Oncological Endocrine Therapy: Tamoxifen, Anastrozole and Letrozole

Mechanism

Pharmacological Class and Group

Selective estrogen receptor modulators (SERM: Tamoxifen) and non-steroidal third-generation selective aromatase inhibitors (Anastrozole and Letrozole).

Mechanism of Action

• Tamoxifen: It is a selective modulator that competitively binds to intracellular estrogen receptors (ER) in various target tissues. It has a selective biphasic action: it acts as a potent estrogenic antagonist in tumor breast tissue, blocking the transcription of mitogenic genes that promote proliferation; but it acts as a partial estrogen agonist in the cellular endometrium, bone tissue and the blood coagulation system.
• Anastrozole and Letrozole: They are highly selective and reversible inhibitors of the enzyme cytochrome P450 Aromatase (CYP19A1), which mediates the conversion and peripheral transformation of adrenal androgens (androstenedione and testosterone) into estrogens (estrone and estradiol) in body adipose tissues. This drastically reduces (up to 95-98%) circulating estrogen levels in postmenopausal women, depriving the tumor of the estrogenic signal for cell growth.

Pharmacokinetics

The Metabolism of Tamoxifen by CYP2D6 to Endoxifen

Tamoxifen is largely a low-affinity prodrug for the estrogen receptor; requires phase I hepatic biotransformation to produce its active therapeutic metabolites, the one with the greatest cellular potency being Endoxifen (4-hydroxy-N-desmethyltamoxifen), which has up to 100 times greater affinity for the estrogen receptor:

Tamoxifen CYP3A4 N-desmethyltamoxifen CYP2D6 Endoxifen (Primary Active Metabolite)

Patients who inherit poor metabolizer phenotypes for the CYP2D6 isoenzyme, or those treated simultaneously with potent CYP2D6 inhibitor drugs (such as the SSRI antidepressants Fluoxetine or Paroxetine), present undetectable levels of plasma endoxifen, measurably doubling the rate of tumor recurrence and adjuvant treatment failure.

High Resolution Pharmacokinetics

• Oral absorption and Bioavailability: Excellent rapid, full-course oral absorption for all compounds, not being affected by food.
• Metabolism: Tamoxifen is extensively metabolized by the isoenzymes CYP3A4 (to N-desmethyltamoxifen) and CYP2D6 (to endoxifen). Anastrozole and letrozole are cleared by CYP3A4-mediated phase I hepatic metabolism and conjugation with glucuronides.
• Half-life (t_1/2): The half-life of circulating tamoxifen is extremely long, approximately 5 to 7 days, taking up to 4 weeks to reach stable plasma levels; that of anastrozole is 40 to 50 hours, and that of letrozole is approximately 45 to 120 hours.

Indicators and dose

Clinical Indications and Frequent Regimens

• Tamoxifen: Estrogen receptor-positive (ER+) breast cancer in premenopausal and postmenopausal women on an adjuvant course for 5 to 10 continuous years, or in metastatic disease.
• Anastrozole / Letrozole: First-choice adjuvant treatment in ER+ early breast cancer in postmenopausal women exclusively (in premenopausal women, peripheral inhibition stimulates compensatory pituitary feedback that increases ovarian production of estrogen, canceling its therapeutic effect).

Dosage and Clinical Adjustment

• Oral tamoxifen: 20 mg orally once a day continuously and without interruptions for 5 to 10 years.
• Oral anastrozole: 1 mg orally once a day continuously for 5 years.
• Oral letrozole: 2.5 mg orally once a day continuously for 5 years.
• No adjustments are suggested for mild-moderate renal or hepatic failure.

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Absolute and Relative Contraindications

Contraindications of Tamoxifen

• Hypersensitivity to the active ingredient.
• Personal history of venous thromboembolism (DVT or Pulmonary Embolism) active or previous.
• Concomitant use of strong CYP2D6 inhibitor antidepressants (Fluoxetine, Paroxetine).
• Pregnancy confirmed.

Contraindications of Aromatase Inhibitors

• Women with active premenopausal hormonal status (due to absolute futility and severe ovarian stimulation).
• Severe persistent osteoporosis not treated with antiresorptives.

Adverse Effects (ADR) and Specific Toxicity

• Tamoxifen: Deep venous thromboembolism and pulmonary embolism (due to procoagulant estrogenic effect on the synthesis of hepatic coagulation factors), hot flashes, Endometrial Hyperplasia or Cancer (due to estrogenic stimulation in the uterine epithelium, requiring mandatory ultrasound monitoring if vaginal bleeding appears abnormal).
• Aromatase Inhibitors: Arthralgias and severe joint stiffness in 30% of the treated patients (due to loss of estrogens that modulate the synovial fluid), Accelerated loss of bone mineral density with marked osteoporosis and risk of bone fracture, dyslipidemia.