Abstract 3486: Triple hormone receptor signatures as novel prognostic markers in breast cancer

Abstract

Abstract Background: Tumor phenotype across various cancers, including breast cancer, is predominantly shaped by a synergy between genomic alterations and the cell-of-origin from which the tumor originates. These elements collectively influence crucial aspects like tumor aggressiveness, treatment response, and patient prognosis. While existing research highlights that the role of cell-of-origin in shaping the molecular architecture of breast cancer, leveraging this information for actionable clinical insights has proven challenging. Here, we introduce two robust models leveraging cellular ancestry signatures of breast luminal cells to improve patient stratification and outcome prediction. Methods: In this study, we developed a unique gene signature anchored in the expression levels of triple hormone receptors (THR)—namely androgen (AR), estrogen (ER), and vitamin D (VDR)—in breast cancer cells. Building on this, we formulated two distinct mRNA markers, THR-50 and THR-70, aimed at categorizing breast tumors based on their THR expression profiles. These markers were rigorously validated across 65 independent breast cancer studies, involving a total of 6,679 patients, utilizing Kaplan-Meier survival curves, Cox proportional hazards models, and unsupervised clustering analyses. Results: Our findings indicate that both THR-50 and THR-70 are robustly associated with overall survival and recurrence-free survival in breast cancer patients across all datasets evaluated. Importantly, these THR signatures demonstrate broad applicability across various breast cancer subtypes, grades, and treatment phases—unlike existing prognostic markers that tend to be subtype-specific. Additionally, the THR signatures have revealed four unique patient clusters with divergent survival outcomes, three of which are ER-positive and one is ER-negative. Additionally, we developed an immune-based signature (i20) which can further categorize patients within the ER-negative cluster into two subgroups: one with a highly favorable prognosis, comparable to the ER-positive subtypes, and another that is characterized by exceedingly poor survival outcomes. Conclusion: The THR-based cellular ancestry signatures open a new avenue in understanding the intricacies of breast cancer biology. These signatures offer a robust and stable framework for developing other prognostic markers, thus providing an enhanced stratification of existing breast cancer categories as well as creating new classifications with more distinct survival estimates. Citation Format: Mohamed Omar, J. Chuck Harrell, Rulla M. Tamimi, Luigi Marchionni, Tan Ince. Triple hormone receptor signatures as novel prognostic markers in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3486.