Real-world comparative effectiveness of mRNA-1273 and BNT162b2 vaccines among immunocompromised adults identified in administrative claims data in the United States.

INTRODUCTION: Head-to-head studies comparing COVID-19 mRNA vaccine effectiveness in immunocompromised individuals, who are vulnerable to severe disease are lacking, as large sample sizes are required to make meaningful inferences. METHODS: This observational comparative effectiveness study was conducted in closed administrative claims data from the US HealthVerity database (December 11, 2020-January 10, 2022, before omicron). A 2-dose mRNA-1273 versus BNT162b2 regimen was assessed for preventing medically-attended breakthrough COVID-19 diagnosis and hospitalizations among immunocompromised adults. Inverse probability of treatment weighting was applied to balance baseline characteristics between vaccine groups. Incidence rates from patient-level data and hazard ratios (HRs) using weighted Cox proportional hazards models were calculated. RESULTS: Overall, 57,898 and 66,981 individuals received a 2-dose regimen of mRNA-1273 or BNT161b2, respectively. Among the weighted population, mean age was 51 years, 53 % were female, and baseline immunodeficiencies included prior blood transplant (8%-9%), prior organ transplant (7%), active cancer (12%-13%), primary immunodeficiency (5-6%), HIV (20%-21%), and immunosuppressive therapy use (60%-61%). Rates per 1,000 person-years (PYs; 95% confidence intervals [CI]s) of breakthrough medically-attended COVID-19 were 25.82 (23.83-27.97) with mRNA-1273 and 30.98 (28.93, 33.18) with BNT162b2 (HR, 0.83; 95% CI, 0.75-0.93). When requiring evidence of an antigen or polymerase chain reaction test before COVID-19 diagnosis, the HR for medically-attended COVID-19 was 0.78 (0.67-0.92). Breakthrough COVID-19 hospitalization rates per 1,000 PYs (95% CI) were 3.66 (2.96-4.51) for mRNA-1273 and 4.68 (3.91-5.59) for BNT162b2 (HR, 0.78; 0.59-1.03). Utilizing open and closed claims for outcome capture only, or both cohort entry/outcome capture, produced HRs (95% CIs) for COVID-19 hospitalization of 0.72 (0.57-0.92) and 0.66 (0.58-0.76), respectively. CONCLUSIONS: Among immunocompromised adults, a 2-dose mRNA-1273 regimen was more effective in preventing medically-attended COVID-19 in any setting (inpatient and outpatient) than 2-dose BNT162b2. Results were similar for COVID-19 hospitalization, although statistical power was limited when using closed claims only. STUDY REGISTRATION: NCT05366322.

Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

Who Is Keeping Their Unused Opioids and Why?

OBJECTIVE: To better understand patients' reasoning for keeping unused opioid pills. METHODS: As part of a larger study, patients were asked their plans for their unused opioids. Responses were categorized as "dispose," "keep," and "don't know." Baseline characteristics were compared between the "keep" and "dispose" groups. Verbatim responses categorized as "keep" were analyzed qualitatively using a team-based inductive approach with constant comparison across cases. RESULTS: One hundred patients planned to dispose of their pills; 117 planned to keep them. There were no differences in demographics between the groups. Among patients who planned to keep their pills, the mean age was 43 years and 47% were male. Analysis revealed four categories of patient responses: 1) plans to keep their pills "just in case," with reference to a medical condition (e.g., kidney stone); 2) plans to keep pills "just in case" without reference to any medical condition; 3) plans to dispose in delayed fashion (e.g., after pill expiration) or unsure of how to dispose; and 4) no identified plans, yet intended to keep pills. In this sample, there were no differences in characteristics of those reporting planning to keep vs dispose of pills; however, there were diverse reasons for keeping opioids. CONCLUSIONS: This manuscript describes a sample of patients who kept their unused opioids and presents qualitative data detailing their personal reasoning for keeping the unused pills. Awareness of the range of motivations underpinning this behavior may inform the development of tailored education and risk communication messages to improve opioid disposal.

