Aromatase Inhibitors to Prevent Breast Cancer Recurrence

Aromatase inhibitors are a class of drug used to prevent cancer recurrence in postmenopausal women with estrogen receptor-positive breast cancer. These medications also are prescribed for premenopausal women in combination with ovarian suppression therapy and for men with breast cancer who are unable to take tamoxifen.

They work by reducing estrogen levels in the body, so less of the hormone is available to stimulate the growth of hormone-sensitive cancer cells. The Food and Drug Administration (FDA) has approved three aromatase inhibitors:

• Aromasin (exemestane)
• Arimidex (anastrozole)
• Femara (letrozole)

For women with breast cancer, there is growing evidence aromatase inhibitors are more effective than tamoxifen, the drug traditionally used to prevent breast cancer recurrence. In addition, clinical research is pointing to a day where aromatase inhibitors may be used to prevent breast cancer in postmenopausal women who are at an increased risk of the disease.

Despite these benefits, aromatase inhibitors can cause significant side effects, including accelerated bone loss leading to osteoporosis.

How They Work

In women who have not undergone menopause, estrogen is produced mainly in the ovaries and, to a lesser degree, in peripheral tissues such as the breasts, liver, brain, skin, bone, and pancreas. In postmenopausal women, whose ovaries are no longer functioning, the peripheral tissues are the predominant source of estrogen.

Aromatase inhibitors block a process that occurs within these cells called aromatization—the conversion of the male hormone testosterone into estrone and estradiol (the two primary forms of estrogen) via an enzyme known as aromatase.

Aromatase inhibitors work by binding to aromatase and preventing aromatization from occurring. By doing so, the production of estrogen may be reduced by as much as 95% in postmenopausal women.

Aromatase inhibitors differ from tamoxifen in that tamoxifen binds to estrogen receptors on cells rather than to aromatase. The different mechanisms of action achieve similar outcomes, but with different rates of efficacy.

Indications

Aromatase inhibitors are approved to reduce the risk of recurrence in postmenopausal women with estrogen receptor-positive breast cancer. They can also be used to treat advanced breast cancer, including stage 4 breast cancer, in which the malignancy has spread (metastasized) to other parts of the body.

For men with breast cancer, the 2020 American Society of Clinical Oncology Guidelines recommend tamoxifen be used instead of an aromatase inhibitor to reduce the risk of breast cancer recurrence. An aromatase inhibitor (in combination with ovarian suppression therapy) may be considered, however, for men who are unable to take tamoxifen for some reason.

For some women who have been treated with tamoxifen, changing to an aromatase inhibitor may be recommended at some time depending on her risk of recurrence. (Before making the change in premenopausal women, ovarian suppression therapy should be initiated or menopause should be documented by a blood test in those under 60.) An aromatase inhibitor may also be recommended in women who have advanced cancer that progresses while on tamoxifen.

Each individual aromatase inhibitor has its own specific indications.

Arimidex is indicated for use as:

• Adjuvant therapy for early-stage breast cancer
• First-line treatment for advanced breast cancer
• Treatment of advanced cancer if it progresses with tamoxifen

Aromasin is indicated for use as:

• Second-line adjuvant therapy for early-stage breast cancer after tamoxifen has been used for two to three years
• Treatment of advanced cancer if it progresses with tamoxifen

Femara is indicated for use as:

• Adjuvant therapy for early-stage breast cancer
• Second-line adjuvant therapy for early-stage breast cancer after tamoxifen has been used for five years
• First-line treatment for advanced breast cancer
• Second-line treatment for advanced breast cancer if it progresses with tamoxifen

Aromatase inhibitors are not effective in premenopausal women unless they are combined with ovarian suppression because they mainly inhibit the estrogen produced in the fat tissue and not in the ovaries. The primary source of estrogen prior to menopause are the ovaries (not the peripheral conversion of androgens to estrogen by aromatase as in postmenopausal women).

Reduction of Late Recurrence

In people who have estrogen receptor positive tumors, the risk of recurrence does not decrease with time. In fact, a hormone positive early stage breast cancer is more likely to recur after five years than in the first five years. It's thought that the risk of recurrence remains steady (the same chance of recurrence each year) for at least 20 years following the original diagnosis. Fortunately, while chemotherapy does not appear to significantly reduce the risk of late recurrence, hormonal therapy (such as aromatase inhibitors) can reduce the risk.

