Tamoxifen vs. Aromatase Inhibitors – How do they work?

About 75% of breast cancers are positive for the oestrogen receptor (ER) and/or progesterone receptor (PR)1,2,3. Of these, oestrogen is the main female hormone stimulating breast cancer growth. ER-positive cancer cells have their oestrogen receptors on the cell surface, and when these receptors are activated by oestradiol (a type of circulating oestrogen hormone), cells multiply (proliferate) and therefore the cancer grows4. Both tamoxifen and aromatase inhibitors (AIs) are hormonal therapies used in the treatment of oestrogen positive (ER-positive) breast cancers to stop tumour growth and recurrence. 

Where is oestrogen produced? 

In premenopausal women, oestrogen is mainly produced by the ovaries. However, for everyone including men, a small amount of oestrogen 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 oestradiol. After the menopause, there is no longer oestrogen production in the ovaries, but aromatase activity persists so oestrogen is still present.

How does Tamoxifen work?

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, oestradiol is still present in normal amounts in the body, but it cannot activate the cancer cells to grow further (see diagram).

 

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 oestrogen receptors and cancer growth.

How do Aromatase Inhibitors work?

On the other hand, aromatase inhibitors (AIs) are used to treat post-menopausal women and men with ER-positive breast cancer. AIs work by preventing the enzyme aromatase from doing its job of converting other hormones into oestradiol, thus oestradiol production is stopped (see diagram). These inhibitors are much more effective than tamoxifen for post-menopausal women9,10. The reason why AIs are not used in pre-menopausal breast cancer patients is that they 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 oestrogen 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.

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References

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[7] Bostner J, Karlsson E, Pandiyan MJ, Skoog L, Fornancder T, Nordenskjold B, Stal O.  Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit. Breast Cancer Res Treat. 2013;137(2):397-406.

[8] Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther. 2008;83(1):160-6. 

[9] Geisler J, King N, Dowsett M, Ottestad L, Lundgren S, Walton P, Kormeset PO, Lonning PE. Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer. 1996; 74:1286–1291.

[10] Geisler J, King N, Anker G, Ornati G, Salle ED, Lonning PE, Dowsett M. In-vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in post-menopausal breast cancer patients. Clinical Cancer Research. 1998; 4: 2089-2093.

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[12] Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002, 20: 751-757. 

[13] Miller WR, Jackson J. The therapeutic potential of aromatase inhibitors. Expert Opin Investig Drugs. 2003, 12: 1-12. 10.1517/13543784.12.1.1.

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