A population-level digital histologic biomarker for enhanced prognosis of invasive breast cancer.

Breast cancer is a heterogeneous disease with variable survival outcomes. Pathologists grade the microscopic appearance of breast tissue using the Nottingham criteria, which are qualitative and do not account for noncancerous elements within the tumor microenvironment. Here we present the Histomic Prognostic Signature (HiPS), a comprehensive, interpretable scoring of the survival risk incurred by breast tumor microenvironment morphology. HiPS uses deep learning to accurately map cellular and tissue structures to measure epithelial, stromal, immune, and spatial interaction features. It was developed using a population-level cohort from the Cancer Prevention Study-II and validated using data from three independent cohorts, including the Prostate, Lung, Colorectal, and Ovarian Cancer trial, Cancer Prevention Study-3, and The Cancer Genome Atlas. HiPS consistently outperformed pathologists in predicting survival outcomes, independent of tumor-node-metastasis stage and pertinent variables. This was largely driven by stromal and immune features. In conclusion, HiPS is a robustly validated biomarker to support pathologists and improve patient prognosis.

A population-level computational histologic signature for invasive breast cancer prognosis.

Breast cancer is a heterogeneous disease with variable survival outcomes. Pathologists grade the microscopic appearance of breast tissue using the Nottingham criteria, which is qualitative and does not account for non-cancerous elements within the tumor microenvironment (TME). We present the Histomic Prognostic Signature (HiPS), a comprehensive, interpretable scoring of the survival risk incurred by breast TME morphology. HiPS uses deep learning to accurately map cellular and tissue structures in order to measure epithelial, stromal, immune, and spatial interaction features. It was developed using a population-level cohort from the Cancer Prevention Study (CPS)-II and validated using data from three independent cohorts, including the PLCO trial, CPS-3, and The Cancer Genome Atlas. HiPS consistently outperformed pathologists' performance in predicting survival outcomes, independent of TNM stage and pertinent variables. This was largely driven by stromal and immune features. In conclusion, HiPS is a robustly validated biomarker to support pathologists and improve prognosis.

Racial Disparities in Flavored Tobacco Product Use, Curiosity, Susceptibility, and Harm Perception, National Youth Tobacco Survey 2019-2020.

Introduction: Studies characterizing differences in youth flavored tobacco product use prevalence, curiosity/susceptibility, and harm perceptions by race and ethnicity are limited. This study comprehensively examines flavored tobacco product use and harm perceptions among U.S. middle and high school students, by race and ethnicity. Methods: Data came from the 2019 (N=19,018) and 2020 (N=14,531) National Youth Tobacco Surveys (NYTS). Weighted prevalence estimates of flavored tobacco product use and curiosity, susceptibility, and harm perception are reported by race and ethnicity (non-Hispanic [NH] White, NH Black, Hispanic, or NH Other). t-Tests assessed differences in prevalence by years and racial/ethnic groups. Results: Among youth with past 30-day tobacco use, use of most flavored tobacco products increased across all racial/ethnic groups; the largest increase was observed among Hispanic youth using other flavored tobacco products (30.3%). The group with the highest susceptibility to future electronic cigarette (e-cigarette) use was Hispanic students (42.3%). Hispanic students had the highest curiosity about and susceptibility to future use of cigarettes and cigars as well. Conclusions: Increases in the use of and higher susceptibility to other flavored tobacco products, particularly among Hispanic youth, suggest a need for additional changes in environmental conditions and possibly targeted or tailored tobacco control interventions for Hispanic youth. Implications: Given that flavored tobacco use is prevalent among youth and aggressively marketed more to racial/ethnic minority populations, it is important to understand how susceptibility and perceptions relate to tobacco use. Our results suggest a need for a better understanding of social and environmental factors that drive tobacco use behaviors and perceptions, particularly among Hispanic youth, to address the root causes of these differences and create more equitable tobacco control interventions.

