokers with lower life-expectancies due to comorbidities. OBJECTIVES: To compare selecting ever-smokers for screening based on gains in life-expectancy vs. based on lung cancer risk. DESIGN: Cohort analyses and model-based projections. SETTING: US population of ever-smokers aged 40-84 years. PARTICIPANTS: n=130,964 National Health Interview Survey participants, representing ~60 million US ever-smokers during 1997-2015. INTERVENTIONS: Annual CT screening for 3 years vs. no screening. MEASUREMENTS: Estimated lung-cancer deaths-averted and life-years gained after developing a mortality model. RESULTS: Using the calibrated and validated mortality model in US ever-smokers aged 40-84 years and selecting equivalent 8.3 million ever-smokers to match USPSTF-guideline eligibility in 2013-2015, our analysis estimated that life-gained-based versus risk-based selection would increase the total life-expectancy from CT screening (633,400 versus 607,800 years) but prevent fewer lung-cancer deaths (52,600 versus 55,000) in the population. The 1.56 million individuals included in life-gained-based but not risk-based selection were younger (mean age=59 versus 75 years) with fewer comorbidities (mean=0.75 versus 3.7). LIMITATIONS: Estimates are model-based and presume the implementation of lung-cancer screening with short-term effectiveness similar to that from trials. CONCLUSION: Life-gained-based selection could maximize the benefits of lung-cancer screening in the US population by including ever-smokers who have not only high lung-cancer risk but also high life-expectancy. FUNDING SOURCE: Intramural Research Program of the National Institute of Health/National Cancer Institute. This is the prepublication, author-produced version of a manuscript accepted for publication in Annals of Internal Medicine. This version does not include post-acceptance editing and formatting. The American College of Physicians, the publisher of Annals of Internal Medicine, is not responsible for the content or presentation of the author-produced accepted version of the manuscript or any version that a third party derives from it. Readers who wish to access the definitive published version of this manuscript and any ancillary material related to this manuscript (e.g., correspondence, corrections, editorials, linked articles) should go to Annals.org or to the print issue in which the article appears. Those who cite this manuscript should cite the published version, as it is the official version of record.

Previous studies have suggested that longer donor leukocyte telomere length (TL) is associated with improved survival after hematopoietic cell transplantation (HCT) in severe aplastic anemia (SAA). This study aimed to determine whether cell-specific lymphocyte TL is associated with certain post-HCT causes of death. We used flow cytometry and fluorescence in situ hybridization to measure TL in donor total lymphocytes and subsets: naïve enriched T cells (CD45RA(+)CD20(−)), memory enriched T cells (CD45RA(−)CD20(−)), natural killer (NK) fully differentiated T cells (CD45RA(+)CD57(+)), and B cells (CD45RA(+)CD20(+)). Competing risk survival regression was used for cause-specific death analyses. Clinical data and biospecimens were available from the Center for International Blood and Marrow Transplant Research database and biorepository. The study included 197 patients who underwent unrelated-donor HCT for SAA between 1988 and 2004. The median age at HCT was 15 years (range, 0.5-40 years), and the median follow-up was 5 years (range, .05). However, a trend toward excess risk of graft-versus-host mortality was noted (HR for total lymphocyte TL, 1.26; P = .15). In conclusion, longer donor TL was associated with reduced rate of infection-related deaths after HCT for SAA.

Our work involves assessing whether new biomarkers might be useful for cervical-cancer screening across populations with different disease prevalences and biomarker distributions. When comparing across populations, we show that standard diagnostic accuracy statistics (predictive values, risk-differences, Youden's index and Area Under the Curve (AUC)) can easily be misinterpreted. We introduce an intuitively simple statistic for a 2 × 2 table, Mean Risk Stratification (MRS): the average change in risk (pre-test vs. post-test) revealed for tested individuals. High MRS implies better risk separation achieved by testing. MRS has 3 key advantages for comparing test performance across populations with different disease prevalences and biomarker distributions. First, MRS demonstrates that conventional predictive values and the risk-difference do not measure risk-stratification because they do not account for test-positivity rates. Second, Youden's index and AUC measure only multiplicative relative gains in risk-stratification: AUC = 0.6 achieves only 20% of maximum risk-stratification ( AUC = 0.9 achieves 80%). Third, large relative gains in risk-stratification might not imply large absolute gains if disease is rare, demonstrating a “high-bar” to justify population-based screening for rare diseases such as cancer. We illustrate MRS by our experience comparing the performance of cervical-cancer screening tests in China vs. the USA. The test with the worst AUC = 0.72 in China (visual inspection with acetic acid) provides twice the risk-stratification (i.e. MRS) of the test with best AUC = 0.83 in the USA (human papillomavirus and Pap cotesting) because China has three times more cervical precancer/cancer. MRS could be routinely calculated to better understand the clinical/public-health implications of standard diagnostic accuracy statistics.

