Tamoxifen and antidepressants: What to do?

Tamoxifen has been used for the treatment of hormone receptor-positive breast cancer for more than 3 decades.

Despite the advent of newer endocrine agents, (eg, aromatase inhibitors), tamoxifen remains the preferred adjuvant endocrine agent for premenopausal women with hormone receptor-positive early-stage breast cancer and is often also utilized sequentially with aromatase inhibitors for postmenopausal women with either early stage or metastatic breast cancer. Tamoxifen is metabolized through multiple cytochrome P450 enzymes, including CYP3A4, CYP2D6, CYP2C19 and others. Active metabolites of tamoxifen also undergo catabolism and inactivation through other enzymatic pathways (eg, sulfotransferases, UDP-glucuronosyltransferases), making the metabolic picture very complex (Figure 1).

Until recently, the understanding of tamoxifen’s metabolism was limited to identification of the primary active metabolite, 4-hydroxytamoxifen (4OH-TAM), and much of the clinical activity of tamoxifen was attributed to 4OH-TAM. In 2003, Stearns and colleagues published a report suggesting that a secondary active metabolite, 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), may be more important to the clinical activity of tamoxifen than first thought. Both metabolites are nearly 100 times more potent than tamoxifen in suppressing estrogen-dependent cell growth. However, endoxifen is present in the serum at concentrations up to 20-fold higher compared with 4OH-TAM. Therefore, many clinicians now consider endoxifen concentrations as a critical factor for clinical activity.

Formation of endoxifen is highly dependent on the enzymatic activity of CYP2D6, and early reports of diminished formation of endoxifen due to polymorphisms in or inhibition of CYP2D6 have generated great interest in the oncology community. However, this enzyme may not be entirely responsible for the anticancer activity of tamoxifen; inhibition of other enzymatic pathways may also be important.

Tamoxifen and CYP2D6 status

The clinical effect of CYP2D6 polymorphisms and subsequent functional status of this enzyme are widely debated, and conflicting data exist regarding the role of genetic testing for CYP2D6 functional status in breast cancer patients who are going to receive tamoxifen. Nonetheless, the use of concomitant drugs that may also affect the function of CYP2D6 are more readily accepted as problematic and should be evaluated in all patients to adequately counsel them on the risks and benefits of tamoxifen compared with other potential therapeutic options. Some studies investigating the relationship between CYP2D6 functional status and tamoxifen/endoxifen reported drug/metabolite serum concentrations alone, whereas others have reported clinical endpoints of therapeutic outcomes. The number of conflicting publications regarding this relationship and the limited clinical outcome data make application of this information to individual patient cases difficult.

There are many databases that collect and display information regarding drug interactions, many of which are especially helpful in making treatment decisions for a patient on tamoxifen. Although these may be somewhat difficult to navigate, most clinical pharmacists are well-educated on utilizing these databases, interpreting and applying the information to clinical scenarios.

Antidepressant effects on CYP2D6

Contemporary antidepressants, including the selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, are perhaps the most frequently encountered CYP2D6 inhibitors in breast cancer patients due to the use of these agents for the management of hot flashes and clinical depression in this patient population. Paroxetine and fluoxetine, both potent CYP2D6 inhibitors, have demonstrated significant reductions in the formation of endoxifen in patients taking tamoxifen, and most clinicians agree that these agents should be avoided in conjunction with tamoxifen. Bupropion and duloxetine are also considered potent CYP2D6 inhibitors, although studies specifically investigating their interactions with tamoxifen are lacking. Nonetheless, these agents are also typically avoided by clinicians treating patients already on tamoxifen.

Sertraline, citalopram and fluvoxamine are weak to moderate CYP2D6 inhibitors and may or may not produce clinically meaningful reductions in endoxifen concentrations. Venlafaxine, desvenlafaxine and escitalopram also appear to be weak inhibitors of CYP2D6. Importantly, sertraline, citalopram and venlafaxine are the only other agents besides paroxetine and fluoxetine to have been tested in conjunction with tamoxifen in vivo. No data regarding in vivo effects on endoxifen levels are available for other antidepressants, and clinicians are left to make clinical decisions based on in vitro data. Therefore, clinical decisions regarding the use of these other antidepressant agents with tamoxifen are more difficult and are compromised by a lack of detailed, reliable information with which to guide these decisions.

