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

Gierach, Gretchen L.; Patel, Deesha A.; Pfeiffer, Ruth M.; Figueroa, Jonine D.; Linville, Laura; Papathomas, Daphne; Johnson, Jason M.; Chicoine, Rachael E.; Herschorn, Sally D.; Shepherd, John; Wang, Jeff; Malkov, Serghei; Vacek, Pamela M.; Weaver, Donald L.; Fan, Bo; Mahmoudzadeh, Amir Pasha; Palakal, Maya; Xiang, Jackie; Oh, Hyuncheol; Horne, Hisani N.; Sprague, Brian L.; Hewitt, Stephen M.; Brinton, Louise A.; Sherman, Mark E.

doi:10.1158/1940-6207.capr-15-0282

Cited by 46 publications

(92 citation statements)

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“…This work extends prior research in this cohort linking decreased TDLU involution to increased risk of developing breast cancer [7, 15]. We note that several groups have developed automated methods to assess TDLU histology and to estimate levels of involution [15, 17, 18, 33, 34] that agree well with visual assessment. Hence, we view visual assessment of involution levels as a temporary approach to advance this area as automated algorithms are developed.…”

Section: Discussionsupporting

confidence: 80%

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

Figueroa

Pfeiffer

Brinton

et al. 2016

Breast Cancer Res Treat

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Lesser degrees of terminal duct-lobular unit (TDLU) involution predict higher breast cancer risk; however, standardized measures to quantitate levels of TDLU involution have only recently been developed. We assessed whether three standardized measures of TDLU involution, with high intra/inter pathologist reproducibility in normal breast tissue, predict subsequent breast cancer risk among women in the Mayo benign breast disease (BBD) cohort. We performed a masked evaluation of biopsies from 99 women with BBD who subsequently developed breast cancer (cases) after a median of 16.9 years and 145 age-matched controls. We assessed three metrics inversely related to TDLU involution: TDLU count/mm2, median TDLU span (microns, which approximates acini content), and median category of acini counts/TDLU (0–10; 11–20; 21–30; 31–50; >50). Associations with subsequent breast cancer risk for quartiles (or categories of acini counts) of each of these measures were assessed with multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI). In multivariable models, women in the highest quartile compared to the lowest quartiles of TDLU counts and TDLU span measures were significantly associated with subsequent breast cancer diagnoses; TDLU counts quartile4 versus quartile1, OR = 2.44, 95 %CI 0.96–6.19, p-trend = 0.02; and TDLU spans, quartile4 versus quartile1, OR = 2.83, 95 %CI = 1.13–7.06, p-trend = 0.03. Significant associations with categorical measures of acini counts/TDLU were also observed: compared to women with median category of <10 acini/TDLU, women with >25 acini counts/TDLU were at significantly higher risk, OR = 3.40, 95 %CI 1.03–11.17, p-trend = 0.032. Women with TDLU spans and TDLU count measures above the median were at further increased risk, OR = 3.75 (95 %CI 1.40–10.00, p-trend = 0.008), compared with women below the median for both of these metrics. Similar results were observed for combinatorial metrics of TDLU acini counts/TDLU, and TDLU count. Standardized quantitative measures of TDLU counts and acini counts approximated by TDLU span measures or visually assessed in categories are independently associated with breast cancer risk. Visual assessment of TDLU numbers and acini content, which are highly reproducible between pathologists, could help identify women at high risk for subsequent breast cancer among the million women diagnosed annually with BBD in the US.

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Section: Discussionsupporting

confidence: 80%

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

Figueroa

Pfeiffer

Brinton

et al. 2016

Breast Cancer Res Treat

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“…In the studies of urinary EMs and mammographic density [37,38], 2-pathway catechols in premenopausal women were suggestively positively associated with higher percent mammographic density [37] and the ratios of 2-, 4-, and 16-pathway EMs to parent estrogens in postmenopausal women were inversely associated with percent and absolute dense area [38]. Previous data suggest that TDLU involution is inversely related to mammographic density [39,26], suggesting that further etiologic research incorporating hormone measures with these features of breast composition are warranted.…”

Section: Discussionmentioning

confidence: 99%

“…TDLU assessment was performed as described previously [20,26]. Briefly, hematoxylin and eosin (H&E) stained sections were digitized at 20× magnification (Aperio ScanScope CS, Vista, CA) and evaluated using a web-based system (Digital Image Hub software; SlidePath/Leica, Dublin, Ireland).…”

Section: Methodsmentioning

confidence: 99%

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

Khodr

Sherman

et al. 2016

HORM CANC

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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 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. 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.

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“…Absolute lesional volume (cm 3 ) and percent lesional volume were estimated using SXA within the biopsy target, centered at the biopsy site [9]. A repeat set of 25 images was assessed for reliability.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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BackgroundWomen 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.MethodsMVD 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.ResultsMVD 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.ConclusionsIncreased 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0746-9) contains supplementary material, which is available to authorized users.

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

Cited by 46 publications

References 36 publications

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

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

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

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