Anastrozole is first-line therapy in the management of postmenopausal estrogen-receptor positive (ER+) breast cancer (BC). Although in general 1 mg of anastrozole reduces estradiol concentrations by >83.5% and estrone plasma concentrations by >86.5%, approximately 10% of patients do not have a decrease in their estrogen levels and may actually have an increase instead.
Identifying those women who do not experience biochemical benefit from therapy has been difficult, however, due to the lack of studies examining whether variations in plasma anastrozole concentrations may be attributed to alterations in genomic parameters. Furthermore, until now, no transporter for anastrozole has been identified. Nevertheless, being able to distinguish these biochemical malresponders may have clinical relevance since about 10% of women on anastrozole experience BC recurrence within 5 years, and wide variations in the occurrence and severity of adverse drug reactions have been observed in women on the aromatase inhibitor (AI).
To address these concerns, researchers conducted a genome-wide association study of plasma anastrozole concentrations in 687 postmenopausal women with ER+ BC enrolled in the Mayo Clinic-MD Anderson-Memorial Sloan Kettering Pharmacogenomics Research Network Breast Cancer Aromatase Inhibitor Pharmacogenomics study. Using expression quantitative trait loci analysis, which links genetic variation to phenotypical expression, investigators identified a top single-nucleotide polymorphism (SNP) signal on SLC38A7 rs11648166 SNP on Chromosome 16 that encodes for an anastrozole influx transporter.
Additionally, another significant SNP signal was found that mapped near ALPPL2 rs28845026 SNP on Chromosome 2; this repressed SLC3847 expression, thereby decreasing anastrozole plasma concentrations. ALPPL2, which is found in the gut and which may affect oral absorption of the AI, was found to have a significant effect on SCL38A7 expression and on anastrozole transport. In women with ER+ BC who were receiving the AI, both the SNP in SLC38A7 and the SNP near ALPPL2 were associated with plasma anastrozole concentrations, albeit producing opposite effects on drug levels.
These findings further showed that two separate genetic loci have the potential to interact to influence phenotypic expression, which in this case was reflected as anastrozole plasma drug concentrations.
Patients who were homozygous for variant genotypes of both the SLC3847 and ALPPL2 SNPs demonstrated the highest drug concentrations, the highest SLC3847 expression, and the lowest ALPPL2 expression. Higher mean plasma anastrozole concentrations were associated with lower (undetectable) levels of both estradiol and estrone.
In summary, researchers identified a gene encoding an anastrozole transporter, SLC3847, and identified epistatic interaction (i.e., suppressive effect of one gene on another) between SNPs in SLC3847 and SNPs near ALPPL2 that impacted both the expression of the transporter and anastrozole plasma concentrations.
Investigators speculated that these SNPs may one day serve as tools for the individualization of plasma anastrozole dosing.
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