Background The main goal of cervical screening programs is to detect and treat precancer before cancer develops. Human papillomavirus (HPV) testing is more sensitive than cytology for detecting precancer. However, reports of rare HPV-negative, cytology-positive cancers are motivating continued use of both tests (cotesting) despite increased testing costs. Methods We quantified the detection of cervical precancer and cancer by cotesting compared with HPV testing alone at Kaiser Permanente Northern California (KPNC), where 1 208 710 women age 30 years and older have undergone triennial cervical cotesting since 2003. Screening histories preceding cervical cancers (n = 623) and precancers (n = 5369) were examined to assess the relative contribution of the cytology and HPV test components in identifying cases. The performances of HPV testing and cytology were compared using contingency table methods, general estimating equation models, and nonparametric statistics; all statistical tests were two-sided. Results HPV testing identified more women subsequently diagnosed with cancer (P < .001) and precancer (P < .001) than cytology. HPV testing was statistically significantly more likely to be positive for cancer at any time point (P < .001), except within 12 months (P = .10). HPV-negative/cytology-positive results preceded only small fractions of cases of precancer (3.5%) and cancer (5.9%); these cancers were more likely to be regional or distant stage with squamous histopathology than other cases. Given the rarity of cancers among screened women, the contribution of cytology to screening translated to earlier detection of at most five cases per million women per year. Two-thirds (67.9%) of women found to have cancer during 10 years of follow-up at KPNC were detected by the first cotest performed. Conclusions The added sensitivity of cotesting vs HPV alone for detection of treatable cancer affected extremely few women.

Historically in the United States, cancer incidence has been significantly higher in men than women. This disparity is often attributed to gender-related behavioral risk factors, such as smoking and drinking. The degree to which differences in age-adjusted cancer rates are due to sex (e.g., chromosomes, hormones) is unknown. We estimated the effect of sex on cancer risk by comparing cancer incidence at 21 shared sites between men and women while adjusting for known gender-related risk factors. We analyzed data from 122,826 women and 171,274 men enrolled in the NIH AARP Diet and Health Study (1995-2011), contributing 3.5 million person-years of follow-up. Cox proportional hazards models were used to estimate male-to-female (M:F) adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for each of the cancers, controlling for relevant baseline cancer-specific demographic (age, race, marital status, education), lifestyle (self-reported health status, family history of cancer, diet, body mass index, physical activity), and behavioral factors (tobacco, alcohol use). We used the Peters-Belson method to partition the observed differences between the sexes in cancer incidence into the proportion of the difference explained by the modifiable environmental and behavioral exposures (explained disparity) and the remaining proportion that cannot be explained by these exposures (unexplained disparity). After adjustment for cancer-specific risk factors, risks remained significantly higher in men for nearly all sites. The highest M:F aHR was for esophageal adenocarcinoma (aHR: 10.59, 95% CI: 7.19, 15.61) followed by gastric cardia (aHR: 4.55, 95% CI: 3.28, 6.31) and larynx (aHR: 3.73, 95% CI: 2.84, 4.89) cancers. In contrast, men had a lower adjusted incidence of thyroid (aHR: 0.57, 95% CI: 0.48, 0.68) and gallbladder (aHR: 0.55, 95% CI: 0.37, 0.82) cancers compared with women. Using the Peters-Belson method we found that, if men had the same exposure distribution as the women (under a counterfactual), the male predominance would remain for 12 cancers (bladder, skin, lung, colon, kidney, rectum, esophageal adenocarcinoma, larynx, gastric cardia, esophageal squamous cell carcinoma, pancreas, and oropharynx). For 4 cancers (liver, gastric non-cardia, oral cavity, and anus), if men had the exposure distribution of women, they would have experienced a higher cancer incidence than what was observed. This elevated risk in men compared with women, after adjustment for risk factors, indicates potential innate sex differences across nearly all shared cancer sites. Funding: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics Citation Format: Sarah S. Jackson, Morgan A. Marks, Hormuzd Katki, Barry I. Graubard, Michael D. Cook, Anil Chaturvedi. Estimating the influence of sex on cancer risk: An analysis in a large US prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 787.