Dosage

Aromatase inhibitors are delivered in tablet form and prescribed as a once-daily dose. Arimidex and Femara can be taken with or without food. Aromasin should be taken after a meal as fat in food aids in the drug's absorption.

Side Effects

As with any medication, aromatase inhibitors can cause side effects and adverse reactions. Some of the more common ones are related to the reduction of estrogen in the body, leading to menopausal symptoms and other more potentially serious complications.

The common short-term side effects associated with all three aromatase inhibitors include:

• Hot flashes
• Joint pain
• Muscle pain
• Headache
• Night sweats
• Hair loss
• Insomnia
• Nausea
• Upset stomach
• Diarrhea
• Fatigue
• Depression
• Edema (tissue swelling)

Of these, persistent joint and muscle pain are the commonly cited reasons for treatment termination. Hot flashes are the most frequent side effect, impacting as many as 59% of women on aromatase inhibitors, according to a 2014 study in Cancer.

Osteoporosis Risk

The long-term effects of aromatase inhibitors are arguably more concerning. Unlike tamoxifen, aromatase inhibitors tend to speed up osteopenia (bone loss) in older women who are already at risk of bone problems.

Women on aromatase inhibitors are at a two- and four-fold increased risk of bone loss compared to a matched set of women in the general population, says a 2015 review in the Journal of Bone Oncology.

These losses can lead to osteoporosis, a condition characterized by the collapse of spinal vertebras, stooped posture, a loss of height, and an increased risk of bone fractures.

Treatment with tamoxifen for two to five years before aromatase inhibitors may slow down the rate of bone loss. Similarly, bisphosphonate drugs like Zometa (zoledronic acid) may help counteract osteopenia, though they increase the risk of osteonecrosis of the jaw.

Other Complications

Aromatase inhibitors are also associated with an increased risk of cardiovascular disorders, including hyperlipidemia (high cholesterol), arrhythmia (abnormal heart rhythm), heart valve problems, and pericarditis (inflammation of the membranes around the heart). With that being said, serious or life-threatening cardiovascular events, such as heart attacks or stroke, are no more common in women who take aromatase inhibitors than those who don't.

A 2018 study in the Journal of Clinical Oncology also noted that the risk of diabetes was 240% greater in women on aromatase inhibitors than in the general population. Although the risk was far lower with tamoxifen, aromatase inhibitors do not pose the risk of thromboembolism (blood clots) or endometrial cancer that tamoxifen does.

Interactions

Aromatase inhibitors can interact with certain medications. Some interactions may decrease the concentration of the aromatase inhibitor in the blood and require a dose adjustment to compensate for the effect.

Among the commonly cited drug interactions:

• Arimidex should not be taken with any estrogen-containing medications, such as hormonal contraceptives containing ethinylestradiol or Premarin (conjugated estrogen) used to treat hot flashes. Tamoxifen can also reduce Arimidex concentrations and should be avoided.
• Aromasin may interact with a wide range of drugs that use the same enzyme (CYP 3A4) for metabolization. These include certain antibiotics, antidepressants, antifungals, antipsychotics, heart medications, and HIV drugs, among others, as well as St. John’s Wort supplements. A dose increase of up to 50 milligrams daily may be needed.
• Femara may interact with tamoxifen, reducing the concentration of Femara by as much as 38%.

Contraindications

Aromatase inhibitors should not be used in people with a known hypersensitivity to any of the active or inactive ingredients in the drug. With that being said, a drug allergy is not common with aromatase inhibitors, affecting less than one out of 10,000 users.

Armidex, Aromasin, and Femara can cause fetal harm and should not be used if there is any chance of pregnancy. As a safeguard, pregnancy testing is recommended seven days prior to the start of treatment if a woman's menopausal status is unknown.

Ongoing Research

There is growing evidence that aromatase may benefit more than just postmenopausal women. A number of studies shown that the drugs may be beneficial in premenopausal women whose ovaries have suppressed with gonadotropin-releasing hormone agonists (GnHRa).

A 2015 study in the New England Journal of Medicine reported that the use of Aromasin in women on ovary suppression therapy was just as effective in preventing recurrence after five years as tamoxifen. Similar results have been seen with Arimidex and Femara.

Even more impressive, a number of clinical studies have suggested that aromatase inhibitors may be just as effective in preventing breast cancer as preventing breast cancer recurrence.

Although the FDA has not yet approved aromatase inhibitors for any of these purposes, many believe that supporting research will one day broaden the current treatment recommendations.