Associations between quantitative measures of mammographic density and terminal ductal lobular unit involution in Chinese breast cancer patients.

BACKGROUND: Higher mammographic density (MD), a radiological measure of the proportion of fibroglandular tissue in the breast, and lower terminal duct lobular unit (TDLU) involution, a histological measure of the amount of epithelial tissue in the breast, are independent breast cancer risk factors. Previous studies among predominantly white women have associated reduced TDLU involution with higher MD. METHODS: In this cohort of 611 invasive breast cancer patients (ages 23-91 years [58.4% ≥ 50 years]) from China, where breast cancer incidence rates are lower and the prevalence of dense breasts is higher compared with Western countries, we examined the associations between TDLU involution assessed in tumor-adjacent normal breast tissue and quantitative MD assessed in the contralateral breast obtained from the VolparaDensity software. Associations were estimated using generalized linear models with MD measures as the outcome variables (log-transformed), TDLU measures as explanatory variables (categorized into quartiles or tertiles), and adjusted for age, body mass index, parity, age at menarche and breast cancer subtype. RESULTS: We found that, among all women, percent dense volume (PDV) was positively associated with TDLU count (highest tertile vs. zero: Expbeta = 1.28, 95% confidence interval [CI] 1.08-1.51, ptrend = < .0001), TDLU span (highest vs. lowest tertile: Expbeta = 1.23, 95% CI 1.11-1.37, ptrend = < .0001) and acini count/TDLU (highest vs. lowest tertile: Expbeta = 1.22, 95% CI 1.09-1.37, ptrend = 0.0005), while non-dense volume (NDV) was inversely associated with these measures. Similar trend was observed for absolute dense volume (ADV) after the adjustment of total breast volume, although the associations for ADV were in general weaker than those for PDV. The MD-TDLU associations were generally more pronounced among breast cancer patients ≥ 50 years and those with luminal A tumors compared with patients < 50 years and with luminal B tumors. CONCLUSIONS: Our findings based on quantitative MD and TDLU involution measures among Chinese breast cancer patients are largely consistent with those reported in Western populations and may provide additional insights into the complexity of the relationship, which varies by age, and possibly breast cancer subtype.

The relationship between terminal duct lobular unit features and mammographic density among Chinese breast cancer patients.

Extensive mammographic density (MD), a well-established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low-risk population but with high prevalence of dense breasts. Diagnostic pre-treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI-RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm2 , span [µm], and acini count/TDLU) in benign tissues. Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI-RADS, c-d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 µm [SE = 24.6] vs. 393.8 µm [SE = 31.8]; p = 0.03), and greater acini count (ORtrend = 16.1; 95%CI = 4.08-63.1; ptrend < 0.0001) compared to those with non-dense breasts (BI-RADS, a-b). Among women <50 years, 91% had dense breasts, precluding our ability to detect associations. Our findings are consistent with previously reported associations between extensive MD and reduced TDLU involution, supporting the hypothesis that breast cancer risk associated with extensive MD may be related to the amount of "at-risk" epithelium.

Associations between mammographic density and tumor characteristics in Chinese women with breast cancer.

PURPOSE: Mammographic density (MD) is a strong risk factor for breast cancer, yet its relationship with tumor characteristics is not well established, particularly in Asian populations. METHODS: MD was assessed from a total of 2001 Chinese breast cancer patients using Breast Imaging Reporting and Data System (BI-RADS) categories. Molecular subtypes were defined using immunohistochemical status on ER, PR, HER2, and Ki-67, as well as tumor grade. Multinomial logistic regression was used to test associations between MD and molecular subtype (luminal A = reference) adjusting for age, body mass index (BMI), menopausal status, parity, and nodal status. RESULTS: The mean age at diagnosis was 51.7 years (SD = 10.7) and the average BMI was 24.7 kg/m2 (SD = 3.8). The distribution of BI-RADS categories was 7.4% A = almost entirely fat, 24.2% B = scattered fibroglandular dense, 49.4% C = heterogeneously dense, and 19.0% D = extremely dense. Compared to women with BI-RADS = A/B, women with BI-RADS = D were more likely to have HER2-enriched tumors (OR = 1.81, 95% CI 1.08-3.06, p = 0.03), regardless of menopausal status. The association was only observed in women with normal (< 25 kg/m2) BMI (OR = 2.43, 95% CI 1.24-4.76, p < 0.01), but not among overweight/obese women (OR: 0.98, 95% CI 0.38-2.52, p = 0.96). CONCLUSIONS: Among Chinese women with normal BMI, higher breast density was associated with HER2-enriched tumors. The results may partially explain the higher proportion of HER2+ tumors previously reported in Asian women.