Although these data warrant concern, little information exists regarding clinical outcomes associated with lower levels of endoxifen (eg, breast cancer recurrences). Some studies, but not all, associate poorer outcomes with patients receiving potent CYP2D6 inhibitors concurrently with tamoxifen. In a population-based cohort study, concomitant use of tamoxifen and paroxetine (but not other antidepressants) resulted in an increased risk for breast cancer death. In a separate analysis, co-prescription of a moderate or potent CYP2D6 inhibitor with tamoxifen in patients with breast cancer resulted in a nearly twofold higher risk for breast cancer recurrence compared with tamoxifen alone. However, another study failed to show an association between concomitant CYP2D6 inhibitor use and breast cancer recurrence in patients receiving adjuvant tamoxifen.

All of these reports suffer from biases associated with retrospective analyses. There are currently no data from prospective clinical trials to support adverse clinical outcomes resulting from drug interactions with tamoxifen and moderate or potent CYP2D6 inhibitors. Additionally, patient outcomes may also depend on other factors, such as underlying CYP2D6 genetic status (eg, poor metabolizer, extensive metabolizer) and/or adherence to endocrine therapy.

Treatment alternatives

Despite the lack of irrefutable evidence indicating a negative clinical outcome, most clinicians would prefer to avoid potent inhibitors of CYP2D6 altogether in breast cancer patients on tamoxifen. That is relatively easy to do, given the number of other agents available in the class to treat symptoms such as hot flashes and depression.

The more complicated question is raised when a newly diagnosed breast cancer patient requires tamoxifen but has been previously maintained on paroxetine (or another potent inhibitor) for some time and is at a higher risk for complications from changing her antidepressant (eg, suicidal tendencies) than from changing her anticancer therapy. For these patients, alternatives to tamoxifen may also be considered (eg, oophorectomy followed by aromatase inhibitor therapy in a premenopausal patient), although data to support the use of these therapies in premenopausal women in the adjuvant setting for early stage breast cancer are lacking.

For postmenopausal women, the options are more clearly available with sound evidence to support them (eg, anastrozole, exemestane, letrozole). For patients on moderate CYP2D6 inhibitors, decisions are controversial, and each agent and indication should be evaluated independently. For agents such as sertraline, a moderate inhibitor, most clinicians would prefer to avoid use in conjunction with tamoxifen. However, individual circumstances may warrant the use of these agents. Clinicians should be less concerned with co-administration of a weak CYP2D6 inhibitor with tamoxifen, but discussions should still be undertaken with the patient to ascertain the need for the particular medication in question.

Careful risk assessment for breast cancer recurrence and other outcomes should be undertaken when making these types of decisions. A clinician may be less comfortable continuing a potent CYP2D6 inhibitor in a patient receiving tamoxifen for early stage breast cancer in the adjuvant setting (ie, curative setting) compared with a patient receiving palliative therapy with tamoxifen for metastatic breast cancer. As with any clinical situation, risks and benefits must be considered and discussed with the patient.

Tamoxifen remains a clinically relevant option for the management of hormone receptor-positive breast cancer. Many reports have described alterations in tamoxifen metabolism due to polymorphisms in the CYP2D6 enzyme and/or use of concomitant medications. Although there are data to suggest that certain polymorphisms in CYP2D6 may result in poorer clinical outcomes in patients receiving tamoxifen, these analyses are based mostly on retrospective analyses, and contradictory studies exist.

Similarly, data linking drug interactions between tamoxifen and potent CYP2D6 inhibitors to clinical outcomes are also inconclusive. However, it would seem reasonable to avoid this combination if possible. Other treatment options for management of vasomotor symptoms, depression or other medical conditions are often available without potent inhibitory effects on CYP2D6. Due to the paucity of clinical data, no definitive recommendations can be made regarding tamoxifen combined with weak or moderate CYP2D6 inhibitors. Because drug interactions with tamoxifen could potentially affect breast cancer recurrence and survival, additional studies clarifying the role of CYP2D6 inhibitors and tamoxifen are desperately needed. Ongoing clinical trials investigating the role of CYP2D6 functional status are currently under way and promise to someday lead us to better understanding the disposition of tamoxifen in humans and its clinical relevance.

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