Can’t tolerate tamoxifen side effects, can I stop taking it? Pharmacogenetic testing improves treatment

Tamoxifen is one of the most effective treatments for preventing estrogen receptor-positive (ER-positive) breast cancer from coming back, but side effects such as hot flashes, mood changes and fatigue lead many women to consider stopping. Stopping early on your own can increase the risk of recurrence, but there are better options: managing side effects, switching to another hormone therapy, or adjusting treatment based on your genes and other medications. A pharmacogenetic test of the CYP2D6 gene shows how well your body activates tamoxifen and helps you and your oncologist choose.

Why is tamoxifen prescribed?

Most breast cancers are ER-positive, which means estrogen helps them grow. Hormone (endocrine) therapy blocks this effect and is recommended for almost all women with ER-positive invasive breast cancer, usually for 5 to 10 years after surgery. In an analysis of 20 randomized trials with more than 21,000 women, 5 years of tamoxifen in ER-positive breast cancer roughly halved the rate of recurrence in the first 5 years and reduced breast cancer deaths by about a third over 15 years.

Tamoxifen can be used before or after menopause. Aromatase inhibitors, such as anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin), are used after menopause, or before menopause together with treatment that suppresses the ovaries. Tests such as Oncotype DX and MammaPrint help decide whether chemotherapy is needed; they do not decide whether hormone therapy is needed.

What are the side effects of tamoxifen?

Common side effects include hot flashes and night sweats, vaginal discharge or dryness, mood changes, fatigue and lower libido. Less common but serious risks include blood clots in the legs or lungs, stroke and, in women past menopause, cancer of the lining of the uterus, which is why any unusual vaginal bleeding should be reported. The benefits of tamoxifen for women with ER-positive breast cancer are much larger than these risks.

Can I stop taking tamoxifen?

Do not stop without talking to your oncologist. Stopping early is linked with a higher risk of the cancer coming back. If side effects are hard to live with, ask about:

• Treating the side effects. Hot flashes can be eased with non-hormonal options such as venlafaxine or gabapentin. Read more in Precision medicine of menopause and depression.
• Switching hormone therapy. After menopause, an aromatase inhibitor is an alternative; before menopause, an aromatase inhibitor can be combined with ovarian suppression.
• Checking your genes and medications. CYP2D6 results and a medication review can show whether tamoxifen is likely to work well for you and whether another drug is interfering with it.

How do genes affect tamoxifen?

Tamoxifen itself is a weak drug. The liver enzyme CYP2D6 converts it into endoxifen and 4-hydroxytamoxifen, which block the estrogen receptor 30 to 100 times more strongly. People with low CYP2D6 activity make less endoxifen. The CPIC guideline for CYP2D6 and tamoxifen recommends:

CYP2D6 metabolizer type	CPIC recommendation
Ultrarapid or normal	Standard tamoxifen dose (20 mg/day). Avoid drugs that block CYP2D6.
Intermediate	Consider an aromatase inhibitor (with ovarian suppression if premenopausal), or a higher tamoxifen dose of 40 mg/day if an aromatase inhibitor cannot be used. Avoid drugs that block CYP2D6.
Poor	An aromatase inhibitor (with ovarian suppression if premenopausal) is recommended. If it cannot be used, 40 mg/day of tamoxifen can be considered, although it may not fully make up for the low endoxifen levels.

About 5% to 10% of people of European ancestry are CYP2D6 poor metabolizers. In a Swedish study of 1,309 women taking tamoxifen, the risk of dying from breast cancer was higher in both poor and ultrarapid metabolizers than in normal metabolizers. Ultrarapid metabolizers were also much more likely to stop tamoxifen within 6 months (18.8% compared with about 7% in the other groups), probably because of stronger side effects.

Which medications should be avoided with tamoxifen?

Some medications block CYP2D6 and lower endoxifen levels, which can make tamoxifen less effective. In an Ontario study of women aged 66 and older, the longer women took paroxetine at the same time as tamoxifen, the higher their risk of dying from breast cancer; no such risk was seen with other antidepressants.

• Strong CYP2D6 blockers to avoid: paroxetine (Paxil), fluoxetine (Prozac), bupropion (Wellbutrin), quinidine and terbinafine.
• Moderate blocker to use with caution: duloxetine (Cymbalta).
• Usually preferred antidepressants: venlafaxine, desvenlafaxine, escitalopram and citalopram, which have little or no effect on CYP2D6.

Pain medications such as codeine, tramadol and oxycodone do not reduce tamoxifen's effect, but CYP2D6 also affects how well codeine and tramadol relieve pain. Read more in Pain and depression drugs not working? and preparing for cancer surgery. A Pillcheck pharmacist can check all your medications for interactions with tamoxifen.

Do genes and drug interactions affect aromatase inhibitors?

Aromatase inhibitors work without being activated by CYP2D6, which is why they are a good choice for women whose CYP2D6 does not work well. Instead, the liver clears them mostly through another enzyme, CYP3A4, and letrozole also through CYP2A6.

