Search

Background: Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions.Purpose: To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor.Data Sources: MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium.Study Selection: English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor.Data Extraction: Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means.Data Synthesis: Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk.Limitations: Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered.Conclusion: Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening.Primary Funding Source: National Cancer Institute. [ABSTRACT FROM AUTHOR]

Background: Timing of initiation of screening for breast cancer is controversial in the United States.Objective: To determine the threshold relative risk (RR) at which the harm-benefit ratio of screening women aged 40 to 49 years equals that of biennial screening for women aged 50 to 74 years.Design: Comparative modeling study.Data Sources: Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and medical literature.Target Population: A contemporary cohort of women eligible for routine screening.Time Horizon: Lifetime.Perspective: Societal.Intervention: Mammography screening starting at age 40 versus 50 years with different screening methods (film, digital) and screening intervals (annual, biennial).Outcome Measures: Benefits: life-years gained, breast cancer deaths averted; harms: false-positive mammography findings; harm-benefit ratios: false-positive findings/life-years gained, false-positive findings/deaths averted.Results Of Base-case Analysis: Screening average-risk women aged 50 to 74 years biennially yields the same false-positive findings/life-years gained as biennial screening with digital mammography starting at age 40 years for women with a 2-fold increased risk above average (median threshold RR, 1.9 [range across models, 1.5 to 4.4]). The threshold RRs are higher for annual screening with digital mammography (median, 4.3 [range, 3.3 to 10]) and when false-positive findings/deaths averted is used as an outcome measure instead of false-positive findings/life-years gained. The harm-benefit ratio for film mammography is more favorable than for digital mammography because film has a lower false-positive rate.Results Of Sensitivity Analysis: The threshold RRs changed slightly when a more comprehensive measure of harm was used and were relatively insensitive to lower adherence assumptions.Limitation: Risk was assumed to influence onset of disease without influencing screening performance.Conclusion: Women aged 40 to 49 years with a 2-fold increased risk have similar harm-benefit ratios for biennial screening mammography as average-risk women aged 50 to 74 years. Threshold RRs required for favorable harm-benefit ratios vary by screening method, interval, and outcome measure.Primary Funding Source: National Cancer Institute. [ABSTRACT FROM AUTHOR]

Background: Chinese-American women have much lower mammography screening rates than the general population. This study examined the collective impact of knowledge, cultural views, and health beliefs on intentions to obtain mammography among Chinese women who had not had a mammogram in the previous year.Methods: Five hundred sixty-six immigrant Chinese women from the Washington, District of Columbia and New York metropolitan areas completed baseline assessments for a longitudinal intervention study. Validated surveys were used to measure variables of interest. The outcomes were 1) past mammography use (ever vs never) and 2) future screening intention.Results: Only 35% of the participants reported intentions to obtain mammograms, with approximately 19% of the never users reporting intentions (vs 44% ever users). Ever users had higher knowledge (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.03-1.25), less Eastern cultural views (OR, 0.78; 95% CI, 0.70-0.87), and perceived fewer barriers (OR, 0.78; 95% CI, 0.70-0.87) than never users, controlling for covariates. Never users were more likely to be recent immigrants, have low income, have limited English ability, and lack regular sources of care than ever users (all P<.001). Multivariate models showed that ever users who were employed received physician recommendations, had less Eastern views, perceived higher susceptibility, and were more likely to have intentions. Among never users, being 40-49 years of age and perceiving fewer barriers led to increased intention.Conclusions: Understanding cultural patterns and health beliefs in Chinese women is critical to changing their screening behaviors. Interventions that address their common beliefs and specific group barriers are optimal for promoting mammography adherence. [ABSTRACT FROM AUTHOR]

CONTEXT: Cancer is a leading cause of morbidity and mortality in the USA and despite many recent advances in detection and treatment, over half a million cancer patients in this country will die from their disease each year. OBJECTIVE: Using cancer as a prototype, we provide a conceptual framework to identify and review barriers to optimal end-of-life care and propose examples of linked process and outcome measures that could be used to evaluate whether standards of optimal end-of-life care are being achieved. METHODS: We propose a conceptual model of end-of-life care and use this model to review the published literature to identify the key goals of optimal end-of-life care and summarize existing barriers to optimal end-of-life care. We then provide examples of process and outcome measures linked to the goals of optimal end-of-life care and domains within the conceptual framework. RESULTS: Within all components of care at the end-of-life--societal attitudes, health care system(s), providers, and patients and their families--there are significant barriers to the quality of care. Some of the most critical barriers to optimal care at the end-of-life in the USA are limited availability, and coverage of, co-ordinated service delivery; poor provider communication and diagnostic skills; limited opportunities for training in palliative care; patient fears and attitudes towards the sick role, and a lack of, or inadequate health insurance. Proposed patient, provider, and system level measures of the quality of care were guided by goals of optimal end-of-life care, and focus on communication about prognosis and risks and benefits of treatment, development of clear and informed treatment goals, delivery of services consistent with treatment goals, and promotion of quality of life. CONCLUSIONS: At present, there are substantial societal, health care system, provider, and patient barriers to obtaining optimal cancer care at the end-of-life. Ongoing discussions about appropriate measures of the quality of end-of-life care are gaining momentum, however. The proposed process and outcome measures for assessing optimal end-of-life care use cancer as a prototype, but are broadly applicable to other patient populations with life-threatening disease. [ABSTRACT FROM AUTHOR]

Background: We used modeling techniques to assess the relative and absolute contributions of screening mammography and adjuvant treatment to the reduction in breast-cancer mortality in the United States from 1975 to 2000. Methods: A consortium of investigators developed seven independent statistical models of breast-cancer incidence and mortality. All seven groups used the same sources to obtain data on the use of screening mammography, adjuvant treatment, and benefits of treatment with respect to the rate of death from breast cancer. Results: The proportion of the total reduction in the rate of death from breast cancer attributed to screening varied in the seven models from 28 to 65 percent (median, 46 percent), with adjuvant treatment contributing the rest. The variability across models in the absolute contribution of screening was larger than it was for treatment, reflecting the greater uncertainty associated with estimating the benefit of screening. Conclusions: Seven statistical models showed that both screening mammography and treatment have helped reduce the rate of death from breast cancer in the United States. [ABSTRACT FROM AUTHOR]

