Pharmacogenomics of Aromatase Inhibitors in Early-Stage Postmenopausal Breast Cancer

Endocrine therapy plays a central role in the management of the majority of women with breast cancer whose tumors have an estrogen receptor (ER) target.

A recent meta-analysis showed that aromatase inhibitors (AIs) were superior to tamoxifen as adjuvant therapy in early-stage disease. Despite this superiority, about one-fifth of women treated with aromatase inhibitors had recurrence of their breast cancer within 10 years.

There is also a marked variability in patient tolerance of aromatase inhibitors, which can adversely impact adherence to treatment. Aromatase inhibitors act by decreasing a woman's estrogen levels. The assumption is that all aromatase inhibitors produce sufficient estrogen suppression.

However, preliminary data from this project team in the Mayo Clinic Breast Cancer SPORE showed marked variation in estrogen levels before and while on treatment with the aromatase inhibitor anastrozole. It remains unknown whether the degree of estrogen suppression, or how to best quantify it, is related to the degree of clinical benefit provided by aromatase inhibitors.

The Breast Cancer SPORE project team also has preliminary data from a genome-wide association study using germline DNA from patients receiving AIs. Results show that the variability in AI-related adverse events and outcomes is related to variation in germline genetics.

In preliminary findings, this genetic variability in single nucleotide polymorphisms (SNPs) and genes has been identified as associated with estrogen suppression by aromatase inhibitors and breast cancer recurrences.

Hypothesis

This project is testing the hypothesis that genetic variability plays an important role in aromatase inhibitor response and that this effect might be through the regulation of estrogen suppression.

The project team's functional studies of these genetic variants and genes also showed an SNP- and individual AI-dependent regulation of the expression of the aromatase gene. The aromatase gene encodes the enzyme aromatase, which is responsible for generation of estrogens. This novel finding has potentially important implications for precision aromatase inhibitor treatment.

Clinical trials

This project is taking advantage of the preliminary data already obtained by the project team, as well as three major multicenter clinical trials involving all three third-generation aromatase inhibitors (anastrozole, exemestane, letrozole) for which genome-wide genotyping is already available:

  • A Mayo Clinic M3 study of anastrozole alone with estrogen levels before and during anastrozole, and anastrozole and anastrozole-metabolite concentrations
  • The MA.27 trial, comparing anastrozole and exemestane, from which the project team has published two GWAS relating to adverse events
  • The PreFace trial, a single-arm letrozole trial

The project team is using data and biospecimens from before and during aromatase inhibitor treatment from the MA.27 and PreFace trials to determine if the degree of estrogen suppression correlates with clinical AI treatment outcomes and, through genotyping data, determining the associated common or AI-specific SNPs.

The project team is then testing the SNPs related to estrogen suppression in a prospective trial. The team is also performing functional studies of those SNPs to explore mechanisms by which they might affect estrogen levels and aromatase inhibitor response.

Findings from this project will have direct implications for the majority of women with breast cancer and will contribute to precision endocrine therapy with aromatase inhibitors.

Project aims

This project in the Mayo Clinic Breast Cancer SPORE has three aims:

  • Determine the relationship between the degree of estrogen suppression by aromatase inhibitors and early breast cancer events using the PreFace trial as a discovery set and the MA.27 trial as a validation set
  • Determine SNPs and genes associated with degree of estrogen suppression and early breast cancer events
  • Determine functional significance of SNPs and genes associated with AI-related estrogen suppression and early breast cancer events and evaluate SNPs in a prospective clinical trial