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[Preprint]. 2023 Mar 22:rs.3.rs-2693555.
doi: 10.21203/rs.3.rs-2693555/v1.

Molecular Features of Androgen-Receptor Low, Estrogen Receptor-Negative Breast Cancers in the Carolina Breast Cancer Study

Nikita Jinna  1 , Sarah Van Alsten  2 , Padmashree Rida  3 , Victoria Seewaldt  1 , Melissa Troester  4
Affiliations

Molecular Features of Androgen-Receptor Low, Estrogen Receptor-Negative Breast Cancers in the Carolina Breast Cancer Study

Nikita Jinna et al. Res Sq. .

Update in

Abstract

Purpose: Androgen receptor (AR) expression is absent in 40-90% of estrogen receptor (ER)-negative breast cancers. The prognostic value of AR in ER-negative patients and therapeutic targets for patients absent in AR remains poorly explored.

Methods: We used an RNA-based multigene classifier to identify AR-low and AR-high ER-negative participants in the Carolina Breast Cancer Study (CBCS; n=669) and The Cancer Genome Atlas (TCGA; n=237). We compared AR-defined subgroups by demographics, tumor characteristics, and established molecular signatures [PAM50 risk of recurrence (ROR), homologous recombination deficiency (HRD), and immune response].

Results: AR-low tumors were more prevalent among Black (relative frequency difference (RFD) = +7%, 95% CI = 1% to 14%) and younger (RFD = +10%, 95% CI = 4% to 16%) participants in CBCS and were associated with HER2-negativity (RFD = -35%, 95% CI = -44% to -26%), higher grade (RFD = +17%, 95% CI = 8% to 26%), and higher risk of recurrence scores (RFD = +22%, 95% CI = 16.1% to 28%), with similar results in TCGA. The AR-low subgroup was strongly associated with HRD in CBCS (RFD = +33.3%, 95% CI = 23.8% to 43.2%) and TCGA (RFD = +41.5%, 95% CI = 34.0% to 48.6%). In CBCS, AR-low tumors had high adaptive immune marker expression.

Conclusion: Multigene, RNA-based low AR expression is associated with aggressive disease characteristics as well as DNA repair defects and immune phenotypes, suggesting plausible precision therapies for AR-low, ER-negative patients.

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Conflict of interest statement

Competing Interests

The University of North Carolina, Chapel Hill has a license of intellectual property interest in GeneCentric Diagnostics and BioClassifier, LLC, which may be used in this study. The University of North Carolina, Chapel Hill may benefit from this interest that is/are related to this research. The terms of this arrangement have been reviewed and approved by the University of North Carolina, Chapel Hill Conflict of Interest Program in accordance with its conflict of interest policies.

Figures

Figure 1
Figure 1. RNA Expression of androgen receptor (AR) correlates with AR protein levels in The Cancer Genome Atlas (N = 872).
Figure 2
Figure 2. Kernel density estimates of androgen receptor (AR) expression according to estrogen receptor (ER) status in 1202 Carolina Breast Cancer Study participants.
ER status assessed via central pathology review of immunohistochemistry. Dashed line is derived from finite mixture model of AR distribution in ER-negative samples, and represents cutpoint defining empirical AR groups.
Figure 3
Figure 3. Performance of expression-based low-androgen receptor (AR) classifier in estrogen receptor (ER) negative samples in the Carolina Breast Cancer Study (CBCS) samples.
A/B.Five-fold cross validated Youden’s index and sensitivity of Classification to Nearest Centroids classifier according to number of genes used to predict each AR phenotype. Confidence intervals represent mean plus or minus standard error. Blue lines represent predictions in the training set (N = 375–389), and red lines represent predictions in the test set (N = 93 – 97). C. Final performance of Youden’s Index-maximizing classifier using seven genes per group. Correct classifications are shown in green, while incorrect classifications are shown in red. Sensitivity was 86.8%, specificity was 87.5%, and overall accuracy was 87.1%. D. Principal component analysis based on RNA expression of classifier-selected genes in ER-negative CBCS samples. Red samples are those with low AR expression, and blue samples have high AR expression.
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