Background: Delayed or incomplete follow-up after abnormal screening results may compromise the effectiveness of breast cancer screening programs, particularly in medically underserved and minority populations. This study examined the role of socioeconomic status, breast cancer risk factors, health care system barriers, and patient cognitive-attitudinal factors in the timing of diagnostic resolution after abnormal breast cancer screening exams among Black women receiving breast cancer screening at three New York city clinics.Methods: We identified 184 Black women as having an abnormal mammogram or clinical breast exam requiring immediate follow-up and they were interviewed and their medical records examined. Bivariate and multivariate logistic regression analyses were used to assess the association between patient and health care system factors and diagnostic resolution within 3 months of the abnormal finding.Results: Within 3 months, 39% of women were without diagnostic resolution and 28% within 6 months. Neither socioeconomic status nor system barriers were associated with timely diagnostic resolution. Timely resolution was associated with mammogram severity, patients asking questions (OR, 2.73; 95% CI, 1.25-5.96), or receiving next step information (OR, 2.6; 95% CI, 1.08-6.21) at the initial mammogram. Women with prior breast abnormalities were less likely to complete timely diagnostic resolution (OR, 0.42; 95% CI, 0.20-0.85), as were women with higher levels of cancer anxiety (OR, 0.50; 95% CI, 0.27-0.92).Conclusions: Interventions that address a woman's prior experience with abnormal findings and improve patient/provider communication may improve timely and appropriate follow-up. [ABSTRACT FROM AUTHOR]

Importance: Information on long-term benefits and harms of screening with digital breast tomosynthesis (DBT) with or without supplemental breast magnetic resonance imaging (MRI) is needed for clinical and policy discussions, particularly for patients with dense breasts., Objective: To project long-term population-based outcomes for breast cancer mammography screening strategies (DBT or digital mammography) with or without supplemental MRI by breast density., Design, Setting, and Participants: Collaborative modeling using 3 Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation models informed by US Breast Cancer Surveillance Consortium data. Simulated women born in 1980 with average breast cancer risk were included. Modeling analyses were conducted from January 2020 to December 2023., Intervention: Annual or biennial mammography screening with or without supplemental MRI by breast density starting at ages 40, 45, or 50 years through age 74 years., Main Outcomes and Measures: Lifetime breast cancer deaths averted, false-positive recall and false-positive biopsy recommendations per 1000 simulated women followed-up from age 40 years to death summarized as means and ranges across models., Results: Biennial DBT screening for all simulated women started at age 50 vs 40 years averted 7.4 vs 8.5 breast cancer deaths, respectively, and led to 884 vs 1392 false-positive recalls and 151 vs 221 false-positive biopsy recommendations, respectively. Biennial digital mammography had similar deaths averted and slightly more false-positive test results than DBT screening. Adding MRI for women with extremely dense breasts to biennial DBT screening for women aged 50 to 74 years increased deaths averted (7.6 vs 7.4), false-positive recalls (919 vs 884), and false-positive biopsy recommendations (180 vs 151). Extending supplemental MRI to women with heterogeneously or extremely dense breasts further increased deaths averted (8.0 vs 7.4), false-positive recalls (1088 vs 884), and false-positive biopsy recommendations (343 vs 151). The same strategy for women aged 40 to 74 years averted 9.5 deaths but led to 1850 false-positive recalls and 628 false-positive biopsy recommendations. Annual screening modestly increased estimated deaths averted but markedly increased estimated false-positive results., Conclusions and Relevance: In this model-based comparative effectiveness analysis, supplemental MRI for women with dense breasts added to DBT screening led to greater benefits and increased harms. The balance of this trade-off for supplemental MRI use was more favorable when MRI was targeted to women with extremely dense breasts who comprise approximately 10% of the population.

The central premise of this article is that a portion of the established relationships between social determinants of health and racial/ethnic disparities in cancer morbidity and mortality are mediated through differences in rates of biological aging processes. We further posit that using knowledge about aging could enable discovery and testing of new mechanism-based pharmaceutical and behavioral interventions ("gerotherapeutics") to differentially improve the health of minoritized cancer survivors and reduce cancer disparities. These hypotheses are based on evidence that lifelong differences in adverse social determinants of health contribute to disparities in rates of biological aging ("social determinants of aging"), with minoritized groups having accelerated aging (ie, a steeper slope or trajectory of biological aging over time relative to chronological age) more often than non-minoritized groups. Acceleration of biological aging can increase the risk, age of onset, aggressivity and/or stage of many adult cancers. There are also documented negative feedback loops whereby the cellular damage caused by cancer and its therapies act as drivers of additional biological aging. Together, these dynamic intersectional forces can contribute to differences in cancer outcomes between minoritized vs non-minoritized survivor populations. We highlight key targetable biological aging mechanisms with potential applications to reducing cancer disparities and discuss methodological considerations for pre-clinical and clinical testing of the impact of gerotherapeutics on cancer outcomes in minoritized populations. Ultimately, the promise of reducing cancer disparities will require broad societal policy changes that address the structural causes of accelerated biological aging and ensure equitable access to all new cancer control paradigms., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known., Objective: To estimate outcomes of various mammography screening strategies., Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses., Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment., Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women., Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women., Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.