Youth Indoor and Outdoor Exposure to Secondhand Smoke and Secondhand Aerosol.

INTRODUCTION: Secondhand smoke and secondhand aerosol exposure are important public health concerns. This is the first study to present separate estimates of public indoor and outdoor secondhand smoke and secondhand aerosol exposure among U.S. youth. METHODS: Data came from the 2020 National Youth Tobacco Survey, an annual cross-sectional survey of U.S. students in Grades 6-12. Self-reported past 30-day indoor and outdoor secondhand smoke and secondhand aerosol exposures were assessed separately. Weighted prevalence and adjusted prevalence ratios for each outcome were assessed among students overall and stratified by sex, school level, race/ethnicity, sexual orientation, and current tobacco product use; prevalence also was calculated among those who did not currently use tobacco. RESULTS: Exposure to secondhand smoke and secondhand aerosol was reported by 60.6% (95% CI=58.7, 62.4) and 44.5% (95% CI=42.1, 46.9) of U.S. youth, respectively. Among all students, 37.6% (95% CI=36.0, 39.2) and 53.3% (95% CI=51.4, 55.2) reported indoor and outdoor secondhand smoke exposure, respectively; 34.9% (95% CI=32.9, 37.4) and 36.8% (95% CI=34.6, 38.9) reported indoor and outdoor secondhand aerosol exposure, respectively. After adjustment, female versus male students (adjusted prevalence ratio=1.15-1.30) and those who currently use versus do not use combustible tobacco products (adjusted prevalence ratio=1.15-1.36) were more likely to report exposure to all outcomes. CONCLUSIONS: Approximately 1 in 2 students overall reported outdoor secondhand smoke exposure, and 1 in 3 students reported exposures to each indoor secondhand smoke, indoor secondhand aerosol, and outdoor secondhand aerosol. Separate estimates of indoor and outdoor secondhand smoke and secondhand aerosol exposure, along with data on correlates of exposure, provide information to support comprehensive indoor and outdoor smoke-free policies.

Awareness and Use of Heated Tobacco Products Among Middle School and High School Students, United States, 2019-2020.

PURPOSE: Heated tobacco products (HTP) heat-processed tobacco leaf into an aerosol inhaled by the user. This study assessed prevalence and correlates of HTP awareness, ever use, and current use among US middle and high school students. METHODS: Data came from the 2019 and 2020 National Youth Tobacco Survey, a cross-sectional survey of US public and private, middle and high school students. HTP awareness, ever use, and current (past 30-day) use were assessed. Weighted prevalence estimates and adjusted prevalence ratios (aPR) were assessed overall and by sex, school level, race/ethnicity, and current other tobacco product use. RESULTS: In 2019, 12.8% (3.44 million) of all students reported HTP awareness, increasing to 19.3% (5.29 million) in 2020 (p < .01). Ever [2019: 2.6% (630 000); 2020: 2.4% (620 000)] and current [2019: 1.6% (420 000); 2020: 1.4% (370 000)] HTP use did not significantly change from 2019 to 2020. Current e-cigarette users were more likely to report ever (2020 aPR = 1.79, 95% CI:1.23, 2.62) or current HTP use (2019 aPR = 5.16, 95% CI: 3.48, 7.67; 2020 aPR = 3.39, 95% CI: 2.10, 5.47) than nonusers. In both years, ever and current HTP use was more likely among current combustible (aPR range = 3.59-8.17) and smokeless tobacco product (aPR range = 2.99-4.09) users than nonusers. CONCLUSIONS: HTP awareness increased 51% among US students during 2019-2020; however, HTP use did not significantly change during this period. Students who used other tobacco products were more likely to currently use HTPs. Estimates of HTP awareness and use provided serve as a baseline as future monitoring of these products is warranted. IMPLICATIONS: Awareness of heated tobacco products (HTPs) increased among US youth from 2019 to 2020; however, HTP use did not change. These estimates of HTP awareness and use serve as a baseline for future surveillance of these products as their availability in the US increases.

