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Pharmacogenetics of Aromatase Inhibitors in Endocrine Responsive Breast Cancer: Lessons Learnt from Tamoxifen and
K J Baatjes1, M Conradie2, J P Apffelstaedt1
1Department Surgical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive Tygerberg. South Africa.
Background:
Genetics play a significant role in drug metabolism of endocrine therapy of breast cancer. These aspects have been studied extensively in patients on tamoxifen, but the pharmacogenetics of aromatase inhibitors are less established. In contrast to the protective effect of tamoxifen, aromatase inhibitors are linked with an increased risk for bone loss and fractures.
Objective:
This review outlines key issues in the implementation of pharmacogenetics of cytochrome P450 and tamoxifen as a model for optimal use of aromatase inhibitors in postmenopausal women with estrogen receptor positive breast cancer.
Methods:
Lessons learnt from the association between tamoxifen and CYP2D6 genotyping were applied to identify polymorphisms with the potential to change clinical decision-making in patients on aromatase inhibitors. The ability of next generation sequencing to supersede single-gene analysis was furthermore evaluated in a subset of breast cancer patients on aromatase inhibitors selected from a central genomics database.
Results:
Methodological flaws in major randomised controlled trials and continued referral to incorrect results in expert consensus statements are important factors delaying the implementation of CYP2D6 pharmacogenetics in tamoxifen treatment. This highlighted the importance of a clinical pipeline including comprehensive genotyping, to define the target population most likely to benefit from aromatase inhibitor pharmacogenetics.
Conclusion:
The clinical utility of CYP2D6 genotyping is well-established in patients at increased risk of tamoxifen resistance due to cumulative risk. The pharmacogenetics of CYP19A1 requires further clarification in terms of bone risk assessment for appropriate use in the treatment algorithm of high-risk patients at the onset of aromatase inhibitors.
Insights
Pharmacogenetics of aromatase inhibitors are less established than tamoxifen, impacting breast cancer treatment. Further research is needed to clarify genetic influences on bone risk for optimal patient selection.
Area of Science:
- Endocrinology
- Pharmacogenomics
- Oncology
Background:
- Genetic factors significantly influence drug metabolism in endocrine therapy for breast cancer.
- While tamoxifen pharmacogenetics are well-studied, aromatase inhibitor pharmacogenetics remain less established.
- Aromatase inhibitors are associated with increased bone loss and fracture risk, unlike tamoxifen.
Purpose of the Study:
- To review the implementation of cytochrome P450 pharmacogenetics, using tamoxifen as a model for aromatase inhibitor use.
- To optimize aromatase inhibitor therapy in postmenopausal women with estrogen receptor-positive breast cancer.
Main Methods:
- Applied lessons from CYP2D6 genotyping in tamoxifen treatment to identify polymorphisms affecting aromatase inhibitor therapy.
- Evaluated next-generation sequencing versus single-gene analysis in breast cancer patients on aromatase inhibitors using a genomics database.
Main Results:
- Methodological flaws in trials and expert statements hinder CYP2D6 pharmacogenetics implementation for tamoxifen.
- A clinical pipeline with comprehensive genotyping is crucial for identifying patients who benefit from aromatase inhibitor pharmacogenetics.
Conclusions:
- CYP2D6 genotyping is clinically valuable for patients at risk of tamoxifen resistance.
- CYP19A1 pharmacogenetics require further study for bone risk assessment in aromatase inhibitor treatment algorithms for high-risk patients.
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