Positive childhood experiences and ideal cardiovascular health in midlife: Associations and mediators.

In 2010, the American Heart Association introduced a new conceptual framework to encourage a focus on primary prevention and provided a definition for "ideal cardiovascular health". In this study we examined the relationship between positive childhood experience and ideal cardiovascular health in mid-life, and the extent to which education, depression, and social support mediate this association. Data are from participants in the Midlife and Aging in the United States study who completed a clinic-based assessment of health (N=1255, aged 34-84years, 2004-2005). We created a positive childhood experiences index based on retrospective report of eight childhood experiences, and calculated a continuous ideal cardiovascular health score for each participant following the American Heart Association's definition of ideal, intermediate and poor cardiovascular health across seven health metrics (analyses conducted in 2015-2016). Positive childhood experiences were associated with ideal cardiovascular health: compared to individuals in the lowest quartile, respondents in the second, third, and fourth quartile of positive childhood experiences scored 0.42 (standard error (SE)=0.18), 0.92 (SE=0.18) and 1.04 (SE=0.18) units higher on ideal cardiovascular health, adjusting for age, sex, and race. Respondent's education, depression status, and social support fully mediated the direct effect of positive childhood experiences on ideal cardiovascular health, with the largest indirect effect for education. These results suggest that positive childhood experiences are associated with ideal cardiovascular health in midlife. Strategies to promote cardiovascular wellbeing may benefit from a focus on social interventions early in life; educational attainment, major depression, and social support may represent key points of intervention.

Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort.

Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6-6.44 years biologically older compared to controls and 5-16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging.

Blood-based biomarkers of frailty in solid tumors: a systematic review.

This review examines the current literature to identify biomarkers of frailty across patients with solid tumors. We conducted the systematic review using preferred reporting items for systematic reviews and meta-analysis guidelines (PRISMA). PubMed, Web of Science, and Embase databases were searched from their inception to December 08, 2021, for reports of biomarkers and frailty. Two reviewers independently screened titles, abstracts, and full-text articles. A quality assessment was conducted using NHLBI Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, and Quality Assessment of Case-Control Studies. In total, 915 reports were screened, and 14 full-text articles were included in the review. Most studies included breast tumors, were cross-sectional in design, and measured biomarkers at baseline or pre-treatment. Frailty tools varied with Fried Frailty Phenotype and the geriatric assessment most frequently used. Increased inflammatory parameters (i.e., Interleukin-6, Neutrophil Lymphocyte Ratio, Glasgow Prognostic Score-2) were associated with frailty severity. Only six studies were rated as good quality using assessment ratings. Together, the small number of studies and heterogeneity in frailty assessment limited our ability to draw conclusions from the extant literature. Future research is needed to identify potential target biomarkers of frailty in cancer survivors that may aid in early detection and referral.

Integrating sleep health into resilience research.

Sleep is a biological necessity that is a critical determinant of mental and physical well-being. Sleep may promote resilience by enhancing an individual's biological preparedness to resist, adapt and recover from a challenge or stressor. This report analyzes currently active National Institutes of Health (NIH) grants focussed on sleep and resilience, specifically examining the design of studies that explore sleep as a factor that promotes health maintenance, survivorship, or protective/preventive pathways. A search of NIH R01 and R21 research project grants that received funding in Fiscal Years (FY) 2016-2021 and focussed on sleep and resilience was conducted. A total of 16 active grants from six NIH institutes met the inclusion criteria. Most grants were funded in FY 2021 (68.8%), used the R01 mechanism (81.3%), were observational studies (75.0%), and measured resilience in the context of resisting a stressor/challenge (56.3%). Early adulthood and midlife were most commonly studied and over half of the grants focussed on underserved/underrepresented populations. NIH-funded studies focussed on sleep and resilience, or the ways in which sleep can influence an individual's ability to resist, adapt, or recover from a challenging event. This analysis highlights an important gap and the need to expand research focussed on sleep as a promotor of molecular, physiological, and psychological resilience.

