Abstract C024: Evaluation of PI3K/AKT/mTOR pathway signaling as a prognostic indicator in Hispanic Mexican women with breast cancer
Authors: Martinez Mario Morales , Soca-Chafre Giovanny , Maldonado-Valenzuela Altagracias , Rivera-Pazos Clara M , Antonio-Andres Gabriela , Montecillo-Aguado Mayra , Rocha-Lopez Georgina , Alcala-Mota-Velazco Berenice , Gomez-Garcia Anel , Wadehra Madhuri , Pietras Richard J , Gutierrez-Castro Sergio , Huerta-Yepez Sara , Marquez-Garban Diana 
Published: September 2024

Abstract
Breast cancer (BC) is among the most commonly diagnosed cancer in women and a leading cause of cancer death worldwide. Hispanic/Latina women represent a heterogeneous group with diverse genetic backgrounds, including varying proportions of Native American, European, African and to a lesser extent Asian ancestry. In the US, Hispanic and African American women have lower BC incidence overall yet higher incidence of triple negative breast cancer (TNBC). Furthermore, African American and Hispanic women tend to present with more aggressive disease, at younger ages and worse survival compared to women of European ancestry. These disparities have been attributed to biologic and non-biologic socioeconomic factors. Genomic analyses of Hispanic Mexican (HM) women have revealed specific genetic signatures distinct from those of non-Hispanic women. These variations include AKT kinase mutations activating PI3K/AKT/mTOR signaling pathway and PI3KCA mutations which could potentially benefit from targeted therapies. 4EBP1 phosphorylation by mTORC1 is generally considered a marker of activated mTOR signaling and high levels in tumors associate with worse outcomes in different cancers. To evaluate clinical significance of PI3KCA expression and PI3K/AKT/mTOR signaling, we performed immunohistochemical (IHC) analyses of tissue microarrays (TMA) including 272 BC patient samples from HM women. Protein expression of PI3KCA and p4EBP1 were evaluated quantitatively by receiver operator characteristics (ROC) curves based on area under the curve (AUC) as well as sensibility and specificity. p4EBP1 levels were associated with clinicopathological characteristics. Chi-squared and Fisher’s Exact tests showed higher p4EBP1 expression correlated with estrogen (P=0.001) and progesterone receptor negative BC (P=0.003), TNBC (P&lt;0.001), tumor size (P&lt;0.090), and advanced stage (P&lt;0.001). PI3KCA expression was positively correlated with 4EBP1 expression (P=0.044) as shown by Mann Whitney U tests; but PI3KCA lacked prognostic value after screening through ROC curves. However, uni- and multi-variate Cox regression analyses did show that increased 4EBP1 expression correlates with worse OS. Overall, our study indicates that higher p4EBP1 expression is an independent prognostic factor of worse OS in BC patients. The activation of 4EBP1 may result from several upstream oncogenic alterations or mutations, representing a potential therapeutic target and biomarker. Further research is necessary to better define biological differences in Hispanic women to advance understanding and targeting of health disparities. [Funded by California Breast Cancer Research Program Idea Award B27IB3869, JCCC Breast Cancer Award, Hickey Family Foundation, NCI U54 CA143930, Team Research Grant, UCLA TDG, CIRM DISC2-14166].
Citation Format: Mario Morales Martinez, Giovanny Soca-Chafre, Altagracias Maldonado-Valenzuela, Clara M Rivera-Pazos, Gabriela Antonio-Andres, Mayra Montecillo-Aguado, Georgina Rocha-Lopez, Berenice Alcala-Mota-Velazco, Anel Gomez-Garcia, Madhuri Wadehra1, Richard J Pietras, Sergio Gutierrez-Castro, Sara Huerta-Yepez, Diana Marquez-Garban. Evaluation of PI3K/AKT/mTOR pathway signaling as a prognostic indicator in Hispanic Mexican women with breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C024.