Purpose: Cancer survivors commonly report cognitive declines after cancer therapy. Due to the complex etiology of cancer-related cognitive decline (CRCD), predicting who will be at risk of CRCD remains a clinical challenge. We developed a model to predict breast cancer survivors who would experience CRCD after systematic treatment., Methods: We used the Thinking and Living with Cancer study, a large ongoing multisite prospective study of older breast cancer survivors with complete assessments pre-systemic therapy, 12 months and 24 months after initiation of systemic therapy. Cognition was measured using neuropsychological testing of attention, processing speed, and executive function (APE). CRCD was defined as a 0.25 SD (of observed changes from baseline to 12 months in matched controls) decline or greater in APE score from baseline to 12 months (transient) or persistent as a decline 0.25 SD or greater sustained to 24 months. We used machine learning approaches to predict CRCD using baseline demographics, tumor characteristics and treatment, genotypes, comorbidity, and self-reported physical, psychosocial, and cognitive function., Results: Thirty-two percent of survivors had transient cognitive decline, and 41% of these women experienced persistent decline. Prediction of CRCD was good: yielding an area under the curve of 0.75 and 0.79 for transient and persistent decline, respectively. Variables most informative in predicting CRCD included apolipoprotein E4 positivity, tumor HER2 positivity, obesity, cardiovascular comorbidities, more prescription medications, and higher baseline APE score., Conclusions: Our proof-of-concept tool demonstrates our prediction models are potentially useful to predict risk of CRCD. Future research is needed to validate this approach for predicting CRCD in routine practice settings., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Guidelines recommend shared decision-making (SDM) around mammography screening for women ≥ 75 years old., Objective: To use microsimulation modeling to estimate the lifetime benefits and harms of screening women aged 75, 80, and 85 years based on their individual risk factors (family history, breast density, prior biopsy) and comorbidity level to support SDM in clinical practice., Design, Setting, and Participants: We adapted two established Cancer Intervention and Surveillance Modeling Network (CISNET) models to evaluate the remaining lifetime benefits and harms of screening U.S. women born in 1940, at decision ages 75, 80, and 85 years considering their individual risk factors and comorbidity levels. Results were summarized for average- and higher-risk women (defined as having breast cancer family history, heterogeneously dense breasts, and no prior biopsy, 5% of the population)., Main Outcomes and Measures: Remaining lifetime breast cancers detected, deaths (breast cancer/other causes), false positives, and overdiagnoses for average- and higher-risk women by age and comorbidity level for screening (one or five screens) vs. no screening per 1000 women., Results: Compared to stopping, one additional screen at 75 years old resulted in six and eight more breast cancers detected (10% overdiagnoses), one and two fewer breast cancer deaths, and 52 and 59 false positives per 1000 average- and higher-risk women without comorbidities, respectively. Five additional screens over 10 years led to 23 and 31 additional breast cancer cases (29-31% overdiagnoses), four and 15 breast cancer deaths avoided, and 238 and 268 false positives per 1000 average- and higher-risk screened women without comorbidities, respectively. Screening women at older ages (80 and 85 years old) and high comorbidity levels led to fewer breast cancer deaths and a higher percentage of overdiagnoses., Conclusions: Simulation models show that continuing screening in women ≥ 75 years old results in fewer breast cancer deaths but more false positive tests and overdiagnoses. Together, clinicians and 75 + women may use model output to weigh the benefits and harms of continued screening., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Importance: Breast cancer mortality in the US declined between 1975 and 2019. The association of changes in metastatic breast cancer treatment with improved breast cancer mortality is unclear., Objective: To simulate the relative associations of breast cancer screening, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer with improved breast cancer mortality., Design, Setting, and Participants: Using aggregated observational and clinical trial data on the dissemination and effects of screening and treatment, 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models simulated US breast cancer mortality rates. Death due to breast cancer, overall and by estrogen receptor and ERBB2 (formerly HER2) status, among women aged 30 to 79 years in the US from 1975 to 2019 was simulated., Exposures: Screening mammography, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer., Main Outcomes and Measures: Model-estimated age-adjusted breast cancer mortality rate associated with screening, stage I to III treatment, and metastatic treatment relative to the absence of these exposures was assessed, as was model-estimated median survival after breast cancer metastatic recurrence., Results: The breast cancer mortality rate in the US (age adjusted) was 48/100 000 women in 1975 and 27/100 000 women in 2019. In 2019, the combination of screening, stage I to III treatment, and metastatic treatment was associated with a 58% reduction (model range, 55%-61%) in breast cancer mortality. Of this reduction, 29% (model range, 19%-33%) was associated with treatment of metastatic breast cancer, 47% (model range, 35%-60%) with treatment of stage I to III breast cancer, and 25% (model range, 21%-33%) with mammography screening. Based on simulations, the greatest change in survival after metastatic recurrence occurred between 2000 and 2019, from 1.9 years (model range, 1.0-2.7 years) to 3.2 years (model range, 2.0-4.9 years). Median survival for estrogen receptor (ER)-positive/ERBB2-positive breast cancer improved by 2.5 years (model range, 2.0-3.4 years), whereas median survival for ER-/ERBB2- breast cancer improved by 0.5 years (model range, 0.3-0.8 years)., Conclusions and Relevance: According to 4 simulation models, breast cancer screening and treatment in 2019 were associated with a 58% reduction in US breast cancer mortality compared with interventions in 1975. Simulations suggested that treatment for stage I to III breast cancer was associated with approximately 47% of the mortality reduction, whereas treatment for metastatic breast cancer was associated with 29% of the reduction and screening with 25% of the reduction.