Use of Tobacco Products, Alcohol, and Other Substances Among High School Students During the COVID-19 Pandemic - Adolescent Behaviors and Experiences Survey, United States, January-June 2021.

The COVID-19 pandemic has been associated with established risk factors for adolescent substance use, including social isolation, boredom, grief, trauma, and stress. However, little is known about adolescent substance use patterns during the pandemic. CDC analyzed data from the Adolescent Behaviors and Experiences Survey, an online survey of a probability-based, nationally representative sample of public- and private-school students in grades 9-12 (N = 7,705), to examine the prevalence of current use of tobacco products, alcohol, and other substances among U.S. high school students. Prevalence was examined by demographic characteristics and instructional models of the students' schools (in-person, virtual, or hybrid). During January-June 2021, 31.6% of high school students reported current use of any tobacco product, alcohol, or marijuana or current misuse of prescription opioids. Current alcohol use (19.5%), electronic vapor product (EVP) use (15.4%), and marijuana use (12.8%) were more prevalent than prescription opioid misuse (4.3%), current cigarette smoking (3.3%), cigar smoking (2.3%), and smokeless tobacco use (1.9%). Approximately one third of students who used EVPs did so daily, and 22.4% of students who drank alcohol did so ≥6 times per month. Approximately one in three students who ever used alcohol or other drugs reported using these substances more during the pandemic. The prevalence of substance use was typically higher among non-Hispanic American Indian or Alaska Native students, older students, and gay, lesbian, or bisexual students than among students of other racial or ethnic groups, younger students, and heterosexual students. The prevalence of alcohol use also was higher among non-Hispanic White students than those of other racial or ethnic groups. Students only attending school virtually had a lower prevalence of using most of the substances examined than did students attending schools with in-person or hybrid models. These findings characterizing youth substance use during the pandemic can help inform public health interventions and messaging to address these health risks during and after the COVID-19 pandemic.

Breast cancer risk factors by mode of detection among screened women in the Cancer Prevention Study-II.

BACKGROUND: Identifying risk factors for women at high risk of symptom-detected breast cancers that were missed by screening would enable targeting of enhanced screening regimens. To this end, we examined associations of breast cancer risk factors by mode of detection in screened women from the Cancer Prevention Study (CPS)-II Nutrition Cohort. METHODS: Among 77,206 women followed for a median of 14.8 years, 2711 screen-detected and 1281 symptom-detected breast cancer cases were diagnosed. Multivariable-adjusted associations were estimated using joint Cox proportional hazards regression models with person-time calculated contingent on screening. RESULTS: Factors associated with higher risks of symptom-detected and screen-detected breast cancer included current combined hormone therapy (HT) use (HR 2.07, 95% CI 1.72-2.48 and 1.45, 1.27-1.65, respectively) and history of benign breast disease (1.85, 1.64-2.08 and 1.43, 1.31-1.55, respectively). Current estrogen-only HT use was associated with symptom-detected (1.40, 1.15-1.71) but not screen-detected (0.95, 0.83-1.09) breast cancer. Higher risk of screen-detected but not symptom-detected breast cancer was observed for obese vs. normal body mass index (1.22, 1.01-1.48 and 0.76, 0.56-1.01, respectively), per 3 h/day sitting time (1.10, 1.04-1.16 and 0.97, 0.89-1.06, respectively), and ≥ 2 drinks per day vs. nondrinker (1.40, 1.16-1.69 and 1.27, 0.97-1.66, respectively). CONCLUSIONS: Differences in risk factors for symptom-detected vs. screen-detected breast cancer were observed and most notably, use of combined and estrogen-only HT and a history of benign breast disease were associated with increased risk of symptomatic detected breast cancer. IMPACT: If confirmed, these data suggest that such women may benefit from more intensive screening to facilitate early detection.

Epidemiologic risk factors for in situ and invasive ductal breast cancer among regularly screened postmenopausal women by grade in the Cancer Prevention Study-II Nutrition Cohort.