Test-retest reliability of the Newest Vital Sign health literacy instrument: In-person and remote administration.

OBJECTIVE: To determine the reliability of the Newest Vital Sign (NVS) administered via telephone by examining test-retest properties of the measure. METHODS: Data were obtained from a randomized controlled trial promoting opioid safe use. Participants were 18 or older and English-speaking. NVS assessment occurred in-person at baseline and in-person or via telephone at follow-up. Intraclass correlation coefficients (ICCs) were used to assess the test-retest reliability using raw NVS scores by mode of administration of the second NVS assessment. Kappa statistics were used to examine test-retest agreement based on categorized NVS score. Internal consistency was measured with Cronbach's alpha. RESULTS: Data from 216 patients (70 completing follow-up in-person and 146 via telephone) were included. Reliability was high (ICCs: in-person = 0.81, phone = 0.70). Agreement was lower for three category NVS score (Kappas: in-person = 0.58, 95% CI [0.39-0.77]; phone = 0.52, 95% CI [0.39-0.65]) compared to two category NVS (Kappas: in-person = 0.65, 95% CI [0.46-0.85]; phone = 0.64, 95% CI [0.51-0.78]). Correlations decreased as time between administrations increased. Internal consistency was moderately high (baseline NVS in-person (α = 0.76), follow-up NVS in-person (α = 0.76), and phone follow-up (α = 0.78). CONCLUSION: The test-retest properties of the NVS are similar by mode of administration. PRACTICE IMPLICATIONS: This data suggests the NVS measure is reliably administered by telephone.

Parent Preferences and Perceptions of Milliliters and Teaspoons: Role of Health Literacy and Experience.

BACKGROUND AND OBJECTIVES: A recent American Academy of Pediatrics policy statement recommends milliliter-exclusive dosing for pediatric liquid medications. Little is known about parent preferences regarding units, perceptions about moving to milliliters only, and the role of health literacy and prior milliliter-dosing experience. METHODS: Cross-sectional analysis of data collected as part of a randomized controlled study in 3 urban pediatric clinics (SAFE Rx for Kids study). English- and Spanish-speaking parents (n = 493) of children aged ≤8 years were randomized to 1 of 4 study arms and given labels and dosing tools which varied in label instruction format (text plus pictogram, text only) and units (milliliter only ["mL"], milliliter/teaspoon ["mL"/"tsp"]). Outcomes included teaspoon preference in dosing instructions and perceived difficulty with milliliter-only dosing. The predictor variable was health literacy (Newest Vital Sign; low [0-1], marginal [2-3], adequate [4-6]). The mediating variable was prior milliliter-dosing experience. RESULTS: Over two-thirds of parents had low or marginal health literacy. The majority (>70%) preferred to use milliliters, perceived milliliter-only dosing to be easy, and had prior milliliter-dosing experience; 11.5% had a teaspoon preference, 18.1% perceived milliliter-only dosing will be difficult, and 17.7% had no prior milliliter-dosing experience. Parents with lower health literacy had a higher odds of having a teaspoon preference (low vs adequate: adjusted odds ratio [AOR] = 2.9 [95% confidence interval [CI] 1.3-6.2]), and greater odds of perceiving difficulty with milliliter-only dosing (low vs adequate: AOR = 13.9 [95% CI 4.8-40.6], marginal vs adequate: AOR = 7.1 [95% CI 2.5-20.4]). Lack of experience with milliliter dosing partially mediated the impact of health literacy. CONCLUSIONS: Most parents were comfortable with milliliter-only dosing. Parents with low health literacy were more likely to perceive milliliter-only dosing to be difficult; educational efforts will need to target this group to ensure safe medication use.

Pictograms, Units and Dosing Tools, and Parent Medication Errors: A Randomized Study.

