Can’t tolerate tamoxifen side effects, can I stop taking it? Pharmacogenetic testing improves treatmentRuslan Dorfman, PhD, MBA
Have you been prescribed hormone therapy for cancer but can’t tolerate tamoxifen side effects?
For many women, tamoxifen side effects are too much to stomach, and the prospect of enduring them for five years is not appealing even at the risk of cancer recurrence.
Tamoxifen is an option for hormone therapy used to prevent the recurrence of breast cancer in women with estrogen receptor-positive (ER-positive) tumours. Tamoxifen is prescribed as an adjuvant (or add-on) hormone treatment for premenopausal and postmenopausal women. Aromatase inhibitors, anastrozole and letrozole, are approved for use in postmenopausal women. Tamoxifen’s effectiveness and side effects are largely influenced by genetic variations in the CYP2D6 enzyme, which metabolizes tamoxifen and other drugs in the liver. Hot flashes, mood swings, depression, fatigue, weight gain, and loss of libido are common tamoxifen side effects. Genetics-guided selection of hormone therapy can help to improve tolerance to treatment and reduce your risk of cancer recurrence.
When is tamoxifen prescribed?
Women with early-stage ER-positive cancers have similar survival rates with or without tamoxifen. Tamoxifen is recommended for women at higher risk of cancer recurrence based on a tumour risk score assessed by OncotypeDX or Mammaprint. Women who receive at least five years of tamoxifen treatment after breast cancer surgery reduce their risk of cancer recurrence, developing cancer in the other breast, or both. Tamoxifen might also be prescribed before breast cancer surgery to shrink the tumour and reduce the risk of metastasis. Tamoxifen and aromatase inhibitors are also important for preserving brain health in women surviving breast cancer. Continued use of these medications significantly reduces the risk of developing Alzheimer’s disease, Parkinson’s and other neurodegenerative conditions.
How does tamoxifen work?
ER-positive tumours require estrogen for growth. A liver enzyme, CYP2D6, processes tamoxifen into endoxifen (4-OH-N-desmethyl-tamoxifen), a molecule that blocks the Estrogen Receptor, reducing the risk of cancer. Endoxifen and another molecule, afimoxifene, derived from tamoxifen, are 30–100 times more potent than tamoxifen itself. The association between CYP2D6 metabolizer status and breast cancer−specific mortality is U-shaped: both slow and ultrafast metabolizers having worse outcomes. Understanding your genetic profile provides insights about your risk of tamoxifen side effects and the effectiveness of treatment.
Tamoxifen may be less effective for slow metabolizers
Slow (poor) CYP2D6 metabolizers had a greater risk of cancer recurrence because of reduced tamoxifen effectiveness. Women with inherently reduced activity of the CYP2D6 liver enzyme process tamoxifen into the potent endoxifen very slowly. In Canada, 7-10% of women process tamoxifen at significantly reduced rates as their CYP2D6 enzyme does not function and require alternative treatment such as aromatase inhibitors such as anastrozole (Arimidex), exemestane (Aromasin) or letrozole (Femara)
Additionally, 12%-18% of women in North America and Europe may have reduced CYP2D6 activity and may benefit from a dose increase. The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy suggests switching to an aromatase inhibitor for postmenopausal women with reduced CYP2D6 liver enzymes. If aromatase inhibitor use is contraindicated, the tamoxifen dose may be increased to FDA-approved 40 mg/day.
Fast metabolizers have a higher risk of tamoxifen side effects
On the other hand, ultrarapid (fast) CYP2D6 metabolizers process tamoxifen into endoxifen very quickly, leading to more severe side effects. For ultrarapid metabolizers, the cancer recurrence risk is attributed to a higher rate of treatment discontinuation.
Pillcheck’s pharmacogenetic testing can help you and your doctor to assess the function of your CYP2D6 liver enzyme and select an appropriate treatment option and tamoxifen dose to reduce your risk of cancer recurrence.
Breast cancer, antidepressants and pain medication
It is important to note that some commonly used antidepressants such as fluoxetine (Prozac), paroxetine (Paxil) and other SSRIs can interfere with tamoxifen metabolism and increase the risk of cancer recurrence. The risk of antidepressant-tamoxifen interaction is higher for women with reduced function in their CYP2D6 enzyme. Women receiving tamoxifen treatment should avoid CYP2D6-dependent antidepressants and other medications. Pain medications that are processed by the CYP2D6 enzyme include tramadol, oxycodone, codeine (Tylenol #3), duloxetine (Cymbalta), and venlafaxine (Effexor). Pillcheck pharmacists can help you and your doctor to assess which antidepressants and painkillers could be used safely along with tamoxifen.
Reduce the risk of deep vein thrombosis and stroke with pharmacogenetics
Women taking tamoxifen can also be at higher risk of blood clots and stroke, especially if they carry mutations in the F2 or F5 genes. These genes encode for blood clotting factors, and women that carry mutations are at greater risk of deep vein thrombosis and stroke, particularly if smoking or taking estrogen inhibitors such as tamoxifen. Pillcheck assesses whether you carry variations in these two genes and can guide you to safer treatment options.
- Tamoxifen is a crucial breast/ovarian cancer treatment that can reduce the risk of cancer recurrence
- Tamoxifen effectiveness and tolerability are affected by genetic variations in your CYP2D6 liver enzyme
- Tamoxifen should not be taken along with some antidepressants and painkillers that can block CYP2D6 function
- Women that carry mutations in F2 or F5 genes should avoid taking tamoxifen due to increased risk of stroke
- Pillcheck pharmacogenetics-based medication optimization service can help to assess your risk of tamoxifen side effects and help to guide your cancer, depression and pain treatment.