PURPOSE: Histopathologic grade provides an integrated measure of biologic features which affects cancer prognosis. In invasive ductal breast cancer (IDBC), the grade of the ductal carcinoma in situ (DCIS) and invasive components are usually concordant, suggesting grade is established early in tumorigenesis and may be linked to etiologic factors. In this study, we used prospectively collected data from postmenopausal women in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort to compare risk factor associations among low-grade and high-grade DCIS, as well as low-grade and high-grade IDBC. METHODS: Among 73,825 cancer-free women at enrollment in the CPS-II Nutrition Cohort in 1992-1993 (mean age: 62.1 years), we verified 802 diagnosed with DCIS (C50 8500/2; n = 430 low-grade and 372 high-grade) and 3,125 with IDBC (C50 8500/3; n = 2,221 low-grade and 904 high-grade) through June 2013. Person-time contribution was conditional on screening mammograms self-reported on biennial surveys. Multivariable-adjusted joint Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: A personal history of benign breast disease was more strongly associated with higher risk of low-grade DCIS (HR = 2.20, 95% CI 1.81-2.67; p for heterogeneity = 0.0004) than high-grade DCIS. Consumption of two or more alcoholic drinks/day was only associated with a higher risk of low-grade IDBC (HR = 1.58, 95% CI 1.33-1.88; p for heterogeneity = 0.005). CONCLUSIONS: These results suggest heterogeneity by grade for breast cancer etiology. Identification of potential risk factor differences among low-grade and high-grade DCIS and IDBC may help to clarify associations, and ultimately, improve breast cancer risk prediction models.

Using Digital Pathology to Understand Epithelial Characteristics of Benign Breast Disease among Women Undergoing Diagnostic Image-Guided Breast Biopsy.

Delayed terminal duct lobular unit (TDLU) involution is associated with elevated mammographic breast density (MD). Both are independent breast cancer risk factors among women with benign breast disease (BBD). Prior digital analyses of normal breast tissues revealed that epithelial nuclear density (END) and TDLU involution are inversely correlated. Accordingly, we examined associations of END, TDLU involution, and MD in BBD clinical biopsies. This study included digitized images of 262 representative image-guided hematoxylin and eosin-stained biopsies from 224 women diagnosed with BBD, enrolled within the cross-sectional BREAST-Stamp project that were visually assessed for TDLU involution (TDLU count/100 mm2, median TDLU span and median acini count per TDLU). A digital algorithm estimated nuclei count per unit epithelial area, or END. Single X-ray absorptiometry of prebiopsy ipsilateral craniocaudal digital mammograms measured global and localized MD surrounding the biopsy region. Adjusted ordinal logistic regression models assessed relationships between tertiles of TDLU and END measures. Analysis of covariance examined mean differences in MD across END tertiles. TDLU measures were positively associated with increasing END tertiles [TDLU count/100 mm2, ORT3vsT1: 3.42, 95% confidence interval (CI), 1.87-6.28; acini count/TDLUT3vsT1, OR: 2.40, 95% CI, 1.39-4.15]. END was significantly associated with localized, but not, global MD. Relationships were most apparent among patients with nonproliferative BBD. These findings suggest that quantitative END reflects different but complementary information to the histologic information captured by visual TDLU and radiologic MD measures and merits continued evaluation in assessing cellularity of breast parenchyma to understand the etiology of BBD.

Oncotype DX recurrence score implications for disparities in chemotherapy and breast cancer mortality in Georgia.