BACKGROUND AND OBJECTIVES: Poorly designed labels and dosing tools contribute to dosing errors. We examined the degree to which errors could be reduced with pictographic diagrams, milliliter-only units, and provision of tools more closely matched to prescribed volumes. METHODS: This study involved a randomized controlled experiment in 3 pediatric clinics. English- and Spanish-speaking parents (n = 491) of children ≤8 years old were randomly assigned to 1 of 4 groups and given labels and dosing tools that varied in label instruction format (text and pictogram, or text only) and units (milliliter-only ["mL"] or milliliter/teaspoon ["mL/tsp"]). Each parent measured 9 doses of liquid medication (3 amounts [2, 7.5, and 10 mL] and 3 tools [1 cup, 2 syringes (5- and 10-mL capacities)]) in random order. The primary outcome was dosing error (>20% deviation), and large error (>2× dose). RESULTS: We found that 83.5% of parents made ≥1 dosing error (overdosing was present in 12.1% of errors) and 29.3% of parents made ≥1 large error (>2× dose). The greatest impact on errors resulted from the provision of tools more closely matched to prescribed dose volumes. For the 2-mL dose, the fewest errors were seen with the 5-mL syringe (5- vs 10-mL syringe: adjusted odds ratio [aOR] = 0.3 [95% confidence interval: 0.2-0.4]; cup versus 10-mL syringe: aOR = 7.5 [5.7-10.0]). For the 7.5-mL dose, the fewest errors were with the 10-mL syringe, which did not necessitate measurement of multiple instrument-fulls (5- vs 10-mL syringe: aOR = 4.0 [3.0-5.4]; cup versus 10-mL syringe: aOR = 2.1 [1.5-2.9]). Milliliter/teaspoon was associated with more errors than milliliter-only (aOR = 1.3 [1.05-1.6]). Parents who received text only (versus text and pictogram) instructions or milliliter/teaspoon (versus milliliter-only) labels and tools made more large errors (aOR = 1.9 [1.1-3.3], aOR = 2.5 [1.4-4.6], respectively). CONCLUSIONS: Provision of dosing tools more closely matched to prescribed dose volumes is an especially promising strategy for reducing pediatric dosing errors.

Liquid Medication Dosing Errors by Hispanic Parents: Role of Health Literacy and English Proficiency.

OBJECTIVE: Hispanic parents in the United States are disproportionately affected by low health literacy and limited English proficiency (LEP). We examined associations between health literacy, LEP, and liquid medication dosing errors in Hispanic parents. METHODS: Cross-sectional analysis of data from a multisite randomized controlled experiment to identify best practices for the labeling/dosing of pediatric liquid medications (SAFE Rx for Kids study); 3 urban pediatric clinics. Analyses were limited to Hispanic parents of children aged ≤8 years with health literacy and LEP data (n = 1126). Parents were randomized to 1 of 5 groups that varied by pairing of units of measurement on the label/dosing tool. Each parent measured 9 doses (3 amounts [2.5, 5, 7.5 mL] using 3 tools [2 syringes in 0.2 or 0.5 mL increments, and 1 cup]) in random order. Dependent variable was a dosing error of >20% dose deviation. Predictor variables included health literacy (Newest Vital Sign) (limited = 0-3; adequate = 4-6) and LEP (speaks English less than "very well"). RESULTS: A total of 83.1% made dosing errors (mean [SD] errors per parent = 2.2 [1.9]). Parents with limited health literacy and LEP had the greatest odds of making a dosing error compared to parents with adequate health literacy who were English proficient (trials with errors per parent = 28.8 vs 12.9%; adjusted odds ratio = 2.2 [95% confidence interval 1.7-2.8]). Parents with limited health literacy who were English proficient were also more likely to make errors (trials with errors per parent = 18.8%; adjusted odds ratio = 1.4 [95% confidence interval 1.1-1.9]). CONCLUSIONS: Dosing errors are common among Hispanic parents; those with both LEP and limited health literacy are at particular risk. Further study is needed to examine how the redesign of medication labels and dosing tools could reduce literacy- and language-associated disparities in dosing errors.

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

Liquid Medication Errors and Dosing Tools: A Randomized Controlled Experiment.