Background: Populations of African American or Black women have persistently higher breast cancer mortality than the overall US population, despite having slightly lower age-adjusted incidence., Methods: Three Cancer Intervention and Surveillance Modeling Network simulation teams modeled cancer mortality disparities between Black female populations and the overall US population. Model inputs used racial group-specific data from clinical trials, national registries, nationally representative surveys, and observational studies. Analyses began with cancer mortality in the overall population and sequentially replaced parameters for Black populations to quantify the percentage of modeled breast cancer morality disparities attributable to differences in demographics, incidence, access to screening and treatment, and variation in tumor biology and response to therapy., Results: Results were similar across the 3 models. In 2019, racial differences in incidence and competing mortality accounted for a net ‒1% of mortality disparities, while tumor subtype and stage distributions accounted for a mean of 20% (range across models = 13%-24%), and screening accounted for a mean of 3% (range = 3%-4%) of the modeled mortality disparities. Treatment parameters accounted for the majority of modeled mortality disparities: mean = 17% (range = 16%-19%) for treatment initiation and mean = 61% (range = 57%-63%) for real-world effectiveness., Conclusion: Our model results suggest that changes in policies that target improvements in treatment access could increase breast cancer equity. The findings also highlight that efforts must extend beyond policies targeting equity in treatment initiation to include high-quality treatment completion. This research will facilitate future modeling to test the effects of different specific policy changes on mortality disparities., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To identify trajectories of depressive symptoms in older breast cancer survivors and demographic, psychosocial, physical health, and cancer-related predictors of these trajectories., Methods: Recently diagnosed nonmetastatic breast cancer survivors (n = 272), ages 60-98 years, were evaluated for depressive symptoms (Center for Epidemiological Studies Depression Scale, CES-D; scores ≥16 suggestive of clinically significant depressive symptoms). CES-D scores were analyzed in growth-mixture models to determine depression trajectories from baseline (post-surgery, pre-systemic therapy) through 3-year annual follow-up. Multivariable, multinomial logistic regression was used to identify baseline predictors of depression trajectories., Results: Survivors had three distinct trajectories: stable (84.6%), emerging depressive symptoms (10.3%), and recovery from high depressive symptoms at baseline that improved slowly over time (5.1%). Compared to stable survivors, those in the emerging (OR = 1.16; 95% CI = 1.08-1.23) or recovery (OR = 1.26; 95% CI = 1.15-1.38) groups reported greater baseline anxiety. Greater baseline deficit accumulation (frailty composite measure) was associated with emerging depressive symptoms (OR = 3.71; 95% CI = 1.90-7.26). Less social support at baseline (OR = 0.38; 95% CI = 0.15-0.99), but greater improvement in emotional (F = 4.13; p = 0.0006) and tangible (F = 2.86; p = 0.01) social support over time, was associated with recovery from depressive symptoms., Conclusions: Fifteen percent of older breast cancer survivors experienced emerging or recovery depressive symptom trajectories. Baseline anxiety, deficit accumulation, and lower social support were associated with worse outcomes., Implications for Cancer Survivors: Our results emphasize the importance of depression screening throughout the course of cancer care to facilitate early intervention. Factors associated with depressive symptoms, including lower levels of social support proximal to diagnosis, could serve as intervention levers., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Survivors of childhood cancer experience premature aging compared with community controls. The deficit accumulation index (DAI) uses readily available clinical data to measure physiological age in survivors; however, little data exist on how well deficit accumulation represents underlying biological aging among survivors of cancer., Objective: To examine the associations between the DAI and epigenetic age acceleration (EAA) and mean leukocyte telomere length (LTL)., Design, Setting, and Participants: This cross-sectional study analyzed data from the St Jude Lifetime Cohort, an assessment of survivors of childhood cancer who were treated at St Jude Children's Research Hospital in Memphis, Tennessee. Data were collected between 2007 and 2016, assayed between 2014 and 2019, and analyzed between 2022 and 2023. Participants were adult survivors who were diagnosed between 1962 and 2012 and who survived 5 years or more from time of diagnosis. The analyses were restricted to survivors with European ancestry, as there were too few survivors with non-European ancestry., Exposures: The DAI included 44 aging-related items, such as chronic health conditions and functional, psychosocial, and mental well-being. Item responses were summed and divided by the total number of items, resulting in a ratio ranging from 0 to 1. These DAI results were categorized based on reported associations with hospitalization and mortality: low, defined as a DAI less than 0.2; medium, defined as a DAI of 0.2 to less than 0.35; and high, defined as a DAI of 0.35 or higher., Main Outcomes and Measures: Genome-wide DNA methylation was generated from peripheral blood mononuclear cell-derived DNA. The EAA was calculated as the residuals from regressing the Levine epigenetic age on chronological age. The mean LTL was estimated using whole-genome sequencing data., Results: This study included 2101 survivors of childhood cancer (1122 males [53.4%]; mean [SD] age, 33.9 [9.1] years; median [IQR] time since diagnosis, 25.1 [18.7-31.9] years) with European ancestry. Compared with survivors in the low DAI group, those in the high DAI group experienced 3.7 more years of EAA (β = 3.66; 95% CI, 2.47-4.85; P < .001), whereas those in the medium DAI group experienced 1.8 more years of EAA (β = 1.77; 95% CI, 0.84-2.69; P < .001), independent of treatment exposures. The EAA and DAI association was consistent across 3 common diagnoses (acute lymphoblastic leukemia, Hodgkin lymphoma, and central nervous system tumors) and across chronological age groups. For example, among acute lymphoblastic leukemia survivors, those in the medium DAI group (β = 2.27; 95% CI, 0.78-3.76; P = .001) experienced greater EAA vs those in the low DAI group. Similarly, among survivors younger than 30 years, the high DAI group experienced 4.9 more years of EAA vs the low DAI group (β = 4.95; 95% CI, 2.14-7.75; P < .001). There were no associations between mean LTL residual and the DAI., Conclusions and Relevance: This cross-sectional study of survivors of childhood cancer showed that the DAI was associated with EAA, suggesting an underlying biological process to the accumulation of deficits. Both the DAI and EAA were effective at identifying aging phenotypes, and either may be used to measure aging and response to interventions targeting aging pathways.

Importance: Increased use of recommended screening could help achieve the Cancer Moonshot goal of reducing US cancer deaths., Objective: To estimate the number of cancer deaths that could be prevented with a 10-percentage point increase in the use of US Preventive Services Task Force (USPSTF)-recommended screening., Design, Setting, and Participants: This decision analytical model study is an extension of previous studies conducted for the USPSTF from 2018 to 2023. This study simulated contemporary cohorts of US adults eligible for lung, colorectal, breast, and cervical cancer screening., Exposures: Annual low-dose computed lung tomography among eligible adults aged 50 to 80 years; colonoscopy every 10 years among adults aged 45 to 75 years; biennial mammography among female adults aged 40 to 74 years; and triennial cervical cytology screening among female adults aged 21 to 29 years, followed by human papillomavirus testing every 5 years from ages 30 to 65 years., Main Outcomes and Measures: Estimated number of cancer deaths prevented with a 10-percentage point increase in screening use, assuming screening commences at the USPSTF-recommended starting age and continues throughout the lifetime. Outcomes were presented 2 ways: (1) per 100 000 and (2) among US adults in 2021; and they were expressed among the target population at the age of screening initiation. For lung cancer, estimates were among those who will also meet the smoking eligibility criteria during their lifetime. Harms from increased uptake were also reported., Results: A 10-percentage point increase in screening use at the age that USPSTF recommended screening commences was estimated to prevent 226 lung cancer deaths (range across models within the cancer site, 133-332 deaths), 283 (range, 263-313) colorectal cancer deaths, 82 (range, 61-106) breast cancer deaths, and 81 (1 model; no range available) cervical cancer deaths over the lifetimes of 100 000 persons eligible for screening. These rates corresponded with an estimated 1010 (range, 590-1480) lung cancer deaths prevented, 11 070 (range, 10 280-12 250) colorectal cancer deaths prevented, 1790 (range, 1330-2310) breast cancer deaths prevented, and 1710 (no range available) cervical cancer deaths prevented over the lifetimes of eligible US residents at the recommended age to initiate screening in 2021. Increased uptake was also estimated to generate harms, including 100 000 (range, 45 000-159 000) false-positive lung scans, 6000 (range, 6000-7000) colonoscopy complications, 300 000 (range, 295 000-302 000) false-positive mammograms, and 348 000 (no range available) colposcopies over the lifetime., Conclusions and Relevance: In this decision analytical model study, a 10-percentage point increase in uptake of USPSTF-recommended lung, colorectal, breast, and cervical cancer screening at the recommended starting age was estimated to yield important reductions in cancer deaths. Achieving these reductions is predicated on ensuring equitable access to screening.

