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

Abstract

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.

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

“…Cases with low‐quality images or benign changes throughout the section (duct dilation, metaplasia, hyperplasia, microscopic evidence of ductal carcinoma in situ , or invasive cancer) were excluded. We used three standardized TDLU measures previously shown to have high intra/intra reader reproducibility: TDLU count per unit area (count/100 mm 2 ), TDLU span (measured with an electronic ruler in microns, μm), and acini count per TDLU, as an indication for involution (with higher levels of all 3 measures indicating lower levels of TDLU involution) . Among women with observable normal TDLUs, up to 10 sequential TDLUs were evaluated for acini count/TDLU (categories: 1, 2–10; 2, 11–20; 3, 21–30; 4, 31–50; 5, 51–100; and 6, >100) and TDLU span (μm).…”

“…Terminal duct lobular unit (TDLU) involution is a histological measure of breast tissue characterized by a reduction in the epithelial component with aging . Less extent of involution, characterized by greater number and size of observed TDLUs, has been associated with higher breast cancer risk among women with benign breast diseases . Previous studies conducted predominantly among white women using diagnostic biopsy specimens for benign breast diseases have demonstrated that reduced TDLU involution was associated with higher MD: women with no or partial involution were more likely to have higher percent MD or dense parenchymal patterns than those with complete involution .…”

Serum insulin‐like growth factor (IGF)‐I and IGF binding protein‐3 in relation to terminal duct lobular unit involution of the normal breast in Caucasian and African American women: The Susan G. Komen Tissue Bank

“…Higher TDLU count, higher acini count/TDLU, and higher product of the two measures indicate lesser degrees of TDLU involution and have previously been associated with higher breast cancer risk. 3 …”

“…However, levels of involution vary among women of similar ages and multiple studies have shown that having lesser degrees of age-related TDLU involution is a risk factor for subsequent breast cancer. 2, 3 Hence, evaluation of factors associated with TDLU involution may reveal underlying biological pathways related to breast cancer risk.…”

Matrix metalloproteases and TIMPs as prognostic biomarkers in breast cancer patients treated with radiotherapy: A pilot study

“…Breast lobules undergo age‐related lobular involution (ARLI) which begins around the age of 40 and accelerates after menopause. ARLI is associated with a lower risk of BC …”