Tamoxifen is extensively broken down in the body through the process of metabolism to form several intermediate products known as metabolites which have similar or enhanced pharmacological activity in comparison to Tamoxifen. The formation of active metabolites, e.g. Endoxifen, is predominantly mediated by the cytochrome P450 CYP2D6 enzyme ( hereafter referred to as CYP2D6 ).
A number of studies have been published in the medical literature on the potential effect of genetic variants of CYP2D6 on the therapeutic responses of patients to Tamoxifen in the treatment of breast cancer.
The studies gave rise to the concern that patients with inherited non-functional alleles of the gene coding for CYP2D6 or patients who are concomitantly treated with medicines inhibiting CYP2D6, i.e. blocking the action of this enzyme, might not be suitable for adjuvant Tamoxifen therapy, due to reduced concentrations of those metabolites of Tamoxifen that bind most strongly with the oestrogen receptor expressed by the breast cancer.

Therefore, the PhVWP ( Pharmacovigilance Working Party ) reviewed the available evidence in this respect.

Tamoxifen is a selective oestrogen receptor modulator indicated for palliative and adjuvant treatment of oestrogen receptor-positive breast cancer, in both premenopausal and postmenopausal women. Oestrogen receptor-positive breast cancer cells grow in response to the hormone oestrogen. Tamoxifen works by attaching to the receptors for oestrogen on the surface of cancer cells so that these cells are not stimulated to grow by oestrogen and the growth of the cancer is reduced.

Following the studies published in the medical literature, a list of questions was forwarded to the marketing authorisation holder of the originator product requesting its views, in particular on the risk of reduced therapeutic response to Tamoxifen in 1) patients who are poor CYP2D6 metabolisers, 2) patients who are concomitantly treated with potent CYP2D6 inhibitors, and 3) in patients with different ethnicity regarding CYP2D6 polymorphisms.

The PhVWP reviewed all currently available data.

Effect of Tamoxifen in poor CYP2D6 metabolisers

A study [ Schroth W et al, JAMA 2009 ] including 1325 patients from US and German cohorts ( 95.4% postmenopausal ) with hormone receptor-positive non-metastatic breast cancer at diagnosis and treated with Tamoxifen and no chemotherapy afterwards showed a significantly increased risk of breast cancer recurrence for poor CYP2D6 metabolisers ( several alleles were analysed in the study: CYP2D6*3, *4 and *5 ( HR 1.90 ) and heterozygous metabolisers ( HR 1.40 ) compared to extensive metabolisers ).
Additional studies including those providing contradictory results were assessed. Several of the studies indicated that poor CYP2D6 metaboliser status may be associated with a reduced response. The few studies in Caucasian populations showing contradictory results ( n=3 from 2005 or 2007 ) may have been confounded by e.g. the higher Tamoxifen dose used, small number of poor CYP2D6 metabolisers or limited number of CYP2D6 mutations analysed, all of which may reduce the ability to demonstrate a reduced response of Tamoxifen in patients with poor CYP2D6 metaboliser status.

In the most recently published large study [ Abraham JE et al, Breast Cancer Research 2010 ], which included patients with invasive breast cancer from SEARCH ( Studies of Epidemiology and Risk Factors in Cancer Heredity; 3155 patients were treated with Tamoxifen and 3485 patients did not receive Tamoxifen ), there was some evidence that the poor metaboliser variant CYP2D6*6 ( a more uncommon variant with a mean allele frequency, MAF=0.01 ) was associated with decreased breast cancer-specific survival. However, CYP2D6*4 ( the most common poor metaboliser variant with MAF=0.20 ) was not shown to be associated with poorer clinical outcomes, in contrast to the previous findings.

Effect of Tamoxifen in patients treated with potent CYP2D6 inhibitors

Another study [ Kelly CM et al, BMJ 2010 ] referred to data from a population-based cohort study on selective serotonin reuptake inhibitors ( SSRIs ) and breast cancer mortality in women receiving Tamoxifen. In this study, data from a healthcare record database in Ontario, Canada, were used to evaluate the clinical consequences for women with breast cancer who were treated with both Tamoxifen and an SSRI. It was found that the risk of death from breast cancer increased with the length of concomitant treatment with Paroxetine, a potent inhibitor of CYP2D6, but not with other SSRIs. For example, if women used Paroxetine for 41% of the time that they took Tamoxifen, one additional death from breast cancer occurred within five years after stopping Tamoxifen for every 19.7 women treated. The proportion of time on Tamoxifen with overlapping use of Paroxetine of 25%, 50%, and 75% was associated with 24%, 54%, and 91% increases in the risk of death from breast cancer. In a more recent study [ Dezentje VO et al, J Clin Oncol 2010 ], no evidence was found for a decrease in efficacy with the co-administration of CYP2D6 inhibitors and Tamoxifen. However, the authors, considering the results from the available studies and the strong mechanistic model, concluded that their results should be interpreted with caution.


Based on all the evidence, the PhVWP considered that the available published data, mainly on post-menopausal women treated for breast cancer with Tamoxifen, suggest that CYP2D6 polymorphism status may be associated with different therapeutic response of patients to Tamoxifen. Poor CYP2D6 metaboliser status may be associated with reduced response. The consequences of the findings for the treatment of poor CYP2D6 metabolisers have not been fully understood. The available data at present have not clearly shown the clinical utility of CYP2D6 testing to predict Tamoxifen efficacy and clinical outcome. There is insufficient evidence at present to recommend genotyping patients before starting Tamoxifen treatment.
Additionally, the PhVWP noted that pharmacokinetic interactions with CYP2D6 inhibitors were described in the medical literature, showing a 65-75% reduction in plasma levels of one of the more active forms of Tamoxifen, i.e. Endoxifen. Reduced efficacy of Tamoxifen was reported with concomitant use of some SSRI antidepressants ( e.g. Paroxetine ). However, in other studies, a decrease in efficacy of Tamoxifen with the co-administration of CYP2D6 inhibitors was not evident. As a reduced effect of Tamoxifen cannot be excluded, particularly in the context of the pharmacokinetic data and mechanistic plausibility, co-administration with potent CYP2D6 inhibitors ( e.g. Paroxetine, Fluoxetine, Quinidine, Cinacalet or Buproprion ) should be avoided whenever possible.
Therefore, the PhVWP concluded upon recommendations for the summaries of product characteristics and package leaflets for medicinal products containing Tamoxifen to highlight the possible reduction in therapeutic response to Tamoxifen in poor CYP2D6 metabolisers and to warn against using potent CYP2D6 inhibitors during Tamoxifen treatment whenever possible.

Source: EMA – PhVWP, 2010

XagenaMedicine2010


Link: Xapedia - Medical Encyclopedia