Background: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes., Methods: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed-effects models tested survivor-control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve., Results: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001-.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001-.04), and among this group, an older EEA related to worse self-reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001-.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non-Hispanic White survivors., Conclusion: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: There are no consensus guidelines for supplemental breast cancer screening with whole-breast ultrasound. However, criteria for women at high risk of mammography screening failures (interval invasive cancer or advanced cancer) have been identified. Mammography screening failure risk was evaluated among women undergoing supplemental ultrasound screening in clinical practice compared with women undergoing mammography alone., Methods: A total of 38,166 screening ultrasounds and 825,360 screening mammograms without supplemental screening were identified during 2014-2020 within three Breast Cancer Surveillance Consortium (BCSC) registries. Risk of interval invasive cancer and advanced cancer were determined using BCSC prediction models. High interval invasive breast cancer risk was defined as heterogeneously dense breasts and BCSC 5-year breast cancer risk ≥2.5% or extremely dense breasts and BCSC 5-year breast cancer risk ≥1.67%. Intermediate/high advanced cancer risk was defined as BCSC 6-year advanced breast cancer risk ≥0.38%., Results: A total of 95.3% of 38,166 ultrasounds were among women with heterogeneously or extremely dense breasts, compared with 41.8% of 825,360 screening mammograms without supplemental screening (p < .0001). Among women with dense breasts, high interval invasive breast cancer risk was prevalent in 23.7% of screening ultrasounds compared with 18.5% of screening mammograms without supplemental imaging (adjusted odds ratio, 1.35; 95% CI, 1.30-1.39); intermediate/high advanced cancer risk was prevalent in 32.0% of screening ultrasounds versus 30.5% of screening mammograms without supplemental screening (adjusted odds ratio, 0.91; 95% CI, 0.89-0.94)., Conclusions: Ultrasound screening was highly targeted to women with dense breasts, but only a modest proportion were at high mammography screening failure risk. A clinically significant proportion of women undergoing mammography screening alone were at high mammography screening failure risk., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls., Methods: Women >60 years old with primary breast cancer (stages 0-III) (n = 400) were assessed before systemic therapy with frequency-matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor α (TNF-α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate-adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects., Results: Participants were aged 60-90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor-positive tumors (87.6%). Survivors had significantly higher IL-6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤ .001-.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p < .05). Levels of IL-6, IL-10, and TNF-α were related to APE, with IL-6 explaining part of the relationship between survivor/control group and APE (p = .01). The magnitude of this mediation effect decreased but remained significant (p = .047) after the consideration of additional covariates., Conclusions: Older breast cancer survivors had worse long-term neurocognitive performance than controls, and this relationship was explained in part by elevated IL-6., (© 2023 American Cancer Society.)

Background: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ ( N = 325) and age-, racial/ethnic group-, and education-matched controls ( N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 ( HMCN1) gene ( p = 1.624 × 10 -8 ), and rs78786199 (chromosome 2, p = 1.925 × 10 -8 ) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.

Background: Discrimination can adversely affect health and accelerate aging, but little is known about these relationships in cancer survivors. This study examines associations of discrimination and aging among self-identified African American survivors., Methods: A population-based sample of 2232 survivors 20-79 years old at diagnosis were enrolled within 5 years of breast (n = 787), colorectal (n = 227), lung (n = 223), or prostate (n = 995) cancer between 2017 and 2022. Surveys were completed post-active therapy. A deficit accumulation index measured aging-related disease and function (score range, 0-1, where <0.20 is robust, 0.20 to <0.35 is pre-frail, and 0.35+ is frail; 0.06 is a large clinically meaningful difference). The discrimination scale assessed ever experiencing major discrimination and seven types of events (score, 0-7). Linear regression tested the association of discrimination and deficit accumulation, controlling for age, time from diagnosis, cancer type, stage and therapy, and sociodemographic variables., Results: Survivors were an average of 62 years old (SD, 9.6), 63.2% reported ever experiencing major discrimination, with an average of 2.4 (SD, 1.7) types of discrimination events. Only 24.4% had deficit accumulation scores considered robust (mean score, 0.30 [SD, 0.13]). Among those who reported ever experiencing major discrimination, survivors with four to seven types of discrimination events (vs. 0-1) had a large, clinically meaningful increase in adjusted deficits (0.062, p < .001) and this pattern was consistent across cancer types., Conclusion: African American cancer survivors have high deficit accumulated index scores, and experiences of major discrimination were positively associated with these deficits. Future studies are needed to understand the intersectionality between aging, discrimination, and cancer survivorship among diverse populations., (© 2023 American Cancer Society.)