• Some medications can make exemestane (Aromasin) weaker. Drugs that speed up CYP3A4, such as rifampin (an antibiotic), the seizure medications phenytoin, carbamazepine and phenobarbital, and the herbal product St. John's wort, can cut exemestane levels by about half. The exemestane drug label recommends doubling the dose if you need one of these medications.
• Anastrozole (Arimidex) has few important drug interactions.
• Letrozole (Femara) levels vary a lot between people. In a study of about 500 women, blood levels differed more than 10-fold, partly because of the CYP2A6 gene, body weight and age. People with a slower CYP2A6 enzyme clear letrozole more slowly.

There are no genetic dosing guidelines for aromatase inhibitors yet. Pillcheck reports your CYP3A4 status (it does not test CYP2A6), and a Pillcheck pharmacist can check whether any of your medications could make your aromatase inhibitor less effective.

What about blood clots?

Tamoxifen increases the risk of blood clots, especially in women over 55 and during periods of immobility, such as after surgery. The risk is higher in women who have had a clot before or who carry inherited clotting variants in the F5 (Factor V Leiden) or F2 (prothrombin) genes, and smoking adds to it. Aromatase inhibitors do not increase clot risk, so women with these risk factors should discuss the best option with their oncologist. Pillcheck tests for the F5 and F2 variants.

Does tamoxifen affect brain health?

In a US claims study of nearly 58,000 women with breast cancer, those treated with hormone therapy, including tamoxifen, were less likely to be diagnosed with Alzheimer's disease or dementia. This was an observational study, so it shows an association rather than proof.

How can a pharmacogenetic test help?

The Pillcheck test reports your CYP2D6 metabolizer type, which matters for tamoxifen, your CYP3A4 status, which helps check aromatase inhibitors for drug interactions, and the F5 and F2 clotting variants, along with many other genes. A Pillcheck pharmacist reviews your results and all your medications, including antidepressants and pain medications, and sends recommendations to help your oncologist choose the most effective and best-tolerated hormone therapy.

Summary

• Tamoxifen greatly reduces the risk of ER-positive breast cancer coming back and of dying from it.
• Do not stop tamoxifen on your own; side effects can be treated, and other hormone therapies are available.
• CYP2D6 poor and intermediate metabolizers make less active endoxifen, and CPIC recommends considering an aromatase inhibitor.
• Avoid strong CYP2D6 blockers such as paroxetine, fluoxetine and bupropion while taking tamoxifen.
• Women with a history of blood clots or F5/F2 variants should discuss their options with their oncologist.

Frequently asked questions

Can I stop taking tamoxifen because of side effects?

Talk to your oncologist first. Side effects can often be treated, and switching to an aromatase inhibitor (with ovarian suppression before menopause) may be an option. Stopping early increases the risk of recurrence.

How does CYP2D6 affect tamoxifen?

CYP2D6 converts tamoxifen into its active form, endoxifen. Poor and intermediate metabolizers make less endoxifen, which may make tamoxifen less effective.

Which antidepressants are safe with tamoxifen?

Venlafaxine, desvenlafaxine, escitalopram and citalopram are usually preferred. Paroxetine, fluoxetine and bupropion should be avoided because they block CYP2D6.

Does tamoxifen cause blood clots?

It increases the risk, especially in women over 55, after surgery, in smokers and in carriers of F5 or F2 clotting variants. Aromatase inhibitors do not increase clot risk.

How long is tamoxifen usually taken?

Usually 5 to 10 years, depending on the risk of recurrence and how well it is tolerated.

References

Goetz MP, Sangkuhl K, Guchelaar HJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther. 2018;103(5):770-777.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771-784.

He W, Grassmann F, Eriksson M, et al. CYP2D6 Genotype Predicts Tamoxifen Discontinuation and Prognosis in Patients With Breast Cancer. J Clin Oncol. 2020;38(6):548-557.

Desta Z, Kreutz Y, Nguyen AT, et al. Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol Ther. 2011;90(5):693-700.

Puszkiel A, Dalenc F, Tafzi N, et al. Identification of non-adherence to adjuvant letrozole using a population pharmacokinetics approach in hormone receptor-positive breast cancer patients. Eur J Pharm Sci. 2024;199:106809.

AROMASIN (exemestane) tablets: full prescribing information. US Food and Drug Administration. Revised May 2018.

Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ. 2010;340:c693.

Branigan GL, Soto M, Neumayer L, et al. Association Between Hormone-Modulating Breast Cancer Therapies and Incidence of Neurodegenerative Outcomes for Women With Breast Cancer. JAMA Netw Open. 2020;3(3):e201541.

Tamoxifen Therapy and CYP2D6 Genotype. In: Medical Genetics Summaries. National Center for Biotechnology Information (US).

CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study. Breast Cancer Res. 2018.

Impact of CYP2D6 polymorphisms on endoxifen concentrations and breast cancer outcomes. Pharmacogenomics J.