Clonal mosaicism, detectable in peripheral blood, can be an important predictor of developing a hematological malignancy. We sought to determine if mosaic events, in addition to clinical and demographic variables, contributed independent information about acute lymphoblastic leukemia (ALL) patient survival and risk of relapse after allogeneic hematopoietic cell transplant (HCT). HumanOmniExpress-12v1_A BeadChip SNP array data were used to detect mosaicisms >=2Mb based on the log2 relative probe intensity ratio (LRR) and B allele frequency (BAF) for each SNP measured in 773 ALL patients from DISCOVeRY-BMT cohorts. DNA was extracted from recipient peripheral blood samples taken immediately prior to start of conditioning before allogeneic HCT for ALL (2000-2011). Mosaic events include copy-number gain (LRR >0), loss (LRR The impact of mosaicism on overall survival (OS) probability and cumulative incidence of relapse at 1-year post-HCT were calculated using the Kaplan-Meier estimator and cumulative incidence functions, respectively. The association of clonal mosaicism with OS was evaluated with multivariable Cox proportional hazard models. For disease relapse, competing risk models were used with transplant related mortality (TRM) treated as a competing event. Stratified survival analyses were performed by cytogenetic status at diagnosis. Statistical analyses were conducted using R 3.6.1. Thirty-four patients (4.4%) had 1 or more mosaicisms (82 total detected) with almost half having advanced disease (Table 1). The median proportion of affected cells was 61% (interquartile range = 39 - 93%). Copy-number losses on chromosomes 7 (13.4%) and 9 (8.54%) and 17 (6.10%) were the most frequently detected events (Figure 1). OS at 1-year post HCT in patients with and without a mosaic event was 26.5% and 60.1%, respectively, (P=8.2×10-8, Figure 2A) and normal cytogenetic patients with mosaicism had significantly lower survival compared to all other patients (OSnormal/mosaic+= 8.3% vs. OS= 60.6%, P=3.0×10-10, Figure 2B-C). ALL patients with a mosaic event also had an increased risk of disease relapse overall (Relapsemosaic+= 50% vs. Relapsemosaic-=26%, P=0.00067) and when stratified by cytogenetic abnormalities (P=0.015) and normal cytogenetics (P=0.041) (Figure 2D-F). Multivariable models of OS and relapse included age, race/ethnicity, complete remission or advanced disease status (Figure 3). Patients with a mosaic event had ~2.5 fold increase risk of death (P=2.5×10-5), independent from cytogenetics (P=8.6×10-5, Figure 3). OS associations are likely driven by the 2.8 fold increase risk of relapse (P= 5.9×10-5) which remains highly significant when stratified by cytogenetics (Figure 3). Almost half of the copy-number losses included well-known regions on chromosomes 7, 9 and 17 (Figure 1). Deletions of 7p have been shown to correlate with lower event-free survival in ALL pediatric patients. Our findings suggest mosaic loss of 7p might be an important indicator of poor OS across the lifespan, with 5/6 patients with 7p losses aged >18 years. Higher mortality was also associated with the loss of the chr9p21.3 locus, seen in all patients (N=5) with chromosome 9p losses. This region harbors tumor suppressor CDKN2A; inactivation of CDKN2A can lead to poor survival in both children and adults with ALL. Lastly, we found that all patients (N=4) with copy-number loss of 17p13.1, which contains tumor suppressor TP53 died within 1-year post-HCT. We identified detectable mosaicism prior to transplant in 4.4% of patients and showed that mosaicism was associated with lower survival and higher disease relapse at 1-year post-HCT. While mosaicism is more common in patients with advanced disease stage, mosaic events are an independent contributor to lower survival and higher relapse in the first year after transplant. This is the first study to show that mosaic events detectable in pre-transplant peripheral blood from ALL patients are correlated with poor survival. Future studies replicating these associations in different ethnicities and age groups and evaluating specific chromosomal regions could be informative in classifying patient risk post-HCT attributable to mosaic events. Disclosures McCarthy: Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Lee:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Kadmon: Research Funding; Incyte: Consultancy, Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding.