Among women diagnosed with stage I-IIIa, node-negative, hormone receptor (HR)-positive breast cancer (BC), Oncotype DX recurrence scores (ODX RS) inform chemotherapy treatment decisions. Differences in recurrence scores or testing may contribute to racial disparities in BC mortality among women with HR+ tumors. We identified 12,081 non-Hispanic White (NHW) and non-Hispanic Black (NHB) BC patients in Georgia (2010-2014), eligible to receive an ODX RS. Logistic regression was used to estimate the odds of chemotherapy receipt by race and ODX RS. Cox proportional hazard regression was used to calculate the hazard ratios (HRs) comparing BC mortality rates by race and recurrence score. Receipt of Oncotype testing was consistent between NHB and NHW women. Receipt of chemotherapy was generally comparable within strata of ODX RS-although NHB women with low scores were slightly more likely to receive chemotherapy (OR = 1.16, 95% CI 0.77, 1.75), and NHB women with high scores less likely to receive chemotherapy (OR = 0.77, 95% CI 0.48, 1.24), than NHW counterparts. NHB women with a low recurrence score had the largest hazard of BC mortality (HR = 2.47 95% CI 1.22, 4.99) compared to NHW women. Our data suggest that additional tumor heterogeneity, or other downstream treatment factors, not captured by ODX, may be drivers of racial disparities in HR+ BC.

Mode of detection and breast cancer mortality by follow-up time and tumor characteristics among screened women in Cancer Prevention Study-II.

PURPOSE: In a screened population, breast cancer-specific mortality is lower for screen-detected versus symptom-detected breast cancers; however, it is unclear whether this association varies by follow-up time and/or tumor characteristics. To further understand the prognostic utility of mode of detection, we examined its association with breast cancer-specific mortality, overall and by follow-up time, estrogen receptor status, tumor size, and grade. METHODS: In the Cancer Prevention Study-II Nutrition Cohort, 3975 routinely screened women were diagnosed with invasive breast cancer (1992-2015). Among 2686 screen-detected and 1289 symptom-detected breast cancers, 206 and 209 breast cancer deaths, respectively, occurred up to 24 years post diagnosis. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from Cox proportional hazard regression models. RESULTS: Controlling for prognostic factors, symptom detection was associated with higher risk of breast cancer-specific death up to 5 years after diagnosis (HR≤5years = 1.88, 95% CI 1.21-2.91) this association was attenuated in subsequent follow-up (HR>5years = 1.26, 95% CI 0.98-1.63). Within tumor characteristic strata, there was a 1.3-2.7-fold higher risk of breast cancer death associated with symptom-detected cancers ≤ 5 years of follow-up, although associations were only significant for women with tumors < 2 cm (HR≤5years = 2.42, 95% CI 1.19-4.93) and for women with grade 1 or 2 tumors (HR≤5years = 2.72, 95% CI 1.33-5.57). In subsequent follow-up, associations were closer to the null. CONCLUSIONS: Screen detection is a powerful prognostic factor for short-term survival. Among women who survived at least 5 years after breast cancer diagnosis, other clinical factors may be more predictive of breast cancer survival.

PAM50 and Risk of Recurrence Scores for Interval Breast Cancers.

Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared with screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically screened women diagnosed with primary invasive breast cancer from 1993 to 2013 (n = 370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0 to 24 months before diagnosis, cancers were classified as screen-detected (N = 165) or interval-detected (N = 205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors [>2 cm; OR, 2.3; 95% confidence interval (CI), 1.5-3.7], positive nodal status (OR, 1.8; 95% CI, 1.1-2.8), and triple-negative subtype (OR, 2.5; 95% CI, 1.1-5.5). Interval cancers were more likely to have non-Luminal A subtype (OR, 2.9; 95% CI, 1.5-5.7), whereas screen-detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates. Cancer Prev Res; 11(6); 327-36. ©2018 AACR.

Stroma modifies relationships between risk factor exposure and age-related epithelial involution in benign breast.

