Does Tamoxifen (tamoxifen citrate) cause immunosuppression?

From the Guidelines

Tamoxifen is not considered a significant immunosuppressant in clinical practice, and its mild immunosuppressive effects do not warrant special precautions regarding infection risk or vaccination modifications. Tamoxifen, primarily used as a selective estrogen receptor modulator (SERM) for breast cancer treatment at doses of 20-40 mg daily, may cause modest immunomodulatory effects through its interaction with estrogen receptors on immune cells, as noted in studies such as 1. These effects include decreased T-cell proliferation, altered cytokine production, and some impact on natural killer cell function. However, these immunological changes are generally not clinically significant enough to warrant special precautions regarding infection risk or to contraindicate vaccinations, as supported by guidelines from the American Society of Clinical Oncology, including those outlined in 1 and 1.

Some key points to consider when managing patients on tamoxifen include:

• The primary mechanism of action of tamoxifen is as a selective estrogen receptor modulator, not as an immunosuppressant.
• The immunomodulatory effects of tamoxifen are secondary to its primary mechanism of action and are considerably milder than medications specifically prescribed for immunosuppression, such as corticosteroids, calcineurin inhibitors, or biologics.
• Patients on tamoxifen do not require the same infection prophylaxis or vaccination modifications as those on traditional immunosuppressants.
• Clinicians should focus more on tamoxifen's common side effects, such as hot flashes, thromboembolic risk, and endometrial changes, rather than potential immunosuppression when managing patients on this medication, as emphasized in guidelines like those found in 1 and 1.

Overall, the benefits of tamoxifen in reducing the risk of invasive breast cancer, specifically ER-positive breast cancer, outweigh the mild immunosuppressive effects, making it a valuable option for breast cancer risk reduction in eligible patients, as discussed in 1 and 1. Therefore, tamoxifen should be used according to established guidelines, with careful consideration of its benefits and risks, but without undue concern for its immunosuppressive effects.

From the Research

Tamoxifen Immunosuppression

• Tamoxifen has been found to have immunomodulatory effects, including a shift from cellular (T-helper 1) to humoral (T-helper 2) immunity 2.
• The immunomodulatory effects of tamoxifen appear to be independent of the estrogen-receptor and may be mediated through the multidrug resistance gene product, Permeability-glycoprotein 2.
• Tamoxifen may be useful in the treatment of immune-mediated disorders, particularly those arising from aberrant T-helper 1 cell activity, including allograft rejection, Crohn's disease, and Th1-mediated autoimmune conditions such as diabetes mellitus, scleroderma, and multiple sclerosis 2.
• However, the tamoxifen-induced shift away from cellular immunity may limit the anti-cancer effects of tamoxifen and thus explain why tamoxifen is inferior compared to other anti-estrogens in preventing disease recurrence in early-stage breast tumors 2.

Clinical Implications

• The clinical implications of the immunomodulatory effects of tamoxifen are twofold: it may be useful in the treatment of immune-mediated disorders, but it may also limit the anti-cancer effects of tamoxifen 2.
• Tamoxifen has been found to have estrogen-like activities in postmenopausal women, which may be valuable as a hormone replacement therapy, but it may also increase the risk for developing endometrial carcinoma 3.
• The use of tamoxifen has raised questions about the long-term safety of antiestrogen therapy, particularly with regards to ovarian function in premenopausal women and the potential risks to the fetus if pregnancy occurs 3.

Mechanism of Action

• The mechanism of tamoxifen resistance in breast cancer is complex and involves multiple factors, including downregulation of estrogen receptor alpha (ERα) and protective autophagy of drug-resistant cells 4.
• Recent progress in reducing resistance to tamoxifen has been made, and possible research directions into tamoxifen resistance in the future include the development of novel tamoxifen derivatives with reduced side effects 4, 5.
• The pharmacological activity of Tamoxifen is dependent on its conversion to its active metabolite, endoxifen, by CYP2D6, and it reduces the risk of recurrence and death from breast cancer when given as adjuvant therapy 6.