The Role of Apolipoprotein D in Tamoxifen Resistance Open Access

Klebaner, Daniella (2015)

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Background: Apoliprotein D (ApoD) has been proposed as an indicator of tamoxifen resistance among ER+ patients and a predictor of recurrence.

Methods: We conducted a large case-control study nested in a population of 11251 women aged 35-69 years at diagnosis with stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor-positive (ER+) disease treated with tamoxifen for at least 1 year and 300 cancers in women with ER-negative (ER-) disease never treated with tamoxifen. We matched one control subject per case patient on ER status, menopausal status, stage, calendar time, and county, and assessed ApoD expression in the tumor cell nucleus and cytoplasm using tissue microarray immunohistochemistry (TMA IHC). We estimated the odds ratio (OR) associating ApoD expression with breast cancer recurrence and adjusted for potential confounding with logistic regression. To address bias from potential exposure misclassification of ApoD expression, we used external validation data from TMA whole sections to complete a summary-level probabilistic bias analysis using Monte Carlo simulation.

Results: The frequency of cytoplasmic ApoD expression was 68% in case patients with ER+ tumors, 66% in case patients with ER- tumors, and 66% in control subjects with ER+ and ER- tumors. 39% of case patients with ER+ tumors, 29% of case patients with ER- tumors, and 39% and 26% of control subjects with ER+ and ER- tumors, respectively, had nuclear expression. In women with ER+ tumors, the associations of any cytoplasmic ApoD expression with recurrence (OR = 1.0; 95% confidence interval = 0.7 to 1.4) and increasing cytoplasmic expression with recurrence (OR = 1.0; 95% confidence interval = 1.0 to 1.0) were null, as were those for women with ER- tumors. Nuclear ApoD expression associations were similarly near-null, as were those for combined nuclear and cytoplasmic ApoD expression. All near-null associations persisted after probabilistic bias analysis, and in an analysis restricted to women with ER expression confirmed by re-assay.

Conclusion: The association between ApoD expression and recurrence in tamoxifen- treated patients is likely null or weak.

Table of Contents

Introduction. 1

Materials and Methods. 5

Patients. 5

Immunohistochemistry. 7

Scoring of TMA Cores. 8

Statistical Analysis. 11

Results. 15

Descriptive Statistics. 15

Stain Type Analysis. 18

Conventional Results. 20

Bias-Adjusted Results. 23

Discussion. 24

References. 28

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