Delayed age-related lobular involution has been previously associated with elevated breast cancer risk. However, intraindividual variability in epithelial involution status within a woman is undefined. We developed a novel measure of age-related epithelial involution, density of epithelial nuclei in epithelial areas using digital image analysis in combination with stromal characteristics (percentage of section area comprising stroma). Approximately 1800 hematoxylin and eosin stained sections of benign breast tissue were evaluated from 416 participants having breast surgery for cancer or benign conditions. Two to sixteen slides per woman from different regions of the breast were studied. Epithelial involution status varied within a woman and as a function of stromal area. Percentage stromal area varied between samples from the same woman (median difference between highest and lowest stromal area within a woman was 7.5%, but ranged from 0.01 to 86.7%). Restricting to women with at least 10% stromal area (N = 317), epithelial nuclear density decreased with age (-637.1 cells/mm2 per decade of life after age 40, p < 0.0001), increased with mammographic density (457.8 cells/mm2 per increasing BI-RADs density category p = 0.002), and increased non-significantly with recent parity, later age at first pregnancy, and longer and more recent oral contraceptive use. These associations were attenuated in women with mostly fat samples (<10% stroma (N = 99)). Thirty-one percent of women evaluated had both adequate stroma (≥10%) and mostly fat (<10% stroma) regions of breast tissue, with the probability of having both types increasing with the number breast tissue samplings. Several breast cancer risk factors are associated with elevated age-related epithelial content, but associations depend upon stromal context. Stromal characteristics appear to modify relationships between risk factor exposures and breast epithelial involution.

Mammary Gland Evaluation in Juvenile Toxicity Studies: Temporal Developmental Patterns in the Male and Female Harlan Sprague-Dawley Rat.

There are currently no reports describing mammary gland development in the Harlan Sprague-Dawley (HSD) rat, the current strain of choice for National Toxicology Program (NTP) testing. Our goals were to empower the NTP, contract labs, and other researchers in understanding and interpreting chemical effects in this rat strain. To delineate similarities/differences between the female and male mammary gland, data were compiled starting on embryonic day 15.5 through postnatal day 70. Mammary gland whole mounts, histology sections, and immunohistochemically stained tissues for estrogen, progesterone, and androgen receptors were evaluated in both sexes; qualitative and quantitative differences are highlighted using a comprehensive visual timeline. Research on endocrine disrupting chemicals in animal models has highlighted chemically induced mammary gland anomalies that may potentially impact human health. In order to investigate these effects within the HSD strain, 2,3,7,8-tetrachlorodibenzo-p-dioxin, diethylstilbestrol, or vehicle control was gavage dosed on gestation day 15 and 18 to demonstrate delayed, accelerated, and control mammary gland growth in offspring, respectively. We provide illustrations of normal and chemically altered mammary gland development in HSD male and female rats to help inform researchers unfamiliar with the tissue and may facilitate enhanced evaluation of both male and female mammary glands in juvenile toxicity studies.

Self-regulatory failure and the perpetration of adolescent dating violence: Examining an alcohol use by gene explanation.

Studies report that alcohol use is related to partner violence, but for many, alcohol use does not culminate in violence against partners. Guided by a self-regulatory failure framework, we predicted that alcohol use would be more strongly associated with dating violence perpetration among adolescents with genotypes linked to impulsivity and emotional reactivity. The hypothesis was tested using random coefficient modeling of data from a multi-wave longitudinal study spanning grades 8-12 (ages 13-18) (n = 1,475). Analyses adjusted for multiple testing and race, and the potential for gene by environment correlation was examined. As predicted, alcohol use was more strongly associated with dating violence among adolescents who had a high rather than a low multilocus genetic profile composed of five genetic markers that influence dopamine signaling. Alcohol use was more strongly related to dating violence among boys with long rather than short 5-HTTLPR alleles, the opposite of the prediction. MAOA-uVNTR did not interact with alcohol, but it had a main effect on dating violence by boys in later grades in the expected direction: boys with more low activity alleles perpetrated more dating violence. Exploratory analyses found variation in findings by race. Our findings demonstrate the importance of incorporating genes into etiological studies of adolescent dating violence, which to date has not been done. Aggr. Behav. Aggr. Behav. 42:189-203, 2015. © 2014 Wiley Periodicals, Inc.