Aromatase Inhibitors

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Chapter: Essential pharmacology : Estrogens, Progestins and Contraceptives

Aromatization of ‘A’ ring of testosterone and androstenedione is the final and key step in the production of estrogens (estradiol/estrone) in the body. In addition to the circulating hormone, locally produced estrogens appear to play an important role in the development of breast cancer.


AROMATASE INHIBITORS

 

Aromatization of ‘A’ ring of testosterone and androstenedione is the final and key step in the production of estrogens (estradiol/estrone) in the body. In addition to the circulating hormone, locally produced estrogens appear to play an important role in the development of breast cancer. Though some aromatase inhibitors (AIs) were produced in the past, three recent ‘third generation’ AIs Letrozole, Anastrozole and Exemestane have demonstrated clinical superiority in the treatment of breast cancer.

 

Letrozole

 

It is an orally active nonsteroidal compound that reversibly inhibits aromatization all over the body, including that within the breast cancer cells, resulting in nearly total estrogen deprivation. Proliferation of estrogen dependent breast carcinoma cells is suppressed to a greater extent than with tamoxifen. Letrozole is rapidly absorbed with 100% oral bioavailability, large volume of distribution, slow metabolism and a t½ of ~40 hours. Randomized clinical trials have established its utility in:

 

a)  Early breast cancer: as adjuvant therapy after mastectomy in ER+ive cases. Extension of prophylaxis with letrozole beyond the standard 5 year tamoxifen treatment continues to afford protection, whereas continuation of tamoxifen is not useful. Survival is prolonged in patients who have positive axilary lymph nodes.

 

b)  Advanced breast cancer: Current guidelines recommend letrozole as first line therapy because of longer time to disease progression and higher response rate obtained with it compared to tamoxifen. It is also effective as second line treatment when tamoxifen has failed.

 

Adverse Effects

 

Hot flushes, nausea, diarrhoea, dyspepsia and thinning of hair are the side effects. Joint pain is common and it can accelerate bone loss, but there is no endometrial hyperplasia or increased risk of endometrial carcinoma. Risk of venous thromboembolism is also not increased, and there is no deterioration of lipid profile.

 

Dose: 2.5 mg BD oral.

 

LETOVAL, LETROZ, FEMARA, ONCOLET 2.5 mg tab. Though contraindicated in premenopausal women, letrozole was clandestinely promoted and tested as an ovulation inducing fertility drug. This was stopped after media outcry.

 

Anastrozole

 

Another nonsteroidal and reversible (Type 2) AI, more potent than letrozole and suitable for single daily dosing. It accumulates in the body to produce peak effect after 7–10 days. Anastrozole is useful as adjuvant therapy in early ER+ive breast cancer as well as for palliation of advanced cases in postmenopausal women. In early cases, tumor recurrence time was found to be longer than with tamoxifen. Risk of new tumor appearing in the contralateral breast was also lower with anastrozole. A longer time to disease progression compared to tamoxifen has been obtained in advanced ER+ive breast cancer. Many tamoxifen resistant cases responded with increased survival. Side effects are hot flushes, vaginal dryness, vaginal bleeding, nausea, diarrhoea, thinning of hair. Arthralgia and acceleration of osteoporosis are prominent. However, it does not predispose to endometrial carcinoma or to venous thromboembolism.

 

Dose: 1 mg OD; ALTRAZ, ARMOTRAZ 1 mg tab.

 

Exemestane

 

This steroidal and irreversible (Type 1) inhibitor of aromatase acts like a suicide substrate by covalent binding to the enzyme. As a result >90% suppression of estradiol production is obtained. However, like androstenedione, it has weak androgenic activity. Exemestane has been found beneficial in early breast cancer by reducing the risk of disease progression when it was substituted for tamoxifen as adjuvant therapy. In advanced breast cancer, longer survival, increased time to disease progression and fewer treatment failures have been obtained with exemestane. It is administered orally and is well tolerated. Adverse effects are similar to other AIs.

 

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