KEY TAKEAWAYS
- The study aimed to assess the potential role of AR-targeted drugs in the treatment of pts with BC.
- Researchers have identified AR-related PGx-eQTL SNP-gene pairs for personalized BC treatment biomarkers.
Endocrine therapy stands as the cornerstone of treatment for patients (pts) with breast cancer (BC) whose tumors express estrogen receptor α (ERα). This therapy effectively targets ERα-positive tumors, offering significant therapeutic benefits.
Alongside ERα, the androgen receptor (AR) is also commonly expressed in a substantial majority (80-90%) of these tumors. Despite the prevalence of AR expression, AR-targeting drugs have not yet found a place in routine clinical practice. Nevertheless, their efficacy and safety profiles have been extensively investigated across numerous clinical trials and preclinical studies.
Huanyao Gao and the team aimed to evaluate the potential role of AR-targeted drugs in BC treatment, specifically focusing on ERα-positive tumors where AR was co-expressed.
Researchers conducted a genome-wide study aimed at identifying genotype-dependent gene expression, known as pharmacogenomics expression quantitative trait loci (PGx-eQTL), induced by either an AR agonist (dihydrotestosterone) or a partial-antagonist (enzalutamide). This study utilized a lymphoblastic cell line panel that had been previously well characterized. The goal was to understand how these hormonal and drug interventions influence gene expression patterns across different genetic backgrounds.
Subsequently, they identified SNP-gene pairs from the PGx-eQTL analysis were examined for their association with BC phenotypes. The current investigation involved analyzing data from three genome-wide association studies (GWAS) conducted by our research group, as well as integrating findings from other relevant studies available in the GWAS catalog. By correlating these genetic variants with BC traits, elucidating the potential mechanisms linking AR modulation to BC susceptibility and progression is focussed.
Overall, the study integrated cellular and genetic data to explore the interplay between AR-targeting drugs, genetic variation, and BC risk. By leveraging genomic approaches and large-scale association studies, focusing on providing insights into personalized medicine strategies for BC treatment, focusing on how genetic variability influences response to AR modulation therapies.
The analysis identified a total of 13 PGx-eQTL loci mediated by dihydrotestosterone (DHT) and 23 PGx-eQTL loci mediated by enzalutamide (Enz) that were associated with BC outcomes following treatment with ER antagonists or aromatase inhibitors (AI), or with pharmacodynamic effects of AIs. Additionally, 30 loci were discovered to be linked to cancer risk and levels of sex-hormone-binding globulin.
Among the key loci identified, genes such as IDH2 and TMEM9 showed significant suppression in expression due to DHT in a genotype-dependent manner of PGx-eQTL SNPs. Both genes are known to be overexpressed in BC and are associated with a poorer prognosis. Therefore, the targeted suppression of these genes by AR agonists could potentially benefit pts harboring minor allele genotypes for these SNPs.
The findings underscored the potential therapeutic implications of AR modulation in BC treatment, particularly for pts with specific genetic profiles. By elucidating how DHT and Enz influence gene expression through PGx-eQTL mechanisms, the study provided insights into personalized medicine approaches.
Targeting IDH2 and TMEM9, which are involved in cancer progression and poor prognosis, could offer new avenues for improving treatment outcomes in BC, particularly by tailoring therapies based on individual genetic variations and response profiles.
The study concluded by identifying AR-related PGx-eQTL SNP-gene pairs that were found to be associated with risks, outcomes, and pharmacodynamic (PD) effects of endocrine therapy and provide potential biomarkers for individualized treatment of pts with BC.
The study was funded by P50 CA116201/CA/NCI NIH HHS/United States, MC1351/Regis Foundation Mayo Clinic Center for Individualized Medicine, BCRF-22-076/Breast Cancer Research Foundation, and P50CA 116201/Mayo Clinic Breast Cancer Specialized Program of Research Excellence Grant.
Source: https://pubmed.ncbi.nlm.nih.gov/38965614/
Gao H, Wei L, Indulkar S, et al. (2204). “Androgen receptor-mediated pharmacogenomic expression quantitative trait loci: implications for breast cancer response to AR-targeting therapy.” Breast Cancer Res. 2024 Jul 4;26(1):111. doi: 10.1186/s13058-024-01861-2. PMID: 38965614; PMCID: PMC11225427.