Public Compliance With Social Distancing Measures and SARS-CoV-2 Spread : A Quantitative Analysis of 5 States.

OBJECTIVE: We quantified the association between public compliance with social distancing measures and the spread of SARS-CoV-2 during the first wave of the epidemic (March-May 2020) in 5 states that accounted for half of the total number of COVID-19 cases in the United States. METHODS: We used data on mobility and number of COVID-19 cases to longitudinally estimate associations between public compliance, as measured by human mobility, and the daily reproduction number and daily growth rate during the first wave of the COVID-19 epidemic in California, Illinois, Massachusetts, New Jersey, and New York. RESULTS: The 5 states mandated social distancing directives during March 19-24, 2020, and public compliance with mandates started to decrease in mid-April 2020. As of May 31, 2020, the daily reproduction number decreased from 2.41-5.21 to 0.72-1.19, and the daily growth rate decreased from 0.22-0.77 to -0.04 to 0.05 in the 5 states. The level of public compliance, as measured by the social distancing index (SDI) and daily encounter-density change, was high at the early stage of implementation but decreased in the 5 states. The SDI was negatively associated with the daily reproduction number (regression coefficients range, -0.04 to -0.01) and the daily growth rate (from -0.009 to -0.01). The daily encounter-density change was positively associated with the daily reproduction number (regression coefficients range, 0.24 to 1.02) and the daily growth rate (from 0.05 to 0.26). CONCLUSIONS: Social distancing is an effective strategy to reduce the incidence of COVID-19 and illustrates the role of public compliance with social distancing measures to achieve public health benefits.

Association of objectively measured sleep with frailty and 5-year mortality in community-dwelling older adults.

STUDY OBJECTIVES: To determine whether actigraphy-measured sleep was independently associated with risk of frailty and mortality over a 5-year period among older adults. METHODS: We used data from Waves 2 (W2) and 3 (W3) (2010-2015) of the National Social Life, Health and Aging Project, a prospective cohort of community-dwelling older adults born between 1920 and 1947. One-third of W2 respondents were randomly selected to participate in a sleep study, of whom N = 727 consented and N = 615 were included in the analytic sample. Participants were instructed to wear a wrist actigraph for 72 h (2.93 ± 0.01 nights). Actigraphic sleep parameters were averaged across nights and included total sleep time, percent sleep, sleep fragmentation index, and wake after sleep onset. Subjective sleep was collected via questionnaire. Frailty was assessed using modified Fried Frailty Index. Vital status was ascertained at the time of the W3 interview. W3 frailty/mortality status was analyzed jointly with a four-level variable: robust, pre-frail, frail, and deceased. Associations were modeled per 10-unit increase. RESULTS: After controlling for baseline frailty (robust and pre-frail categories), age, sex, education, body mass index, and sleep time preference, a higher sleep fragmentation index was associated with frailty (OR = 1.70, 95% CI: 1.02-2.84) and mortality (OR = 2.12, 95% CI: 1.09-4.09). Greater wake after sleep onset (OR = 1.24, 95% CI: 1.02-1.50) and lower percent sleep (OR = 0.41, 95% CI: 0.17-0.97) were associated with mortality. CONCLUSIONS: Among community-dwelling older adults, actigraphic sleep is associated with frailty and all-cause mortality over a 5-year period. Further investigation is warranted to elucidate the physiological mechanisms underlying these associations.

Quantitative Mammographic Density Measurements and Molecular Subtypes in Chinese Women With Breast Cancer.

Background: Studies investigating associations between mammographic density (MD) and breast cancer subtypes have generated mixed results. We previously showed that having extremely dense breasts was associated with the human epidermal growth factor receptor-2 (HER2)-enriched subtype in Chinese breast cancer patients. Methods: In this study, we reevaluated the MD-subtype association in 1549 Chinese breast cancer patients, using VolparaDensity software to obtain quantitative MD measures. All statistical tests were 2-sided. Results: Compared with women with luminal A tumors, women with luminal B/HER2- (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.04 to 1.38; P = .01), luminal B/HER2+ (OR = 1.22, 95% CI = 1.03 to 1.46; P = .03), and HER2-enriched tumors (OR = 1.30, 95% CI = 1.06 to 1.59; P = .01) had higher fibroglandular dense volume. These associations were stronger in patients with smaller tumors (<2 cm). In contrast, the triple-negative subtype was associated with lower nondense volume (OR = 0.82, 95% CI = 0.68 to 0.99; P = .04), and the association was only seen among older women (age 50 years or older). Conclusion: Although biological mechanisms remain to be investigated, the associations for the HER2-enriched and luminal B subtypes with increasing MD may partially explain the higher prevalence of luminal B and HER2+ breast cancers previously reported in Asian women.

