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

  • Epidemiology
  • Published:
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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.

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Abbreviations

CI:

95 % confidence intervals

BBD:

Benign breast disease

BMI:

Body mass index

ER:

Estrogen receptor

MH:

Menopausal hormones

ORs:

Odds ratios

RR:

Relative risk

KTB:

Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center

TDLU:

Terminal duct-lobular unit

DCIS:

Ductal carcinoma in situ

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Acknowledgments

JDF would like to thank Montserrat Garcia-Closas for editorial comments on this work.

Funding suppport

This research was supported by Mayo Clinic Breast Specialized Programs of Research Excellence Grant NCI CA116201 (D.W.V., D.C.R., and L.C.H.), the Jimmy V Foundation (D.C.R. and L.C.H.), and ROI CA132879 (MHF). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Division of Cancer Epidemiology and Genetics.

Author contribution

JDF conceived the study, led its design and execution of the study, and interpretation, and drafted the manuscript. RMF provided expertise for the statistical analysis and interpretation of data, and drafted the manuscript. LAB provided expertise for the breast cancer epidemiology and drafted the manuscript. MMP performed statistical analysis and drafted the manuscript. ACD, DR, LCH, MHF, MLM, and DV conceived the study, and participated in its design and coordination and critical revision of the manuscript for intellectual content. DV, SMH and MES provided the expertise for pathology. DP and SMH helped to obtain pathologic annotation, coordination of design and execution of study, and participated in revision of the manuscript. MES conceived the study and study execution, interpreted the data, and drafted the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

    Jonine D. Figueroa, Ruth M. Pfeiffer, Louise A. Brinton, Maya M. Palakal, Daphne Papathomas & Gretchen L. Gierach

  2. Medical School, The Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK

    Jonine D. Figueroa

  3. Mayo Clinic Cancer Center, Rochester, MN, USA

    Amy C. Degnim, Derek Radisky, Lynn C. Hartmann, Marlene H. Frost, Melody L. Stallings Mann & Daniel Visscher

  4. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Stephen M. Hewitt

  5. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada

    Maire A. Duggan

  6. Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA

    Mark E. Sherman

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  1. Jonine D. Figueroa
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  2. Ruth M. Pfeiffer
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Correspondence to Jonine D. Figueroa.

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Figueroa, J.D., Pfeiffer, R.M., Brinton, L.A. et al. Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study. Breast Cancer Res Treat 159, 163–172 (2016). https://doi.org/10.1007/s10549-016-3908-7

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