Introduction: Tamoxifen is a common treatment for estrogen receptor-positive breast cancer. While tamoxifen treatment is generally accepted as safe, there are concerns about adverse effects on cognition., Methods: We used a mouse model of chronic tamoxifen exposure to examine the effects of tamoxifen on the brain. Female C57/BL6 mice were exposed to tamoxifen or vehicle control for six weeks; brains of 15 mice were analyzed for tamoxifen levels and transcriptomic changes, and an additional 32 mice were analyzed through a battery of behavioral tests., Results: Tamoxifen and its metabolite 4-OH-tamoxifen were found at higher levels in the brain than in the plasma, demonstrating the facile entry of tamoxifen into the CNS. Behaviorally, tamoxifen-exposed mice showed no impairment in assays related to general health, exploration, motor function, sensorimotor gating, and spatial learning. Tamoxifen-treated mice showed a significantly increased freezing response in a fear conditioning paradigm, but no effects on anxiety measures in the absence of stressors. RNA sequencing analysis of whole hippocampi showed tamoxifen-induced reductions in gene pathways related to microtubule function, synapse regulation, and neurogenesis., Discussion: These findings of the effects of tamoxifen exposure on fear conditioning and on gene expression related to neuronal connectivity suggest that there may be CNS side effects of this common breast cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Galvano, Pandit, Sepulveda, Ng, Becher, Mandelblatt, Van Dyk and Rebeck.)

The purpose of this study is to evaluate the direct and indirect effects of a web-based, Protection Motivation Theory (PMT)-informed breast cancer education and decision support tool on intentions for risk-reducing medication and breast MRI among high-risk women. Women with ≥ 1.67% 5-year breast cancer risk (N = 995) were randomized to (1) control or (2) the PMT-informed intervention. Six weeks post-intervention, 924 (93% retention) self-reported PMT constructs and behavioral intentions. Bootstrapped mediations evaluated the direct effect of the intervention on behavioral intentions and the mediating role of PMT constructs. There was no direct intervention effect on intentions for risk-reducing medication or MRI (p's ≥ 0.12). There were significant indirect effects on risk-reducing medication intentions via perceived risk, self-efficacy, and response efficacy, and on MRI intentions via perceived risk and response efficacy (p's ≤ 0.04). The PMT-informed intervention effected behavioral intentions via perceived breast cancer risk, self-efficacy, and response efficacy. Future research should extend these findings from intentions to behavior. ClinicalTrials.gov Identifier: NCT03029286 (date of registration: January 24, 2017)., (© 2021. The Author(s).)

Purpose: To examine longitudinal relationships between levels of C-reactive protein (CRP) and cognition in older breast cancer survivors and noncancer controls., Methods: English-speaking women age ≥ 60 years, newly diagnosed with primary breast cancer (stage 0-III), and frequency-matched controls were enrolled from September 2010 to March 2020; women with dementia, neurologic disorders, and other cancers were excluded. Assessments occurred presystemic therapy/enrollment and at annual visits up to 60 months. Cognition was measured using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. Mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP at each visit. Random effect-lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition. All models controlled for age, race, study site, cognitive reserve, obesity, and comorbidities; secondary analyses evaluated if depression or anxiety affected results., Results: There were 400 survivors and 329 controls with CRP specimens and follow-up data (average age of 67.7 years; range, 60-90 years). The majority of survivors had stage I (60.9%), estrogen receptor-positive (87.6%) tumors. Survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits (all P < .05). Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not controls ( P interaction = .008); effects were unchanged by depression or anxiety. Overall, survivors had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. Survivors had poorer neuropsychological test performance ( v controls), with significant interactions with CRP only for the Trails B test., Conclusion: Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems. CRP testing could be clinically useful in survivorship care.