Strategies to Prevent or Remediate Cancer and Treatment-Related Aging.

Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Experts assembled to share evidence of promising strategies to prevent, slow, or reverse the aging consequences of cancer and its treatment. The meeting identified research and resource needs, including geroscience-guided clinical trials; comprehensive assessments of functional, cognitive, and psychosocial vulnerabilities to assess and predict age-related outcomes; preclinical and clinical research to determine the optimal dosing for behavioral (eg, diet, exercise) and pharmacologic (eg, senolytic) therapies; health-care delivery research to evaluate the efficacy of integrated cancer care delivery models; optimization of intervention implementation, delivery, and uptake; and patient and provider education on cancer and treatment-related late and long-term adverse effects. Addressing these needs will expand knowledge of aging-related consequences of cancer and cancer treatment and inform strategies to promote healthy aging of cancer survivors.

Envisioning Arti's 'Cadillac study' to assess aging trajectories in cancer survivors.

The "Cadillac Study" was the term Arti Hurria, MD often used to articulate her vision of the optimal study to investigate the effects of cancer and its treatments on aging trajectories. In her opinion, this study needed to be designed for near-term clinical translation and have the ability to discern subpopulations of cancer survivors at greatest risk for poor outcomes. The purpose of this commentary is to describe, to the best of our knowledge, Arti's Cadillac Study based on personal conversations, group discussions, and her substantial portfolio of research. We describe the necessary study components of the Cadillac Study and discuss approaches to circumvent perceived barriers. In Arti's honor, our goal is to bring awareness and new perspectives to research on the aging consequences of cancer and cancer treatment to move the field forward.

Social Relationships and Functional Impairment in Aging Cancer Survivors: A Longitudinal Social Network Study.

BACKGROUND AND OBJECTIVES: The intersection of cancer, treatment, and aging accelerates functional decline. Social networks, through the provision of social support and resources, may slow the progression of functional deterioration. Socioemotional selectivity theory posits that aging and major life events, like cancer, cause an intentional social network pruning to procure and maintain emotionally fulfilling bonds, while shedding weaker, less supportive relationships. However, it is relatively unknown if such network changes impact functional impairment in cancer survivors. This study examined the relationships between changes in the egocentric social network and functional impairment in older adult cancer survivors and a similarly aged group without cancer (older adults). RESEARCH DESIGN AND METHODS: Data were analyzed from 1,481 community dwelling older adults (n = 201 cancer survivors) aged 57-85 years, from Waves 1 and 2 (2005-2006 and 2010-2011) of the National Social Life, Health and Aging Project. Associations were analyzed with multiple logistic regression. RESULTS: Cancer survivors and older adults reported similar levels of functional impairment and social network change. Adding 2 new relationships exhibited protective effects against functional impairment, irrespective of cancer status (odds ratio [OR]: 0.64, 95% confidence interval [CI]: 0.41-0.99). Declines in frequent contact were associated with higher odds of functional impairment among cancer survivors (OR: 1.92, 95% CI: 1.15-3.20). Social network components were not significantly associated with functional impairment in older adults. DISCUSSION AND IMPLICATIONS: Adding new relationships may reduce disability in older adults and increasing network contact may help cancer survivors remain independent. Social network interventions may improve quality of life for older adults.

Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study.