BACKGROUND AND OBJECTIVES: Poorly designed labels and packaging are key contributors to medication errors. To identify attributes of labels and dosing tools that could be improved, we examined the extent to which dosing error rates are affected by tool characteristics (ie, type, marking complexity) and discordance between units of measurement on labels and dosing tools; along with differences by health literacy and language. METHODS: Randomized controlled experiment in 3 urban pediatric clinics. English- or Spanish-speaking parents (n = 2110) of children ≤8 years old were randomly assigned to 1 of 5 study arms and given labels and dosing tools that varied in unit pairings. Each parent measured 9 doses of medication (3 amounts [2.5, 5, and 7.5 mL] and 3 tools [1 cup, 2 syringes (0.2- and 0.5-mL increments)]), in random order. Outcome assessed was dosing error (>20% deviation; large error defined as > 2 times the dose). RESULTS: A total of 84.4% of parents made ≥1 dosing error (21.0% ≥1 large error). More errors were seen with cups than syringes (adjusted odds ratio = 4.6; 95% confidence interval, 4.2-5.1) across health literacy and language groups (P < .001 for interactions), especially for smaller doses. No differences in error rates were seen between the 2 syringe types. Use of a teaspoon-only label (with a milliliter and teaspoon tool) was associated with more errors than when milliliter-only labels and tools were used (adjusted odds ratio = 1.2; 95% confidence interval, 1.01-1.4). CONCLUSIONS: Recommending oral syringes over cups, particularly for smaller doses, should be part of a comprehensive pediatric labeling and dosing strategy to reduce medication errors.

Relationships between mammographic density, tissue microvessel density, and breast biopsy diagnosis.

BACKGROUND: Women with high levels of mammographic density (MD) have a four- to six-fold increased risk of developing breast cancer; however, most neither have a prevalent tumor nor will they develop one. Magnetic resonance imaging (MRI) studies suggest that background parenchymal enhancement, an indicator of vascularity, is related to increased breast cancer risk. Correlations of microvessel density (MVD) in tissue, MD and biopsy diagnosis have not been defined, and we investigated these relationships among 218 women referred for biopsy. METHODS: MVD was determined by counting CD31-positive vessels in whole sections of breast biopsies in three representative areas; average MVD was transformed to approximate normality. Using digital mammograms, we quantified MD volume with single X-ray absorptiometry. We used linear regression to evaluate associations between MVD and MD adjusted for age and body mass index (BMI) overall, and stratified by biopsy diagnosis: cases (in situ or invasive cancer, n = 44) versus non-cases (non-proliferative or proliferative benign breast disease, n = 174). Logistic regression adjusted for age, BMI, and MD was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between MVD and biopsy diagnosis. We also assessed whether the MVD-breast cancer association varied by MD. RESULTS: MVD and MD were not consistently associated. Higher MVD was significantly associated with higher odds of in situ/invasive disease (ORAdjusted = 1.69, 95 % CI = 1.17-2.44). MVD-breast cancer associations were strongest among women with greater non-dense volume. CONCLUSIONS: Increased MVD in tissues is associated with breast cancer, independently of MD, consistent with MRI findings suggestive of its possible value as a radiological cancer biomarker.

Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue.

Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure (p < 0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.

Relation of Serum Estrogen Metabolites with Terminal Duct Lobular Unit Involution Among Women Undergoing Diagnostic Image-Guided Breast Biopsy.