For cost-effectiveness and efficiency, many large-scale general-purpose cohort studies are being assembled within large health-care providers who use electronic health records. Two key features of such data are that incident disease is interval-censored between irregular visits and there can be pre-existing (prevalent) disease. Because prevalent disease is not always immediately diagnosed, some disease diagnosed at later visits are actually undiagnosed prevalent disease. We consider prevalent disease as a point mass at time zero for clinical applications where there is no interest in time of prevalent disease onset. We demonstrate that the naive Kaplan-Meier cumulative risk estimator underestimates risks at early time points and overestimates later risks. We propose a general family of mixture models for undiagnosed prevalent disease and interval-censored incident disease that we call prevalence-incidence models. Parameters for parametric prevalence-incidence models, such as the logistic regression and Weibull survival (logistic-Weibull) model, are estimated by direct likelihood maximization or by EM algorithm. Non-parametric methods are proposed to calculate cumulative risks for cases without covariates. We compare naive Kaplan-Meier, logistic-Weibull, and non-parametric estimates of cumulative risk in the cervical cancer screening program at Kaiser Permanente Northern California. Kaplan-Meier provided poor estimates while the logistic-Weibull model was a close fit to the non-parametric. Our findings support our use of logistic-Weibull models to develop the risk estimates that underlie current US risk-based cervical cancer screening guidelines. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

OBJECTIVE To compare the risks of histologic high-grade cervical intraepithelial neoplasia (CIN) or worse after different cervical cancer screening test results between two of the largest U.S. clinical practice research data sets. METHODS The New Mexico Human Papillomavirus (HPV) Pap Registry is a statewide registry representing a diverse population experiencing varied clinical practice delivery. Kaiser Permanente Northern California is a large integrated health care delivery system practicing routine HPV cotesting since 2003. In this retrospective cohort study, a logistic-Weibull survival model was used to estimate and compare the cumulative 3- and 5-year risks of histologic CIN 3 or worse among women aged 21-64 years screened in 2007-2011 in the New Mexico HPV Pap Registry and 2003-2013 in Kaiser Permanente Northern California. Results were stratified by age and baseline screening result: negative cytology, atypical squamous cells of undetermined significance (ASC-US) (with or without HPV triage), low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion. RESULTS There were 453,618 women in the New Mexico HPV Pap Registry and 1,307,528 women at Kaiser Permanente Northern California. The 5-year CIN 3 or worse risks were similar within screening results across populations: cytology negative (0.52% and 0.30%, respectively, P

A challenge in implementation of sensitive HPV-based screening is limiting unnecessary referrals to colposcopic biopsy. We combined 2 commonly recommended triage methods: partial HPV typing and "reflex" cytology, evaluating the possibility of automated cytology. This investigation was based on 1,178 exfoliated cervical specimens collected during the enrollment phase of The Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED, Oklahoma City, Oklahoma). We chose a colposcopy clinic population to maximize number of outcomes, for this proof-of-principle cross-sectional study. Residual aliquots of PreservCyt were HPV-typed using Linear Array (LA, Roche Molecular Systems, Pleasanton, CA). High-risk HPV typing data and cytologic results (conventional and automated) were used jointly to predict risk of histologically defined ≥CIN2. We developed a novel computer algorithm that uses the same optical scanning features that are generated by the FocalPoint Slide Profiler (BD, Burlington, NC). We used the LASSO (Least Absolute Shrinkage and Selection Operator) method to build the prediction model based on a training dataset (n=600). In the validation set (n=578), for triage of all HPV-positive women, a cytologic threshold of ≥ASC-US had a sensitivity of 0.94, and specificity of 0.30, in this colposcopy clinic setting. When we chose a threshold for the severity score (generated by the computer algorithm) that had an equal specificity of 0.30, the sensitivity was 0.91. Automated cytology also matched ≥ASC-US when partial HPV typing was added to the triage strategy, and when we re-defined cases as ≥CIN3. If this strategy works in a prospective screening setting, a totally automated screening and triage technology might be possible. This article is protected by copyright. All rights reserved.

