Tamoxifen vs. Aromatase Inhibitors – How do they work?

In this blog we discuss how two different treatments for hormone positive breast cancer (tamoxifen vs. aromatase inhibitors) work.

Hormone Receptor Positive Breast Cancer 

About 75% of breast cancers are positive for the estrogen receptor (ER) and/or progesterone receptor (PR)1,2,3. Cases of hormone receptor (HR+) breast cancer increased between the years of 1990 and 2015, specifically in women aged 40 to 69 years. Increased exposure to estrogen may be one of the reasons for this, caused by an earlier age of period onset, higher body mass index and increased use of hormone therapy (such as hormone replacement therapy in postmenopausal women). 

woman holding iPhone with suggested questions listIf you have HR+ breast cancer, you can receive information that is relevant for your specific breast cancer subtype from the OWise app. Simply fill out the profile questions and from there you can generate a personalised treatment plan and a suggested questions list to ask at your next doctor’s appointment.

What are estrogen and progesterone?

Estrogen and progesterone are both hormones that travel in the blood to tell other parts of the body how to function. In women, estrogen and progesterone are the vital sex hormones that regulate menstrual cycles and play an important role in pregnancy.

In breast cancer, these hormones have a very different function. Once they have made contact with cancer cells, they stimulate them to grow. This discovery has led to a whole new category of treatment called hormone therapy. Carry on reading to find out what they are and how they work!

What do these hormones have to do with breast cancer?

Of these, estrogen is the main female hormone stimulating breast cancer growth. ER-positive cancer cells have their estrogen receptors on the cell surface, and when these receptors are activated by estradiol (a type of circulating estrogen hormone), cells multiply (proliferate) and therefore the cancer grows4. To find out more about how estrogen functions in breast cancer, check out our previous post. Both tamoxifen and aromatase inhibitors (AIs) are hormonal therapies used in the treatment of estrogen positive (ER-positive) breast cancers to stop tumour growth and recurrence. 

Where is estrogen produced? 

In premenopausal women, estrogen is mainly produced by the ovaries. However, for everyone including men, a small amount of estrogen is also produced in other tissues, such as in fat cells, the breast, bone, liver and brain5. In this instance, the enzyme aromatase is used to convert other hormones (such as testosterone) into estradiol. After menopause, there is no longer oestrogen production in the ovaries, but aromatase activity persists so estrogen is still present.

How does Tamoxifen work?

Tamoxifen binds to the estrogen receptors, preventing estrogen from binding to them. This blocks estrogen from being able to promote cell growth.

Tamoxifen was the first specific hormone-based therapy to be used in breast cancer treatment that demonstrated significant clinical success6. This drug is used in the treatment of pre-menopausal and post-menopausal women, as well as men, whose breast cancer biopsies showed elevated levels of the oestrogen receptor. Tamoxifen works by blocking the oestrogen receptors on the cancer cells. This way, estradiol is still present in normal amounts in the body, but it cannot activate the cancer cells to grow further (see diagram). 

What happens when tamoxifen doesn’t work?

However, some ER-positive patients do not respond to tamoxifen, or they may become resistant.  Although the mechanisms to explain the resistance to tamoxifen remains unclear, one of the hypotheses is that when cells are “fed up” with this drug, they sometimes respond by elevating the expression of the gene “AKT”. This is a survival gene that helps to stimulate cell growth and proliferation in normal situations. In breast cancer, the AKT gene can become overactive and confer resistance by allowing cancer cells to continue using the oestrogen receptor even in the presence of tamoxifen7.

Another hypothesis why some patients might not benefit from tamoxifen is because of an enzyme called CYP2D6. This enzyme converts tamoxifen into its active form and about 10% of people have a CYP2D6 enzyme that does not function well8. Having an abnormal CYP2D6 enzyme might prevent tamoxifen from blocking estrogen receptors and cancer growth.

How do Aromatase Inhibitors work?

Aromatase inhibitors prevent the enzyme aromatase from working. This stops estrogen production in the body and therefore there is no estrogen available to promote cancer cell growth.

On the other hand, aromatase inhibitors (AIs) are used to treat postmenopausal women and men with ER-positive breast cancer. AIs work by preventing the enzyme aromatase from doing its job of converting other hormones into estradiol, thus estradiol production is stopped (see diagram). These inhibitors are much more effective than tamoxifen for post-menopausal women9,10.

Tamoxifen vs. Aromatase Inhibitors

Unlike tamoxifen, aromatase inhibitors are not often used to treat pre-menopausal breast cancer patients. This is because AIs cannot block the oestradiol production in the ovaries. However, a pre-menopausal woman can be treated with the aromatase inhibitor exemestane if their ovarian function is suppressed by drugs such as goserelin11. Letrozole, anastrozole and exemestane are third-generation AIs, and often decrease circulating estrogen to undetectable levels12 thereby reducing tumour proliferation and growth13. However, the response rate varies from 35% to 70% in primary breast cancer and might be lower in advanced cancer14.

Keep track of your hormonal therapy side effects with OWise

iPhone XS Trends SlidersHormonal therapies can trigger multiple side effects. Some of the most common include bone and joint pain, hot flashes, nausea, fatigue, mood swings, headaches, constipation, dry skin and loss of libido. With OWise, you can track them over time, and share your well-being data with yourself, doctors and loved ones.

Try out the side-effects tracking and let us know if this article has helped you. Do you have any comments or suggestions? Contact us

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