Higher levels of circulating estrogens and estrogen metabolites (EMs) have been associated with higher breast cancer risk. In breast tissues, reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have also been linked to elevated breast cancer risk. However, it is unknown whether reduced TDLU involution mediates the risk associated with circulating EMs. In a cross-sectional analysis of 94 premenopausal and 92 postmenopausal women referred for clinical breast biopsy at an academic facility in Vermont, we examined the associations of 15 EMs, quantified using liquid chromatography-tandem mass spectrometry, with the number of TDLUs and acini count/TDLU using zero-inflated Poisson regression with a robust variance estimator and ordinal logistic regression models, respectively. All analyses were stratified by menopausal status and adjusted for potential confounders. Among premenopausal women, comparing the highest vs. the lowest tertiles, levels of unconjugated estradiol (risk ratio (RR) = 1.74, 95 % confidence interval (CI) = 1.06-2.87, p trend = 0.03), 2-hydroxyestrone (RR = 1.74, 95 % CI = 1.01-3.01, p trend = 0.04), and 4-hydroxyestrone (RR = 1.74, 95 % CI = 0.99-3.06, p trend = 0.04) were associated with significantly higher TDLU count. Among postmenopausal women, higher levels of estradiol (RR = 2.09, 95 % CI = 1.01-4.30, p trend = 0.04) and 16α-hydroxyestrone (RR = 2.27, 95 % CI = 1.29-3.99, p trend = 0.02) were significantly associated with higher TDLU count. Among postmenopausal women, higher levels of EMs, specifically conjugated estrone and 2- and 4-pathway catechols, were also associated with higher acini count/TDLU. Our data suggest that higher levels of serum EMs are generally associated with lower levels of TDLU involution.

Effect of Medication Label Units of Measure on Parent Choice of Dosing Tool: A Randomized Experiment.

OBJECTIVE: Some experts recommend eliminating "teaspoon" and "tablespoon" terms from pediatric medication dosing instructions, because these terms could inadvertently encourage use of nonstandard tools (ie, kitchen spoons), which are associated with dosing errors. We examined whether use of "teaspoon" or "tsp" on prescription labels affects parents' choice of dosing tools, and the role of health literacy and language. METHODS: Analysis of data collected as part of a controlled experiment (SAFE Rx for Kids [Safe Administration For Every Prescription for Kids] study), which randomized English- and Spanish-speaking parents (n = 2110) of children 8 years of age and younger to 1 of 5 groups, which varied in unit of measurement pairings on medication labels and dosing tools. Outcome assessed was parent self-reported choice of dosing tool. Parent health literacy was measured using the Newest Vital Sign. RESULTS: Seventy-seven percent had limited health literacy (36.0% low, 41.0% marginal); 35.0% completed assessments in Spanish. Overall, 27.7% who viewed labels containing either "tsp" or "teaspoon" units (alone or with "mL") chose nonstandard dosing tools (ie, kitchen teaspoon, kitchen tablespoon), compared with 8.3% who viewed "mL"-only labels (adjusted odds ratio [AOR] = 4.4 [95% confidence interval (CI), 3.3-5.8]). Odds varied based on whether "teaspoon" was spelled out or abbreviated ("teaspoon"-alone: AOR = 5.3 [95% CI, 3.8-7.3]); "teaspoon" with mL: AOR = 4.7 [95% CI, 3.3-6.5]; "tsp" with mL: AOR = 3.3 [95% CI, 2.4-4.7]; P < .001). Similar findings were noted across health literacy and language groups. CONCLUSIONS: Use of teaspoon units ("teaspoon" or "tsp") on prescription labels is associated with increased likelihood of parent choice of nonstandard dosing tools. Future studies might be helpful to examine the real-world effect of eliminating teaspoon units from medication labels, and identify additional strategies to promote the safe use of pediatric liquid medications.

Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.

BACKGROUND: Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. METHODS: Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. RESULTS: Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. CONCLUSIONS: These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system.

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities.

Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLU), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (perilesional). Three measures inversely related to TDLU involution (TDLU count/mm(2), median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40-65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent perilesional MD (P trend = 0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P trend<0.05) and absolute perilesional MD (P = 0.003). Acini count was directly associated with absolute perilesional MD (P = 0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P trend ≤ 0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in perilesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction.

Leukocyte telomere length and its association with mammographic density and proliferative diagnosis among women undergoing diagnostic image-guided breast biopsy.