Longer-than-annual screening intervals have been suggested to improve the balance of benefits and harms in prostate cancer screening. Many researchers, societies, and guideline committees have suggested that screening intervals could depend on the prostate-specific antigen (PSA) result. We analyzed data from men (N = 33,897) ages 55–74 years with a baseline PSA test in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial (United States, 1993–2001). We estimated 5- and 10-year risks of aggressive cancer (Gleason ≥8 and/or stage III/IV) and 15-year risks of prostate cancer–related mortality for men with baseline PSA ≤ 0.5 ng/mL (N = 4,862), ≤1 ng/mL (N = 15,110), and 1.01–2.5 ng/mL (N = 12,422). A total of 217 men died from prostate cancer through 15 years, although no men with PSA ≤ 1 ng/mL died from prostate cancer within 5 years [95% confidence interval (CI), 0.00%–0.03%]. The 5-year incidence of aggressive disease was low (0.08%; 95% CI, 0.03%–0.12%) for men with PSA ≤ 1 ng/mL, and higher for men with baseline PSA 1.01–2.5 ng/mL (0.51%; 95% CI, 0.38%–0.74%). No men aged ≥65 years with PSA ≤ 0.5 ng/mL died from prostate cancer within 15 years (95% CI, 0.00%–0.32%), and their 10-year incidence of aggressive disease was low (0.25%; 95% CI, 0.00%–0.53%). Compared with white men, black men with PSA ≤ 1 ng/mL had higher 10-year rates of aggressive disease (1.6% vs. 0.4%; P < 0.01). Five-year screening intervals may be appropriate for the 45% of men with PSA ≤ 1 ng/mL. Men ages ≥65 years with PSA ≤ 0.5 ng/mL could consider stopping screening. Substantial risk disparities suggest appropriate screening intervals could depend on race/ethnicity.

Background Risk-prediction models have been proposed to select individuals for lung cancer screening. However, their long-term effects are uncertain. This study evaluates long-term benefits and harms of risk-based screening compared with current United States Preventive Services Task Force (USPSTF) recommendations. Methods Four independent natural history models were used to perform a comparative modeling study evaluating long-term benefits and harms of selecting individuals for lung cancer screening through risk-prediction models. In total, 363 risk-based screening strategies varying by screening starting and stopping age, risk-prediction model used for eligibility (Bach, PLCOm2012, or Lung Cancer Death Risk Assessment Tool [LCDRAT]), and risk threshold were evaluated for a 1950 US birth cohort. Among the evaluated outcomes were percentage of individuals ever screened, screens required, lung cancer deaths averted, life-years gained, and overdiagnosis. Results Risk-based screening strategies requiring similar screens among individuals ages 55–80 years as the USPSTF criteria (corresponding risk thresholds: Bach = 2.8%; PLCOm2012 = 1.7%; LCDRAT = 1.7%) averted considerably more lung cancer deaths (Bach = 693; PLCOm2012 = 698; LCDRAT = 696; USPSTF = 613). However, life-years gained were only modestly higher (Bach = 8660; PLCOm2012 = 8862; LCDRAT = 8631; USPSTF = 8590), and risk-based strategies had more overdiagnosed cases (Bach = 149; PLCOm2012 = 147; LCDRAT = 150; USPSTF = 115). Sensitivity analyses suggest excluding individuals with limited life expectancies (

A property of diagnostic tests and risk models deserving more attention is risk stratification, defined as the ability of a test or model to separate those at high absolute risk of disease from those at low absolute risk. Risk stratification fills a gap between measures of classification (ie, area under the curve (AUC)) that do not require absolute risks and decision analysis that requires not only absolute risks but also subjective specification of costs and utilities. We introduce mean risk stratification (MRS) as the average change in risk of disease (posttest-pretest) revealed by a diagnostic test or risk model dichotomized at a risk threshold. Mean risk stratification is particularly valuable for rare conditions, where AUC can be high but MRS can be low, identifying situations that temper overenthusiasm for screening with the new test/model. We apply MRS to the controversy over who should get testing for mutations in BRCA1/2 that cause high risks of breast and ovarian cancers. To reveal different properties of risk thresholds to refer women for BRCA1/2 testing, we propose an eclectic approach considering MRS and other metrics. The value of MRS is to interpret AUC in the context of BRCA1/2 mutation prevalence, providing a range of risk thresholds at which a risk model is "optimally informative," and to provide insight into why net benefit arrives to its conclusion.

