Tamoxifen to Fulvestrant – The Treatment Pathway in HR+ Breast Cancer

The breast cancer therapy in estrogen-positive breast cancer is the transition from tamoxifen, which inhibits estrogen secretion, to complete receptor blockade by fulvestrant at advanced stages.

Tamoxifen provides a partial inhibition, while Fulvestrant, which degrades the estrogen receptor, is widely used in advanced or resistant cancer.

What is Tamoxifen and SERM?

SERMs are the selective receptor (estrogen) modulators that bind to exhibit different actions at different locations. They antagonize receptors in the breast while mimicking estrogen activity in other organs.

Tamoxifen is a SERM drug. It competitively binds to the estrogen receptor, which inhibits estrogen activity. It binds to the estrogen receptor present in the breast tissue and has an antagonistic action. It mimics the estrogen action in other tissues, including bones, ovaries. It is used in women who develop cancer at an early age.

What is Fulvestrant and SERD?

SERDs are the selective estrogen receptor degraders. It selectively blocks estrogen receptors and completely inhibits estrogen expression, without partial agonist activity.

Fulvestrant is a SERD. It works by degrading the estrogen receptor, inhibiting estrogen binding. It is used in advanced-stage breast cancer. It not only blocks estrogen activity but also destroys estrogen receptors and is often used in endocrine therapy-resistant cancers.

Why Switch from Tamoxifen?

• Development of Resistance – Long-term use of tamoxifen leads to drug resistance. The estrogen molecules adapt to the modulated receptor and show their expression.
• Partial Agonist action – The competitive receptor binding does not offer complete blockade. The agonist nature of tamoxifen increases the risk of developing cancer in the ovaries and also increases the formation of blood clots.
• Advanced disease – When the disease is progressing or metastasized, for a stronger blockade of estrogen receptor, fulvestrant or other aromatase inhibitors are used.

Advantages of Fulvestrant

• • It offers a complete blockade of the estrogen receptor
• • No partial agonist action.
• • Widely used in cancers that no longer respond to hormone therapy.
• • Do not increase the risk of endometrial or blood clots.
• • It is widely used in postmenopausal women.
• • It is used to treat advanced-stage breast cancer and metastasized cancer.
• • It reduces the risk of cancer recurrence.

The Treatment Pathway

Early stage therapy – Tamoxifen is commonly used in premenopausal women as adjuvant therapy or after surgery or radiation. It is usually taken for 5 to 10 years in the form of oral preparation.

Progression or post-menopausal setting – In later age, when the cancer progresses after menopause, estrogen is produced primarily from the ovaries, and the treatment is shifted from tamoxifen to aromatase inhibitors or fulvestrant for potent suppression. Aromatase enzyme is responsible for estrogen production.

Resistant cancer – Fulvestrant is used in hormone-resistant or aromatase-resistant breast cancer. It is the resistant case when endocrine therapy is not effective. Fulvestrant degrades and blocks the estrogen receptor.

Combination therapy in advanced cases – In advanced or metastasized breast cancer, fulvestrant is used in combination with other therapies or drugs like CDK4/6 inhibitors that inhibit estrogen signaling, while fulvestrant degrades the estrogen receptor. It offers dual suppression and potent action against cancer cells.

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