Continuing Education Activity

Anastrozole is a medication used in the management and treatment of breast cancer. It is in the aromatase inhibitors class of drugs. This activity describes the indications, action, and contraindications for anastrozole as a valuable agent in managing advanced hormone-receptive breast cancer. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients with breast cancer and related conditions.

Objectives:

• Describe the mechanism of action of aromatase inhibitors.
• Summarize the potential adverse reactions and contraindications of aromatase inhibitor use.
• Review the indicated uses for aromatase inhibitors in current medical practice.
• Outline the importance of improving care coordination amongst interprofessional team members to improve health care outcomes for patients affected by breast cancer and other conditions.

Indications

Aromatase inhibitors (AIs) are indicated in the treatment of hormone-receptive breast cancer in postmenopausal women in various settings. Studies have shown that they are effective when used as adjuvant therapy to chemotherapy and surgery in metastatic estrogen-dependent breast cancer. Their use in preventative and adjuvant therapies for other conditions is currently under investigation.[1][2]

FDA Approved Indications

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer[3]
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer[4]
• Second-line treatment of advanced breast cancer that has progressed on Tamoxifen therapy[5]
• Treatment of male gynecomastia[6] 
• Second-line treatment for the prevention of hormone-receptor-positive breast cancer[7]

FDA Non-approved Indications

• Treatment of benign conditions like cyclical breast pain and recurrent fibrocystic disease[6]
• Treatment of symptomatic myomas and endometriosis as an alternative to surgical intervention [8]
• Ovulation induction in the treatment of infertility[9]
• Treatment of male breast cancer[10]
• Treatment of prostate cancer[6]
• Treatment of late-onset hypogonadism or partial androgen deficiency, obesity-related hypogonadotropic hypogonadism, and male subfertility[11]
• Treatment of rare pediatric conditions associated with sex steroid excess[12]
• Treatment of boys with short stature and constitutional delay of puberty[12]
• Prevention of the initial estrogen flare effect of gonadotropin-releasing hormone agonist treatment[8]

Mechanism of Action

Aromatase inhibitors (AIs) inhibit the action of the enzyme aromatase. Aromatase (estrogen synthetase) is a member of the cytochrome P450 superfamily of monooxygenases and catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens.[13] In postmenopausal women, the conversion of androgens to estrogens via this pathway in the adrenal glands, the skin, the muscle, and the adipose tissue, is the primary source of estrogen. Aromatase inhibitors block this pathway and consequently suppress estrogen levels in postmenopausal women. The breast cancer cells also demonstrate aromatase activity, a likely source of local estrogen for the tumor cells. The inhibition or inactivation of aromatase suppresses serum estrogen levels, which decrease estrogen-mediated cancer cell proliferation in hormone receptor-positive breast cancer.[14]

In premenopausal women, AIs induce an increase in gonadotropin secretion secondary to the reduced negative feedback of estrogen to the pituitary, resulting in ovarian stimulation. Clinicians can use AIs to induce ovulation in the treatment of infertility.[15][14] Aromatase activity increases in endometriosis with extrauterine endometrial tissue acting as a source of estrogens. Estrogen stimulates the synthesis of PGE2, which causes increased aromatase activity in the endometrium. This vicious cycle leads to the growth of ectopic endometrial tissue, which is blocked by aromatase inhibitors by inhibiting the synthesis of estrogen in extrauterine endometrial tissue.[16][17]

In men, estrogen excess shows an association with premature closure of the epiphyses. Aromatase inhibitors decrease estrogen by inhibiting the conversion of testosterone to estrogen and have therefore been used in patients with short stature and/or constitutional delay of puberty. Lowering estrogen levels is associated with an increase in LH, FSH, and testosterone. Therefore aromatase inhibitors have also been used in late-onset hypogonadism or partial androgen deficiency. In obese men, there is an increased conversion of androgens to estrogen in the adipose tissue, leading to increased estrogen levels. Aromatase inhibitors also decrease this conversion causing decreased estrogen and increased testosterone and FSH in men with obesity-related hypogonadotropic hypogonadism and male subfertility.[18]

Administration

Anastrozole, a selective aromatase inhibitor, is available as a 1 mg tablet, which is to be taken orally once a day, with or without food. No dose adjustment is necessary for patients with renal or liver impairment or elderly patients. The American Society of Clinical Oncology recommends the use of aromatase inhibitors as a component of adjuvant hormonal therapy after surgery for ten years in postmenopausal patients who have a diagnosis of early-stage, node-positive, and hormone receptive breast cancer.