PURPOSE: To estimate the prevalence of frailty among childhood cancer survivors and to determine the direct and indirect effects of treatment exposures, lifestyle factors, and severe, disabling, and life-threatening chronic condition on frailty. METHODS: Childhood cancer survivors (≥ 5 years since diagnosis), treated between 1970 and 1999 when < 21 years old (n = 10,899; mean age, 37.6 ± 9.4 years; 48% male, 86% white) and siblings were included (n = 2,097; mean age, 42.9 ± 9.4 years). Frailty was defined as ≥ 3 of the following: low lean mass, exhaustion, low energy expenditure, walking limitations, and weakness. Generalized linear models were used to evaluate direct and indirect associations between frailty and treatment exposures, sociodemographic characteristics, lifestyle factors, and chronic condition. RESULTS: The overall prevalence of frailty among survivors was 3 times higher compared with siblings (6.4%; 95% CI, 4.1% to 8.7%; v 2.2%; 95% CI, 1.2% to 3.2%). Survivors of CNS tumors (9.5%; 95% CI, 5.2% to 13.8%) and bone tumors (8.1%; 95% CI, 5.1% to 11.1%) had the highest prevalence of frailty. Survivors exposed to cranial radiation, pelvic radiation ≥ 34 Gy, abdominal radiation > 40 Gy, cisplatin ≥ 600 mg/m2, amputation, or lung surgery had increased risk for frailty. These associations were partially but not completely attenuated when sociodemographic characteristics, lifestyle factors, and chronic conditions were added to multivariable models. Cranial radiation (prevalence ratio [PR], 1.47; 95% CI, 1.20 to 1.76), pelvic radiation ≥ 34 Gy (PR, 1.46; 95% CI, 1.01 to 2.11), and lung surgery (PR, 1.75; 95% CI, 1.28 to 2.38) remained significant after sociodemographic, lifestyle, and chronic conditions were accounted for. CONCLUSION: Childhood cancer survivors reported a higher prevalence of frailty compared with siblings. Radiation and lung surgery exposures were associated with increased risk for frailty. Interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to decrease the prevalence of frailty and preserve function in this at-risk population.

Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors.

Observational data have shown that some cancer survivors develop chronic conditions like frailty, sarcopenia, cardiac dysfunction, and mild cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to systemic or targeted cancer therapies. In aggregate, cancer- and treatment-related physical, cognitive, and psychosocial late- and long-term morbidities experienced by cancer survivors are hypothesized to represent accelerated or accentuated aging trajectories. However, conceptual, measurement, and methodological challenges have constrained efforts to identify, predict, and mitigate aging-related consequences of cancer and cancer treatment. In July 2018, the National Cancer Institute convened basic, clinical, and translational science experts for a think tank titled "Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors." Through the resulting deliberations, several research and resource needs were identified, including longitudinal studies to examine aging trajectories that include detailed data from before, during, and after cancer treatment; mechanistic studies to elucidate the pathways that lead to the emergence of aging phenotypes in cancer survivors; long-term clinical surveillance to monitor survivors for late-emerging effects; and tools to integrate multiple data sources to inform understanding of how cancer and its therapies contribute to the aging process. Addressing these needs will help expand the evidence base and inform strategies to optimize healthy aging of cancer survivors.

Breast cancer risk factors and mammographic density among high-risk women in urban China.

Elevated mammographic density (MD) is an established breast cancer risk factor. Studies examining relationships between MD and breast cancer risk factors are limited in China, where established breast cancer risk factors are less prevalent but dense breasts are more prevalent than Western countries. This study included 11,478 women (45-69 years; 36% premenopausal) participating in an ongoing national cancer screening program in 11 urban provinces in China and predicted as having high-risk for breast cancer. Polytomous logistic regression was performed to assess associations between MD and risk factors by comparing each higher Breast Imaging Reporting and Data System (BI-RADS) category (2, 3, or 4) to the lowest category (BI-RADS, 1). We found associations of increasing age, body mass index, weight, postmenopausal status, and parity with lower MD. Higher levels of education, increasing height, and later first birth were associated with higher MD. These associations did not vary by menopausal status. Additionally, the association between longer period of breastfeeding and lower MD was seen among postmenopausal women only (Pinteraction = 0.003). Having first-degree relatives with breast cancer diagnosed before 50 years was associated with lower MD only among premenopausal women (Pinteraction = 0.061). We found effects of established breast cancer risk factors on MD showed similar directions in Chinese and Western women, supporting the hypothesis that MD represents cumulative exposure to breast cancer risk factors over the life course. Our findings help to understand the biological basis of the association of MD with breast cancer risk and have implications for breast cancer prevention research in China.