Abstract 876: TP53 pathway function, estrogen receptor status, and breast cancer risk factors in the Carolina Breast Cancer Study
Authors: Hurson Amber N. , Abubakar Mustapha , Conway-Dorsey Kathleen , Hoadley Katherine , Love Michael I. , Olshan Andrew F. , Garcia-Closas Montserrat , Troester Melissa A. 
Published: July 2021

Abstract
Purpose: TP53 and estrogen receptor (ER) both play essential roles in breast cancer development and progression, with recent research revealing crosstalk between TP53 and ER signaling pathways. While many studies have demonstrated heterogeneity of risk factor associations across ER subtypes, TP53 status has been inconsistently linked to breast cancer risk factors. This may be due to few studies evaluating TP53 effects in the context of ER. Additionally, studies have generally classified TP53 status using immunohistochemistry (IHC) staining or DNA sequencing, which are prone to misclassification of TP53 pathway function. RNA-based methods of measuring TP53 pathway activity may reduce misclassification and clarify etiologic associations.
Methods: This case-only analysis included 4,466 incident breast cancer cases from the Carolina Breast Cancer Study (1993-2013). Using RNA expression previously quantified using NanoString assays on FFPE tumor samples, tumors were classified for TP53 functional status (mutant-like or wildtype-like) using a validated 52-gene RNA signature. We used a two-stage polytomous logistic regression model to evaluate sources of risk factor heterogeneity due to RNA-based TP53 or ER, adjusting for each other and for PR, HER2, and grade, while accounting for missing tumor marker data. Risk factor heterogeneity was also evaluated for IHC-based TP53 and ER. For each risk factor, joint effects of TP53 and ER were evaluated by allowing for an interaction between the two markers.
Results: When classifying TP53 status using the RNA signature, the effects of several hormone-related factors (oral contraceptive use, menopausal status, age at menopause, and pre- and post-menopausal BMI) were heterogeneous across TP53 subtypes, while heterogeneity of reproductive factors (age at first birth and parity) and smoking status was observed across ER subtypes. The effect of number of births was heterogenous across both TP53 and ER-based subtype definitions. Additionally, we observed an interaction between RNA-based TP53 and ER status with family history of breast cancer in a first-degree relative (p=0.05). When classifying TP53 status using IHC, the TP53 effects were not recapitulated but there was minimal change in the ER effects. We observed an interaction between IHC-based TP53 and ER status with age at menarche (p=0.02), smoking status (p=0.05), and alcohol use (p=0.06).
Conclusions: This study demonstrates that TP53 and ER are valuable for defining etiologic subtypes of breast cancer, although IHC measures may not have as much value as RNA. Analyses of the joint effects of TP53 and ER with breast cancer risk factors revealed intriguing findings that could lead to new hypotheses. However, larger studies incorporating multiple correlated tumor characteristics will be required to confirm our findings to conclusively define etiologically relevant subtypes of breast cancer.
Citation Format: Amber N. Hurson, Mustapha Abubakar, Kathleen Conway-Dorsey, Katherine Hoadley, Michael I. Love, Andrew F. Olshan, Montserrat Garcia-Closas, Melissa A. Troester. TP53 pathway function, estrogen receptor status, and breast cancer risk factors in the Carolina Breast Cancer Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 876.