Abstract 4632: Automated quantitative measures of terminal duct lobular unit involution and breast cancer risk
Authors: Kensler Kevin H. , Liu Emily Z. , Wetstein Suzanne C. , Onken Allison M. , Luffman Christina I. , Baker Gabrielle M. , Collins Laura C. , Schnitt Stuart J. , Bret-Mounet Vanessa C. , Veta Mitko , Pluim Josien P. , Liu Ying , Colditz Graham A. , Tamimi Rulla M. , Heng Yu Jing Jan 
Published: September 2020

Abstract
Background
Terminal duct lobular units (TDLUs) involute with age. Prior studies using qualitative or semi-quantitative measures of TDLU involution found inverse associations with breast cancer (BC) risk. We applied our validated deep learning computational method to yield quantitative measures of TDLU involution in normal breast tissue and then assessed their association with established BC risk factors and BC risk.
Materials and Methods
This study used a nested case-control design within the Nurses' Health Study cohorts. Cases and controls were diagnosed with benign breast disease (BBD) and cases subsequently developed BC (median 7.75 years later). Cases and controls were matched on year of BBD diagnosis, age at BC diagnosis (or index date for controls), and years between BBD and BC diagnosis (or index date).
We applied our computational method to 3951 whole slide images of normal breast tissue from BBD biopsies (287 cases and 1083 controls; median 3 images per woman). Quantitative estimates of TDLU involution were derived for 3 standardized measures (median TDLU span, TDLU count per non-adipose tissue area, median acini count) and 5 novel measures (median TDLU area, TDLU area as a percentage of total tissue area, TDLU area as a percentage of total non-adipose tissue area, acini count per non-adipose tissue area, median acini density). TDLU involution was also manually categorized in 177 cases and 857 controls.
Associations between TDLU involution measures and risk factors were evaluated among controls using Spearman's rho or Chi-squared tests. The relationship between each measure and BC risk was evaluated using logistic regression models controlling for the matching factors and BBD histological subtypes.
Results
All 8 TDLU measures were significantly inversely correlated with age at BBD biopsy (range: rho -0.07 to -0.42; p&lt;0.05) and menopausal status (p&lt;0.05). Parity was positively associated with 6 metrics (p&lt;0.05); birth index was inversely associated with another 6 metrics (p&lt;0.05). Select TDLU measures were also significantly associated with BBD histological subtype, BMI, age at first birth, and/or length of total breastfeeding (p&lt;0.05). No metric was significantly correlated with body size at ages 5-10 years or age of menarche. No quantitative TDLU involution measure was associated with subsequent BC risk; results remained null within strata of parity and menopausal status. Qualitative categorizations of TDLU involution were also not associated with BC risk (predominant lobule type 1 no type 3 versus no type 1, adjusted OR=0.95, 95%CI 0.54-1.71).
Conclusion
Quantitative measures of TDLU involution were associated with age and reproductive BC risk factors. However, automated and manual assessments of TDLU involution in normal tissue were not associated with BC risk. Further work will include applying our method to assess TDLU involution and BC risk in other cohorts.
Citation Format: Kevin H. Kensler, Emily Z. Liu, Suzanne C. Wetstein, Allison M. Onken, Christina I. Luffman, Gabrielle M. Baker, Laura C. Collins, Stuart J. Schnitt, Vanessa C. Bret-Mounet, Mitko Veta, Josien P. Pluim, Ying Liu, Graham A. Colditz, Rulla M. Tamimi, Yu Jing Jan Heng. Automated quantitative measures of terminal duct lobular unit involution and breast cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4632.