Abstract ML-1: Pharmacogenomics in the Quest for Precision Endocrine Therapy of Breast Cancer
Authors: Ingle James N. 
Published: May 2015

Endocrine therapy, with SERMs and AIs, is the most important treatment modality for the 70% of patients with ER+ early breast cancer. Clinically, there is marked variability between patients in response to treatment and adverse events (AEs) such as musculoskeletal (MS) AEs with AIs. In 649 women with early-stage breast cancer we identified large inter-individual variations in pretreatment and on-anastrozole (A) plasma estrogens as well as plasma A concentrations, suggesting that the approved A dose of 1 mg per day may not be optimal for all patients. We performed a series of genome-wide association studies (GWAS) and identified a genome-wide significant variant SNP associated with concentrations of E2 that created an estrogen response element (ERE), and a significant SNP associated with E1-conjugates, providing potential insights into the variability.

Pharmacogenomics (PGx) is the study of the role of germline and somatic genetic variation in individual variability in drug response phenotypes, i.e., disease response and AEs. The scientific goal is to understand mechanisms for the phenotype and the clinical goal is the determination of the right drug at the right dose for the right patient. The Mayo PGx Research Network Center and Breast SPORE and the RIKEN Center for Integrative Medical Science have worked collaboratively with cooperative groups to perform GWAS in women treated with both SERMs and AIs. The PGx paradigm consists of the GWAS as the initial step in a process that goes beyond the identification of associations to study the relationship of the single nucleotide polymorphisms (SNPs) to genes and the relationships of these SNPs and genes to the drug effect and the phenotype under study.

Using the phenotype of AI-related MS-AEs, the major reason women stop therapy, a case-control GWAS was performed with patients from MA.27. The GWAS identified a SNP on chromosome (Chr) 14 that was associated with MS-AEs, near a gene (TCL1A), and created an ERE. Importantly, TCL1A expression was related to expression of multiple cytokine receptors, NFκB, and chemokines (related to rheumatoid arthritis) in an E2- and SNP-dependent fashion. These results provide a pharmacogenomic basis for MS-AEs with AIs.

Using the phenotype of development of breast cancer in high-risk women receiving SERMs, a case-control GWAS was performed with patients entered on the NSABP P-1 and P-2 trials. The GWAS revealed variant SNPs on Chr 4 near CTSO (deleterious) and Chr 16 in ZNF423 (protective). The OR for differences in risk of breast cancer for participant homozygous for both protective or both deleterious alleles was 5.71. Both CTSO and ZNF423 were shown to participate in E2-dependent induction of BRCA1 expression in a SNP-dependent fashion. Most remarkable was that the presence of a SERM reversed the E2-inducible expression of ZNF423 and BRCA1 in a SNP-dependent fashion. In addition, ZNF423 was shown to be an E2-inducible BRCA1 transcription factor. The deleterious variant SNP near CTSO was found to disrupt an ERE.

The GWAS described led to functional genomic studies that produced new knowledge relating to endocrine biology that provide a focus for further research to move towards precision endocrine therapy for women with breast cancer.

Citation Format: James N. Ingle. Pharmacogenomics in the Quest for Precision Endocrine Therapy of Breast Cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ML-1.