Elsevier

European Journal of Cancer

Volume 45, Issue 13, September 2009, Pages 2274-2283
European Journal of Cancer

Review
Targeting of tamoxifen to enhance antitumour action for the treatment and prevention of breast cancer: The ‘personalised’ approach?

https://doi.org/10.1016/j.ejca.2009.05.032Get rights and content

Abstract

Tamoxifen is a standard endocrine therapy for the treatment of steroid receptor positive breast cancer. Tamoxifen efficacy depends on the formation of clinically active metabolites 4-hydroxytamoxifen and endoxifen which have a greater affinity to the oestrogen receptor and ability to control cell proliferation as compared to the parent drug. The cytochrome P450 2D6 enzyme plays a key role in this biotransformation and lack of tamoxifen efficacy has been linked to low activity. There is now considerable mechanistic, pharmacologic and clinical pharmacogenetic evidence in support of the notion that CYP2D6 genetic variants and phenocopying effects through drug interaction by CYP2D6 inhibitors influence plasma concentrations of active tamoxifen metabolites and negatively impact tamoxifen outcome. These interrelations are particularly critical for patients with non-functional (poor metaboliser) and severely impaired (intermediate metaboliser) CYP2D6 variants, and, moreover, for patients in need of co-medication such as serotonin re-uptake inhibitors to control adverse effects such as hot flashes and other menopausal symptoms. Therefore, in the future, a personalised approach for an optimal tamoxifen benefit should consider a CYP2D6 genotype guided adjuvant endocrine treatment strategy and avoid non-adherence as well as strong CYP2D6 inhibitors such as co-medications.

Introduction

Tamoxifen, a non-steroidal antioestrogen1 (Fig. 1), is used for the treatment of all stages of breast cancer2, 3, 4 and in the US is available to reduce the incidence of breast cancer in both pre- and postmenopausal women at elevated risk.5, 6, 7 It is important to remember that during early clinical studies tamoxifen did not show any improvement in efficacy over standard hormonal treatments (high dose oestrogen or androgen) for metastatic breast cancer.2, 8 The only advantage of tamoxifen was a reduced incidence of side effects for those 30% of patients who responded for about 1 year. However, laboratory studies to target the tumour oestrogen receptor (ER)9 employed long term adjuvant therapy10 and considered the chemoprevention of breast cancer.11, 12 Tamoxifen was thus re-invented from an orphan drug to the ‘gold standard’ for the endocrine treatment of breast cancer between 1984 and 2004. The targeting of tamoxifen to block oestrogen stimulated breast tumour growth with long term (5 years) adjuvant tamoxifen therapy13 resulted in a major improvement in patient survivorship and has contributed significantly to the reduction in national death rates from breast cancer.14, 15 The recent development of aromatase inhibitors as an effective treatment for breast cancer in postmenopausal patients16 has improved disease-free survival and reduced the side effects of endometrial cancer and blood clots noted with tamoxifen.17, 18, 19, 20 However, aromatase inhibitors are not universally available in national health care systems worldwide because of significant financial constraints. Tamoxifen remains a cheap, life-saving, targeted therapy for both pre- and postmenopausal patients with breast cancer.

The application of the ER as a tumour target to treat breast cancer patients appropriately provided a valuable, but admittedly not perfect, test to increase the probability of tumour growth control during long term adjuvant treatment. Tamoxifen does not enhance either disease-free or overall survival in patients with ER negative tumours.14, 15

At present, there are no universally accepted tumour markers to improve response rates for patients with ER positive tumours. However, emerging data on the pharmacogenomics of tamoxifen metabolism through the CYP2D6 enzyme and new knowledge of potential drug interactions with selective serotonin re-uptake inhibitors (SSRIs), to control hot flashes, provide valuable new information to aid in the selection of the appropriate long term endocrine treatment for breast cancer patients with ER positive disease.

The goal of this concise review is to describe the new understanding of the metabolic activation of tamoxifen to its putative active agent endoxifen21, 22, 23 and consider the clinical significance of CYP2D6 polymorphisms together with phenocopying effects through drug interaction. We will summarise the actions necessary to improve the value of tamoxifen as a ‘personalised targeted treatment for breast cancer’.

Section snippets

Tamoxifen efficacy

Our evolving understanding of the relevance of tamoxifen metabolism for its pharmacology has recently been reviewed.24 Nevertheless, the important pharmacological issues and conclusions will be restated to provide a scientific background for evaluating the role of the CYP2D6 enzyme and underlying genetics for the antitumour actions of tamoxifen.

Tamoxifen is a pro-drug that requires metabolic activation to 4-hydroxytamoxifen25, 26 and 4-hydroxy-N-desmethyltamoxifen (endoxifen) (Fig. 1) in order

Conclusion

In summary, we can conclude that endoxifen is formed by the CYP2D6 enzyme21, 22, 23, 28, 35 and it is therefore anticipated that aberrant genotypes and other medicines that are metabolised by the same enzyme impair the actions of tamoxifen in patients.29 We addressed the veracity of the hypothesis from the current literature to explore the possibility of targeting tamoxifen to improve women’s health. There is now strong evidence that hot flashes are indicators of tamoxifen efficacy and that

Conflict of interest statement

None declared.

Acknowledgments

Supported by the following grants: Department of Defense Breast Program under award number BC050277 Center of Excellence (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense) (VCJ), Genuardis Fund (VCJ), the Avon Foundation and the Weg Fund of Fox Chase Cancer Center (VCJ), the Bosch Foundation Stuttgart (HB) and BMBF 01ZP0502 (HB).

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