Introduction: Many cancer survivors report cognitive problems following diagnosis and treatment. However, the clinical significance of patient-reported cognitive symptoms early in survivorship can be unclear. We used a machine learning approach to determine the association of persistent self-reported cognitive symptoms two years after diagnosis and neurocognitive test performance in a prospective cohort of older breast cancer survivors., Materials and Methods: We enrolled breast cancer survivors with non-metastatic disease (n = 435) and age- and education-matched non-cancer controls (n = 441) between August 2010 and December 2017 and followed until January 2020; we excluded women with neurological disease and all women passed a cognitive screen at enrollment. Women completed the FACT-Cog Perceived Cognitive Impairment (PCI) scale and neurocognitive tests of attention, processing speed, executive function, learning, memory and visuospatial ability, and timed activities of daily living assessments at enrollment (pre-systemic treatment) and annually to 24 months, for a total of 59 individual neurocognitive measures. We defined persistent self-reported cognitive decline as clinically meaningful decline (3.7+ points) on the PCI scale from enrollment to twelve months with persistence to 24 months. Analysis used four machine learning models based on data for change scores (baseline to twelve months) on the 59 neurocognitive measures and measures of depression, anxiety, and fatigue to determine a set of variables that distinguished the 24-month persistent cognitive decline group from non-cancer controls or from survivors without decline., Results: The sample of survivors and controls ranged in age from were ages 60-89. Thirty-three percent of survivors had self-reported cognitive decline at twelve months and two-thirds continued to have persistent decline to 24 months (n = 60). Least Absolute Shrinkage and Selection Operator (LASSO) models distinguished survivors with persistent self-reported declines from controls (AUC = 0.736) and survivors without decline (n = 147; AUC = 0.744). The variables that separated groups were predominantly neurocognitive test performance change scores, including declines in list learning, verbal fluency, and attention measures., Discussion: Machine learning may be useful to further our understanding of cancer-related cognitive decline. Our results suggest that persistent self-reported cognitive problems among older women with breast cancer are associated with a constellation of mild neurocognitive changes warranting clinical attention., Competing Interests: Declaration of Competing Interest The authors have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Several studies have reported sleep disturbances during the COVID-19 virus pandemic. Little data exist about the impact of the pandemic on sleep and mental health among older women with breast cancer. We sought to examine whether women with and without breast cancer who experienced new sleep problems during the pandemic had worsening depression and anxiety., Methods: Breast cancer survivors aged ≥60 years with a history of nonmetastatic breast cancer (n = 242) and frequency-matched noncancer controls (n = 158) active in a longitudinal cohort study completed a COVID-19 virus pandemic survey from May to September 2020 (response rate 83%). Incident sleep disturbance was measured using the restless sleep item from the Center for Epidemiological Studies-Depression Scale (CES-D). CES-D score (minus the sleep item) captured depressive symptoms; the State-Anxiety subscale of the State Trait Anxiety Inventory measured anxiety symptoms. Multivariable linear regression models examined how the development of sleep disturbance affected changes in depressive or anxiety symptoms from the most recent prepandemic survey to the pandemic survey, controlling for covariates., Results: The prevalence of sleep disturbance during the pandemic was 22.3%, with incident sleep disturbance in 10% and 13.5% of survivors and controls, respectively. Depressive and anxiety symptoms significantly increased during the pandemic among women with incident sleep disturbance (vs. no disturbance) (β = 8.16, p < 0.01 and β = 6.14, p < 0.01, respectively), but there were no survivor-control differences in the effect., Conclusion: Development of sleep disturbances during the COVID-19 virus pandemic may negatively affect older women's mental health, but breast cancer survivors diagnosed with the nonmetastatic disease had similar experiences as women without cancer., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: Diagnostic delays in breast cancer detection may be associated with later-stage disease and higher anxiety, but data on multilevel factors associated with diagnostic delay are limited., Objective: To evaluate individual-, neighborhood-, and health care-level factors associated with differences in time from abnormal screening to biopsy among racial and ethnic groups., Design, Setting, and Participants: This prospective cohort study used data from women aged 40 to 79 years who had abnormal results in screening mammograms conducted in 109 imaging facilities across 6 US states between 2009 and 2019. Data were analyzed from February 21 to November 4, 2021., Exposures: Individual-level factors included self-reported race and ethnicity, age, family history of breast cancer, breast density, previous breast biopsy, and time since last mammogram; neighborhood-level factors included geocoded education and income based on residential zip codes and rurality; and health care-level factors included mammogram modality, screening facility academic affiliation, and facility onsite biopsy service availability. Data were also assessed by examination year., Main Outcome and Measures: The main outcome was unadjusted and adjusted relative risk (RR) of no biopsy within 30, 60, and 90 days using sequential log-binomial regression models. A secondary outcome was unadjusted and adjusted median time to biopsy using accelerated failure time models., Results: A total of 45 186 women (median [IQR] age at screening, 56 [48-65] years) with 46 185 screening mammograms with abnormal results were included. Of screening mammograms with abnormal results recommended for biopsy, 15 969 (34.6%) were not resolved within 30 days, 7493 (16.2%) were not resolved within 60 days, and 5634 (12.2%) were not resolved within 90 days. Compared with White women, there was increased risk of no biopsy within 30 and 60 days for Asian (30 days: RR, 1.66; 95% CI, 1.31-2.10; 60 days: RR, 1.58; 95% CI, 1.15-2.18), Black (30 days: RR, 1.52; 95% CI, 1.30-1.78; 60 days: 1.39; 95% CI, 1.22-1.60), and Hispanic (30 days: RR, 1.50; 95% CI, 1.24-1.81; 60 days: 1.38; 95% CI, 1.11-1.71) women; however, the unadjusted risk of no biopsy within 90 days only persisted significantly for Black women (RR, 1.28; 95% CI, 1.11-1.47). Sequential adjustment for selected individual-, neighborhood-, and health care-level factors, exclusive of screening facility, did not substantially change the risk of no biopsy within 90 days for Black women (RR, 1.27; 95% CI, 1.12-1.44). After additionally adjusting for screening facility, the increased risk for Black women persisted but showed a modest decrease (RR, 1.20; 95% CI, 1.08-1.34)., Conclusions and Relevance: In this cohort study involving a diverse cohort of US women recommended for biopsy after abnormal results on screening mammography, Black women were the most likely to experience delays to diagnostic resolution after adjusting for multilevel factors. These results suggest that adjustment for multilevel factors did not entirely account for differences in time to breast biopsy, but unmeasured factors, such as systemic racism and other health care system factors, may impact timely diagnosis.

Purpose: Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of cognition prior to adjuvant therapy and tumor aggressivity in older breast cancer patients., Methods: Women diagnosed with non-metastatic breast cancer (n = 705) ages 60-98 were enrolled from August 2010-March 2020. Cognition was measured post-surgery, pre-systemic therapy using self-reported (FACT-Cog Perceived Cognitive Impairment [PCI]) and objective tests of attention, processing speed, and executive function (APE domain) and learning and memory [LM domain]. Linear regression tested associations of pre-treatment tumor features and cognition, adjusting for age, race, and study site. HER2 positivity and higher stage (II/III vs. 0/I) were a priori predictors of cognition; in secondary analyses we explored associations of other tumor features and cognitive impairment (i.e., PCI score < 54 or having 2 tests < 1.5 SD or 1 test < 2 SD from the mean APE or LM domain score)., Results: HER2 positivity and the hormone receptor negative/HER2 + molecular subtype were associated with lower adjusted mean self-reported cognition scores and higher impairment rates (p values < .05). Higher stage of disease was associated with lower objective performance in APE. Other tumor features were associated with cognition in unadjusted and adjusted models, including larger tumor size and lower PCI scores (p = 0.02). Tumor features were not related to LM., Conclusions: Pre-adjuvant therapy cognition was associated with HER2 positivity and higher stage of disease and other features of aggressive tumors. Additional research is needed to confirm these results and assess potential mechanisms and clinical management strategies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There are limited data on the cost-effectiveness of smoking cessation interventions in lung cancer screening settings. We conducted an economic analysis embedded in a national randomized trial of 2 telephone counseling cessation interventions., Methods: We used a societal perspective to compare the short-term cost per 6-month bio-verified quit and long-term cost-effectiveness of the interventions. Trial data were used to micro-cost intervention delivery, and the data were extended to a lifetime horizon using an established Cancer Intervention Surveillance and Modeling Network lung cancer model. We modeled the impact of screening accompanied by 8 weeks vs 3 weeks of telephone counseling (plus nicotine replacement) vs screening alone based on 2021 screening eligibility. Lifetime downstream costs (2021 dollars) and effects (life-years gained, quality-adjusted life-years [QALYs]) saved were discounted at 3%. Sensitivity analyses tested the effects of varying quit rates and costs; all analyses assumed nonrelapse after quitting., Results: The costs for delivery of the 8-week vs 3-week protocol were $380.23 vs $144.93 per person, and quit rates were 7.14% vs 5.96%, respectively. The least costly strategy was a 3-week counseling approach. An 8-week (vs 3-week) counseling approach increased costs but gained QALYs for an incremental cost-effectiveness ratio of $4029 per QALY. Screening alone cost more and saved fewer QALYs than either counseling strategy. Conclusions were robust in sensitivity analyses., Conclusions: Telephone-based cessation interventions with nicotine replacement are considered cost-effective in the lung screening setting. Integrating smoking cessation interventions with lung screening programs has the potential to maximize long-term health benefits at reasonable costs., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: Cancer patients are concerned about treatment-related cognitive problems. We examined effects of antiestrogen hormonal therapy on brain imaging metrics in older women with breast cancer., Methods: Women aged 60 + treated with hormonal therapy only and matched non-cancer controls (n = 29/group) completed MRI and objective and self-reported cognitive assessment at pre-treatment/enrollment and 12 months later. Gray matter was examined using voxel-based morphometry (VBM), FreeSurfer, and brain age calculations. Functional MRI (fMRI) assessed working memory-related activation. Analyses examined cross-sectional and longitudinal differences and tested associations between brain metrics, cognition, and days on hormonal therapy., Results: The cancer group showed regional reductions over 12 months in frontal, temporal, and parietal gray matter on VBM, reduced FreeSurfer cortical thickness in prefrontal, parietal, and insular regions, and increased working memory-related fMRI activation in frontal, cingulate, and visual association cortex. Controls showed only reductions in fusiform gyrus on VBM and FreeSurfer temporal and parietal cortex thickness. Women with breast cancer showed higher estimated brain age and lower regional gray matter volume than controls at both time points. The cancer group showed a trend toward lower performance in attention, processing speed, and executive function at follow-up. There were no significant associations between brain imaging metrics and cognition or days on hormonal therapy., Conclusion: Older women with breast cancer showed brain changes in the first year of hormonal therapy. Increased brain activation during working memory processing may be a sign of functional compensation for treatment-related structural changes. This hypothesis should be tested in larger samples over longer time periods., Gov Identifier: NCT03451383., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women., Objective: To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants., Design, Setting, and Participants: This comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985., Interventions: Screening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years., Main Outcomes and Measures: Estimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges., Results: The mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women., Conclusions and Relevance: This analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit.

