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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.
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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.
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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.
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Neoplasias de la Mama , Detección Precoz del Cáncer , Mamografía , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Factores de Edad , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/diagnóstico por imagen , Técnicas de Apoyo para la Decisión , Reacciones Falso Positivas , Incidencia , Tamizaje Masivo , Uso Excesivo de los Servicios de Salud , Guías de Práctica Clínica como Asunto , Estados Unidos/epidemiología , Modelos EstadísticosAsunto(s)
Antiinflamatorios no Esteroideos , Aspirina , Neoplasias de la Mama , Anciano , Humanos , Factores de Edad , Envejecimiento , Aspirina/uso terapéutico , Estados Unidos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/prevención & control , Antiinflamatorios no Esteroideos/uso terapéuticoAsunto(s)
Envejecimiento , Neoplasias , Humanos , Neoplasias/epidemiología , Niño , Disparidades en Atención de SaludRESUMEN
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.
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Neoplasias de la Mama , Supervivientes de Cáncer , Disfunción Cognitiva , Hominidae , Humanos , Femenino , Animales , Anciano , Supervivientes de Cáncer/psicología , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/psicología , Estudios Prospectivos , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiologíaRESUMEN
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 48/100â¯000 women in 1975 and 27/100â¯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.
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Neoplasias de la Mama , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Mama/diagnóstico por imagen , Mama/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Detección Precoz del Cáncer , Historia del Siglo XX , Historia del Siglo XXI , Mamografía/métodos , Mortalidad/tendencias , Receptores de Estrógenos/metabolismo , Estados Unidos/epidemiología , Receptor ErbB-2/metabolismoRESUMEN
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.
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Neoplasias de la Mama , Mamografía , Femenino , Humanos , Anciano de 80 o más Años , Anciano , Mamografía/efectos adversos , Mamografía/métodos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Mama , Densidad de la Mama , Simulación por Computador , Detección Precoz del Cáncer/efectos adversos , Detección Precoz del Cáncer/métodos , Tamizaje Masivo/efectos adversos , Tamizaje Masivo/métodosRESUMEN
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.
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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 â1% 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.
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Neoplasias de la Mama , Disparidades en el Estado de Salud , Femenino , Humanos , Negro o Afroamericano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/terapia , Grupos Raciales , Estados Unidos/epidemiología , BlancoRESUMEN
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 (ß = 3.66; 95% CI, 2.47-4.85; P < .001), whereas those in the medium DAI group experienced 1.8 more years of EAA (ß = 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 (ß = 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 (ß = 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.
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Supervivientes de Cáncer , Enfermedad de Hodgkin , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Adulto , Masculino , Humanos , Estudios Transversales , Leucocitos Mononucleares , Envejecimiento , BiomarcadoresRESUMEN
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 100â¯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 100â¯000 persons eligible for screening. These rates corresponded with an estimated 1010 (range, 590-1480) lung cancer deaths prevented, 11â¯070 (range, 10â¯280-12â¯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 100â¯000 (range, 45â¯000-159â¯000) false-positive lung scans, 6000 (range, 6000-7000) colonoscopy complications, 300â¯000 (range, 295â¯000-302â¯000) false-positive mammograms, and 348â¯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.
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Neoplasias de la Mama , Neoplasias Colorrectales , Neoplasias Pulmonares , Neoplasias del Cuello Uterino , Adulto , Humanos , Femenino , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/prevención & control , Detección Precoz del Cáncer/métodos , Tamizaje Masivo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/prevención & control , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/prevención & control , Pulmón , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/prevención & controlRESUMEN
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.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Detección Precoz del Cáncer/métodos , Mamografía/métodos , Factores de Riesgo , Ultrasonografía Mamaria , Tamizaje Masivo/métodos , Densidad de la MamaRESUMEN
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.
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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.
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Neoplasias de la Mama , Supervivientes de Cáncer , Femenino , Humanos , Anciano , Lactante , Supervivientes de Cáncer/psicología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/psicología , Envejecimiento/genética , Sobrevivientes , Epigénesis Genética , Metilación de ADNRESUMEN
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.
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Neoplasias de la Mama , Supervivientes de Cáncer , Hominidae , Anciano , Femenino , Humanos , Persona de Mediana Edad , Biomarcadores , Supervivientes de Cáncer/psicología , Cognición , Interleucina-10 , Interleucina-6 , Factor de Necrosis Tumoral alfaRESUMEN
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.
Asunto(s)
Envejecimiento , Negro o Afroamericano , Supervivientes de Cáncer , Neoplasias , Racismo , Determinantes Sociales de la Salud , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Envejecimiento/etnología , Envejecimiento/fisiología , Negro o Afroamericano/estadística & datos numéricos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etnología , Neoplasias de la Mama/fisiopatología , Neoplasias/epidemiología , Neoplasias/etnología , Neoplasias/fisiopatología , Racismo/etnología , Racismo/estadística & datos numéricos , Determinantes Sociales de la Salud/etnología , Determinantes Sociales de la Salud/estadística & datos numéricos , Encuestas y Cuestionarios , Michigan/epidemiologíaRESUMEN
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.
RESUMEN
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.