BACKGROUND: Elevated mammographic density (MD) is a strong breast cancer risk factor but the mechanisms underlying the association are poorly understood. High MD and breast cancer risk may reflect cumulative exposures to factors that promote epithelial cell division. One marker of cellular replicative history is telomere length, but its association with MD is unknown. We investigated the relation of telomere length, a marker of cellular replicative history, with MD and biopsy diagnosis. METHODS: One hundred and ninety-five women, ages 40-65, were clinically referred for image-guided breast biopsies at an academic facility in Vermont. Relative peripheral blood leukocyte telomere length (LTL) was measured using quantitative polymerase chain reaction. MD volume was quantified in cranio-caudal views of the breast contralateral to the primary diagnosis in digital mammograms using a breast density phantom, while MD area (cm(2)) was measured using thresholding software. Associations between log-transformed LTL and continuous MD measurements (volume and area) were evaluated using linear regression models adjusted for age and body mass index. Analyses were stratified by biopsy diagnosis: proliferative (hyperplasia, in-situ or invasive carcinoma) or non-proliferative (benign or other non-proliferative benign diagnoses). RESULTS: Mean relative LTL in women with proliferative disease (n = 141) was 1.6 (SD = 0.9) vs. 1.2 (SD = 0.6) in those with non-proliferative diagnoses (n = 54) (P = 0.002). Mean percent MD volume did not differ by diagnosis (P = 0.69). LTL was not associated with MD in women with proliferative (P = 0.89) or non-proliferative (P = 0.48) diagnoses. However, LTL was associated with a significant increased risk of proliferative diagnosis (adjusted OR = 2.46, 95% CI: 1.47, 4.42). CONCLUSIONS: Our analysis of LTL did not find an association with MD. However, our findings suggest that LTL may be a marker of risk for proliferative pathology among women referred for biopsy based on breast imaging.

Relationship of serum estrogens and metabolites with area and volume mammographic densities.

Elevated mammographic density is a breast cancer risk factor, which has a suggestive, but unproven, relationship with increased exposure to sex steroid hormones. We examined associations of serum estrogens and estrogen metabolites with area and novel volume mammographic density measures among 187 women, ages 40-65, undergoing diagnostic breast biopsies at an academic facility in Vermont. Serum parent estrogens, estrone and estradiol, and their 2-, 4-, and 16-hydroxylated metabolites were measured using liquid chromatography-tandem mass spectrometry. Area mammographic density was measured in the breast contralateral to the biopsy using thresholding software; volume mammographic density was quantified using a density phantom. Linear regression was used to estimate associations of estrogens with mammographic densities, adjusted for age and body mass index, and stratified by menopausal status and menstrual cycle phase. Weak, positive associations between estrogens, estrogen metabolites, and mammographic density were observed, primarily among postmenopausal women. Among premenopausal luteal phase women, the 16-pathway metabolite estriol was associated with percent area (p = 0.04) and volume (p = 0.05) mammographic densities and absolute area (p = 0.02) and volume (p = 0.05) densities. Among postmenopausal women, levels of total estrogens, the sum of parent estrogens, and 2-, 4- and 16-hydroxylation pathway metabolites were positively associated with area density measures (percent: p = 0.03, p = 0.04, p = 0.01, p = 0.02, p = 0.07; absolute: p = 0.02, p = 0.02, p = 0.01, p = 0.02, p = 0.03, respectively) but not volume density measures. Our data suggest that serum estrogen profiles are weak determinants of mammographic density and that analysis of different density metrics may provide complementary information about relationships of estrogen exposure to breast tissue composition.

Circulating sex hormones and terminal duct lobular unit involution of the normal breast.