Background: Early initiation of breast cancer screening is recommended for high-risk women, including survivors of childhood cancer treated with chest radiation. Recent studies suggest that female survivors of childhood leukemia or sarcoma treated without chest radiation are also at elevated early onset breast cancer risk. However, the potential clinical benefits and cost-effectiveness of early breast cancer screening among these women are uncertain., Methods: Using data from the Childhood Cancer Survivor Study, we adapted 2 Cancer Intervention and Surveillance Modeling Network simulation models to reflect the elevated risks of breast cancer and competing mortality among leukemia and sarcoma survivors. Costs and utility weights were based on published studies and databases. Outcomes included breast cancer deaths averted, false-positive screening results, benign biopsies, and incremental cost-effectiveness ratios., Results: In the absence of screening, the lifetime risk of dying from breast cancer among survivors was 6.8% to 7.0% across models. Early initiation of annual mammography with breast magnetic resonance imaging screening between ages 25 and 40 years would avert 52.6% to 64.3% of breast cancer deaths. When costs and quality-of-life impacts were considered, screening starting at age 40 years was the only strategy with an incremental cost-effectiveness ratio below the $100 000 per quality-adjusted life-year (QALY) gained cost-effectiveness threshold ($27 680 to $44 380 per QALY gained across models)., Conclusions: Among survivors of childhood leukemia or sarcoma, early initiation of breast cancer screening at age 40 years may reduce breast cancer deaths by half and is cost-effective. These findings could help inform screening guidelines for survivors treated without chest radiation., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: In 2021, the U.S. Preventive Services Task Force (USPSTF) revised its lung cancer screening recommendations expanding its eligibility. As more smokers become eligible, cessation interventions at the point of screening could enhance the benefits. Here, we evaluate the effects of joint screening and cessation interventions under the new recommendations., Methods: A validated lung cancer natural history model was used to estimate lifetime number of low-dose computed tomography screens, percentage ever screened, lung cancer deaths, lung cancer deaths averted, and life-years gained for the 1960 U.S. birth cohort aged 45 to 90 years (4.5 million individuals). Screening occurred according to the USPSTF 2013 and 2021 recommendations with varying uptake (0%, 30%, 100%), with or without a cessation intervention at the point of screening with varying effectiveness (15%, 100%)., Results: Screening 30% of the eligible population according to the 2021 criteria with no cessation intervention (USPSTF 2021, 30% uptake, without cessation intervention) was estimated to result in 6845 lung cancer deaths averted and 103,725 life-years gained. These represent 28% and 34% increases, respectively, relative to screening according to the 2013 guidelines (USPSTF 2013, 30% uptake, without cessation intervention). Adding a cessation intervention at the time of the first screen with 15% effectiveness (USPSTF 2021, 30% uptake, with cessation intervention with 15% effectiveness) was estimated to result in 2422 additional lung cancer deaths averted (9267 total, ∼73% increase versus USPSTF 2013, 30% uptake, without cessation intervention) and 322,785 life-years gained (∼318% increase). Screening 100% of the eligible according to the 2021 guidelines with no cessation intervention (USPSTF 2021, 100% uptake, without cessation intervention) was estimated to result in 23,444 lung cancer deaths averted (∼337% increase versus USPSTF 2013, 30% uptake, without cessation intervention) and 354,330 life-years gained (∼359% increase). Adding a cessation intervention with 15% effectiveness (USPSTF 2021, 100% uptake, with cessation intervention with 15% effectiveness) would result in 31,998 lung cancer deaths averted (∼497% increase versus USPSTF 2013, 30% uptake, without cessation intervention) and 1,086,840 life-years gained (∼1309% increase)., Conclusions: Joint screening and cessation interventions would result in considerable lung cancer deaths averted and life-years gained. Adding a one-time cessation intervention of modest effectiveness (15%) results in comparable life-years gained as increasing screening uptake from 30% to 100% because while cessation decreases mortality from many causes, screening only reduces lung cancer mortality. This simulation indicates that incorporating cessation programs into screening practice should be a priority as it can maximize overall benefits., (Copyright © 2021 International Association for the Study of Lung Cancer. All rights reserved.)