BACKGROUND The incidence of oropharynx cancers has increased substantially in the United States. However, risk stratification tools for the identification of high-risk individuals do not exist. In this study, an individualized risk prediction model was developed and validated for oropharynx cancers in the US population. METHODS A synthetic, US population-based case-control study was conducted. Oropharynx cancer cases diagnosed at Ohio State University (n = 241) were propensity-weighted to represent oropharynx cancers occurring annually in the United States during 2009-2014 (n = 12,656). Controls (n = 9327) included participants in the National Health and Nutrition Examination Survey (2009-2014) and represented the annual US population aged 30 to 69 years (n = 154,532,508). The individualized 1-year absolute risk of oropharynx cancer was estimated with weighted logistic regression. RESULTS The risk prediction model included age, sex, race, smoking, alcohol use, lifetime sexual partners, and oral oncogenic human papillomavirus (HPV) status. The model had good discrimination and calibration in split-sample validation (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.92-0.97; observed/expected [O/E], 1.01; 95% CI, 0.70-1.32) and external validation (AUC, 0.87; 95% CI, 0.84-0.90; O/E, 1.08; 95% CI, 0.77-1.39). In the US population, 1-year predicted risks of oropharynx cancer were highest for older individuals (21.1/100,000 for 65- to 69-year-olds), men (13.9/100,000), whites (10.4/100,000), smokers (18.0/100,000 for >20 pack-years), heavy alcohol users (18.4/100,000), and those with prevalent oral oncogenic HPV (140.4/100,000). The risk prediction model provided substantial risk stratification, with approximately 77% of all oropharynx cancers and approximately 99% of HPV-positive oropharynx cancers occurring in the 10% of the US population with the highest model-predicted risk. CONCLUSIONS This risk prediction model will enable the efficient design of studies to address the outstanding questions pertaining to the natural history, screening, and secondary prevention of oropharynx cancers.

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (10th percentile-for-age) or very short (5th or1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age = 20 years). One hundred and twelve patients (22·86%) had pre-HCT RTL10th percentile-for-age, with the majority below the 5th percentile (N = 80, 71·43%). RTL10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR] = 1·78, 95% confidence interval [CI]=1·18-2·69, P = 0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P 0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL5th versus ≥5th percentile = 1·38, P = 0·15 for the first 12 months after HCT, and HR = 3·91, P 0·0001, thereafter, P-heterogeneity = 0·008; the corresponding HRs for RTL1st versus ≥1st percentile = 1·29, P = 0·41, and HR = 5·18, P 0·0001, P-heterogeneity = 0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.

Background In the National Lung Screening Trial (NLST), screen-detected cancers that would not have been identified by the Lung Computed Tomographic Screening Reporting and Data System (Lung-RADS) nodule management guidelines were frequently ground-glass opacities (GGOs). Lung-RADS suggests that GGOs with diameter less than 20 mm return for annual screening, and GGOs greater than or equal to 20 mm receive 6-month follow-up. We examined whether this 20-mm threshold gives consistent management of GGOs compared with solid nodules. Methods First, we calculated diameter-specific malignancy probabilities for GGOs and solid nodules in the NLST. Using the solid-nodule malignancy risks as benchmarks, we suggested risk-based management categories for GGOs based on their probability of malignancy. Second, we compared lung-cancer mortality between GGOs and solid nodules in the same risk-based category. Results Using the Lung-RADS v1.0 classifications, malignancy probability is higher for GGOs than solid nodules within the same category. A risk-based classification of GGOs would assign annual screening for GGOs 4 to 5 mm (0.4% malignancy risk); 6-month follow-up for GGOs 6 to 7 mm (1.1%), 8 to 14 mm (3.0%), and 15 to 19 mm (5.2%); and 3-month follow-up for greater than or equal to 20 mm (10.9%). This reclassification would have assigned similarly fatal cancers to 3-month follow-up (hazard ratio = 2.0 for lung-cancer death in GGOs versus solid-nodule cancers, 95% confidence interval: 0.4–8.7), but for 6-month follow-up, mortality was lower in GGO cancers (hazard ratio = 0.18, 95% confidence interval: 0.05–0.67). Conclusions If Lung-RADS categories for GGOs were based on malignancy probability, then 6- to 19-mm GGOs would receive 6-month follow-up and greater than or equal to 20-mm GGOs would receive 3-month follow-up. Such risk-based management for GGOs could improve the sensitivity of Lung-RADS, especially for large GGO cancers. However, small GGO cancers were less aggressive than their solid-nodule counterparts.