BACKGROUND: Terminal duct lobular units (TDLU) are the predominant source of breast cancers. Lesser degrees of age-related TDLU involution have been associated with increased breast cancer risk, but factors that influence involution are largely unknown. We assessed whether circulating hormones, implicated in breast cancer risk, are associated with levels of TDLU involution using data from the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (2009-2011). METHODS: We evaluated three highly reproducible measures of TDLU involution, using normal breast tissue samples from the KTB (n = 390): TDLU counts, median TDLU span, and median acini counts per TDLU. RRs (for continuous measures), ORs (for categorical measures), 95% confidence intervals (95% CI), and Ptrends were calculated to assess the association between tertiles of estradiol, testosterone, sex hormone-binding globulin (SHBG), progesterone, and prolactin with TDLU measures. All models were stratified by menopausal status and adjusted for confounders. RESULTS: Among premenopausal women, higher prolactin levels were associated with higher TDLU counts (RRT3vsT1:1.18; 95% CI: 1.07-1.31; Ptrend = 0.0005), but higher progesterone was associated with lower TDLU counts (RRT3vsT1: 0.80; 95% CI: 0.72-0.89; Ptrend < 0.0001). Among postmenopausal women, higher levels of estradiol (RRT3vsT1:1.61; 95% CI: 1.32-1.97; Ptrend < 0.0001) and testosterone (RRT3vsT1: 1.32; 95% CI: 1.09-1.59; Ptrend = 0.0043) were associated with higher TDLU counts. CONCLUSIONS: These data suggest that select hormones may influence breast cancer risk potentially through delaying TDLU involution. IMPACT: Increased understanding of the relationship between circulating markers and TDLU involution may offer new insights into breast carcinogenesis. Cancer Epidemiol Biomarkers Prev; 23(12); 2765-73. ©2014 AACR.

Terminal duct lobular unit involution of the normal breast: implications for breast cancer etiology.

BACKGROUND: Greater degrees of terminal duct lobular unit (TDLU) involution have been linked to lower breast cancer risk; however, factors that influence this process are poorly characterized. METHODS: To study this question, we developed three reproducible measures that are inversely associated with TDLU involution: TDLU counts, median TDLU span, and median acini counts/TDLU. We determined factors associated with TDLU involution using normal breast tissues from 1938 participants (1369 premenopausal and 569 postmenopausal) ages 18 to 75 years in the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center. Multivariable zero-inflated Poisson models were used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) for factors associated with TDLU counts, and multivariable ordinal logistic regression models were used to estimate odds ratios (ORs) and 95% CIs for factors associated with categories of median TDLU span and acini counts/TDLU. RESULTS: All TDLU measures started declining in the third age decade (all measures, two-sided P trend ≤ .001); and all metrics were statistically significantly lower among postmenopausal women. Nulliparous women demonstrated lower TDLU counts compared with uniparous women (among premenopausal women, RR = 0.79, 95% CI = 0.73 to 0.85; among postmenopausal, RR = 0.67, 95% CI = 0.56 to 0.79); however, rates of age-related TDLU decline were faster among parous women. Other factors were related to specific measures of TDLU involution. CONCLUSION: Morphometric analysis of TDLU involution warrants further evaluation to understand the pathogenesis of breast cancer and assessing its role as a progression marker for women with benign biopsies or as an intermediate endpoint in prevention studies.

Comparison of mammographic density assessed as volumes and areas among women undergoing diagnostic image-guided breast biopsy.

BACKGROUND: Mammographic density (MD), the area of non-fatty-appearing tissue divided by total breast area, is a strong breast cancer risk factor. Most MD analyses have used visual categorizations or computer-assisted quantification, which ignore breast thickness. We explored MD volume and area, using a volumetric approach previously validated as predictive of breast cancer risk, in relation to risk factors among women undergoing breast biopsy. METHODS: Among 413 primarily white women, ages 40 to 65 years, undergoing diagnostic breast biopsies between 2007 and 2010 at an academic facility in Vermont, MD volume (cm(3)) was quantified in craniocaudal views of the breast contralateral to the biopsy target using a density phantom, whereas MD area (cm(2)) was measured on the same digital mammograms using thresholding software. Risk factor associations with continuous MD measurements were evaluated using linear regression. RESULTS: Percent MD volume and area were correlated (r = 0.81) and strongly and inversely associated with age, body mass index (BMI), and menopause. Both measures were inversely associated with smoking and positively associated with breast biopsy history. Absolute MD measures were correlated (r = 0.46) and inversely related to age and menopause. Whereas absolute dense area was inversely associated with BMI, absolute dense volume was positively associated. CONCLUSIONS: Volume and area MD measures exhibit some overlap in risk factor associations, but divergence as well, particularly for BMI. IMPACT: Findings suggest that volume and area density measures differ in subsets of women; notably, among obese women, absolute density was higher with volumetric methods, suggesting that breast cancer risk assessments may vary for these techniques.