Letrozole is also a selective aromatase inhibitor. It is manufactured in 2.5 mg tablets. For postmenopausal breast cancer, dosing is 2.5 mg daily. As an agent to induce ovulation, dosing is 2.5 mg to 5 mg daily for 5 days starting on day 3 of the menstrual cycle. Renal adjustment is unnecessary if creatinine clearance is above 10. In patients with cirrhosis of the liver, CHild-Pugh Class C, increase the dosing interval to every 48 hours.

Exemestane, another selective agent, comes in 25 mg tablets, and for postmenopausal breast cancer, dosing is 25 mg daily for 2 to 3 years. No renal or hepatic dose adjustments are necessary.

Adverse Effects

Various adverse reactions can happen with aromatase inhibitors. (Seen in less than 1 in 10,000 patients). Some of them are as follows:

1. Ulcers and blisters are the common skin manifestations;
2. Allergic reactions, such as swelling of the face along with lips and tongue and occasionally throat; these reactions can result in difficulty swallowing and/or breathing;
3. Liver function abnormality with or without jaundice due to inflammation of the liver;
4. Bone loss due to estrogen deficiency with long-term use.

Common adverse reactions (10% incidence) include the following: hot flashes, asthenia, joint disorders such as arthritis or arthralgia, osteoporosis, fractures, bone pain, back pain, vaginal dryness, dyspareunia, sexual dysfunction, uterine atrophy, hypertension, hyperlipidemia, hypercholesterolemia, thromboembolic disease, cardiac and cerebrovascular events, insomnia, nausea.[19][20][21][22][14]

The most common reason for discontinuing aromatase inhibitor therapy is the development of arthralgias, known as aromatase inhibitor-associated arthralgia syndrome. Patients will present with joint pain and mild swelling in the absence of other systemic diseases or other causes. The deficiency of estrogen causes a decrease in bone mineral density, which contributes to joint pain. Estrogen also shows links to the regulation of cytokine activity as well as the modulation of pain reception in the nervous system.[23]

Contraindications

There are two major contraindications to aromatase inhibitors.

1. Hypersensitivity: Aromatase inhibitors are contraindicated in patients with hypersensitivity reactions to AI. Hypersensitivity can present as anaphylaxis, angioedema, and urticaria. 
2. Pregnancy and Premenopausal women: Aromatase inhibitors can harm the fetus or cause loss of pregnancy in pregnant patients.[24] Due to their mechanism of action, AIs have no clinical benefit in breast cancer patients who are premenopausal. 

Monitoring

All patients on aromatase inhibitors should have initial routine lab work, including a complete blood count, serum calcium, vitamin D levels, lipid profile, and liver function tests.[25][26] Patients should also have a baseline bone mineral density test (DEXA scan) before initiating the treatment.[27][14]

Toxicity

Clinical trials have shown aromatase inhibitors were well tolerated, even at high doses.[27] There is no established dose of aromatase inhibitors considered life-threatening. There is no specific treatment for the overdose of this class of medications. Standard treatment of care, such as frequent vital sign checks, induced emesis, and management of symptoms, is recommended. 

Enhancing Healthcare Team Outcomes

Interprofessional communication between healthcare teams is essential, especially in the management of cancer patients. Every professional has a vital role to play. Oncologists should select the treatment regimen based on the guidelines after thoroughly assessing the patient factors. For example, in hormone receptor-negative breast cancer or premenopausal patients with breast cancer, aromatase inhibitors may not be appropriate. Clinicians and nurses should be concerned enough about the adverse effects of long-term therapy with aromatase inhibitors, especially osteoporosis and hyperlipidemia. Pharmacists should evaluate the patient's medication history to prevent any drug interactions, especially with tamoxifen and warfarin. Nursing will provide patient counseling on the medication, answer patient questions, and serve as a contact point for patients and other interprofessional team members. Case management should include counseling regarding improving bone health and early initiation of bisphosphonates in the case of osteopenia. Utilizing these interprofessional strategies when using aromatase inhibitor therapy will lead to improved therapeutic patient results with fewer adverse events. [Level 5]