Background: For the same age and smoking history as whites, minorities have substantially different lung-cancer risk. However, current US Preventive Services Task Force (USPSTF) lung-cancer screening recommendations make no allowance for race/ethnicity and may induce health disparities. Incorporating individualized prediction-models into USPSTF guidelines may reduce racial/ethnic disparities in lung-cancer screening eligibility. We examine whether expanding current USPSTF lung cancer screening eligibility to include ever-smokers whose risk (calculated by an individualized prediction model) exceeded a threshold would reduce racial/ethnic disparities induced by current USPSTF guidelines. Methods: We used the US- representative 2015 National Health Interview Survey to examine screening eligibility. We identified the thresholds for each of 5 models: lung-cancer risk (Bach, PLCOM2012 and LCRAT models), lung-cancer death risk (LCDRAT model), and life- years gained by attending screening (LYFS-CT model), which select the same number of ever-smokers aged 50-80yrs as USPSTF guidelines. We defined 5 cohorts of ever- smokers as eligible for screening if they were eligible by each screening model or USPSTF guidelines. Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung-cancer deaths prevented (LCD sensitivity), proportion of gainable life-years gained (LYG sensitivity) and screening effectiveness (the number needed to screen to prevent one lung-cancer death). Results: USPSTF criteria performed best for whites (20% eligible, preventing 55% of preventable lung- cancer deaths). Asian-Americans had the least effective screening (NNS=419), only 13% of African-Americans were eligible despite having the most effective screening (NNS=135), and Hispanic-Americans had the lowest percentages eligible (9%) and deaths preventable (30%). Augmenting USPSTF criteria with LCDRAT or LYFS-CT prediction-models nearly equalized the performance of screening for African- Americans with that of whites, doubling the number of African-Americans eligible and increasing the number of preventable deaths and life-years gained by nearly 80%, although at a 25% loss in effectiveness. Prediction-models improved all screening metrics for Asian-Americans and Hispanic-Americans. However models estimated risk more accurately for whites than minorities. Conclusions: Augmenting USPSTF criteria with the LCDRAT or LYFS-CT prediction-models nearly eliminated the white/African-American disparity. All screening metrics were substantially improved for Asian/Hispanic-Americans. Citation Format: Rebecca Landy, Corey D. Young, Martin Skarzynski, Li C. Cheung, Christine D. Berg, M. Patricia Rivera, Hilary A. Robbins, Anil K. Chaturvedi, Hormuzd A. Katki. Use of prediction models to reduce racial/ethnic disparities in eligibility for lung-cancer screening [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-247.

HPV-positive oropharynx cancer is frequently characterized as a disease of never-smokers due to higher HPV prevalence in oropharynx tumors among never-smokers than ever-smokers. We sought to estimate the burden (incidence rates and case counts) of HPV-positive oropharynx cancers among never, former, and current smokers in the US population by combining data from several sources.We decomposed the SEER population-level incidence of oropharynx cancers into rates among never-, former-, and current-smokers using a formula based upon rate ratios (RR) for the smoking-oropharynx cancer association (NIH-AARP cohort study) and smoking prevalence in the U.S. population (NHANES 2007/2008). These rates were multiplied by smoking strata-specific HPV prevalence in oropharynx cancer patients (RTOG0129) to estimate incidence of HPV-positive and HPV-negative oropharynx cancers, which were applied to the US population of smokers to calculate annual case counts. Analyses were conducted overall and gender-stratified.The incidence of HPV-positive oropharynx cancers was significantly higher among ever versus never-smokers in the US population aged 20+ years during 2007/2008 (RR=1.81; 95%CI=1.32-2.47), including significantly higher incidence in current smokers (RR=2.26; 95%CI=1.60-3.21) and former smokers (RR=1.38; 95%CI=1.02-1.85). Of the estimated 6677 (5418 in men and 1259 in women) annually incident HPV-positive oropharynx cancers in the U.S during 2007/2008, 63.3% arose among ever smokers and 36.7% among never-smokers (p0.001). In both men and women, incidence rates and annual cases of HPV-positive oropharynx cancers were higher in ever smokers versus never smokers.The population-level burden of HPV-positive oropharynx cancers is significantly higher among ever-smokers than never-smokers in the U.S.