What Is Aromatase Inhibitors (AIs)?


About Aromatase Inhibitors (AIs)

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when using external testosterone. They may also be used for chemoprevention in high risk women.

Aromatase is the enzyme that synthesizes estrogen. As breast and ovarian cancers require estrogen to grow, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors.

Aromatase inhibitors stop the production of estrogen in postmenopausal women. Aromatase inhibitors work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body. This means that less estrogen is available to stimulate the growth of hormone-receptor-positive breast cancer cells.

Aromatase inhibitors can’t stop the ovaries from making estrogen, so aromatase inhibitors are mainly used to treat postmenopausal women. But because aromatase inhibitors are so much more effective than tamoxifen in postmenopausal women, researchers wondered if there were a way to successfully treat premenopausal women diagnosed with hormone-receptor-positive, early-stage breast cancer with an aromatase inhibitor.

Results from the SOFT (Suppression of Ovarian Function Trial) study published in 2015 suggest that premenopausal women diagnosed with hormone-receptor-positive breast cancer can be successfully treated with the aromatase inhibitor Aromasin if their ovarian function is suppressed. If you’re a premenopausal woman willing to take medicine to suppress your ovaries, you may be able to take Aromasin instead of tamoxifen for your hormonal therapy treatment.

You should not take an aromatase inhibitor if you are breastfeeding, pregnant, trying to get pregnant, or if there is any chance that you could be pregnant. Aromatase inhibitors may cause damage to developing embryos. You should use an effective non-hormonal type of birth control — such as condoms, a diaphragm along with spermicide, or a non-hormonal I.U.D. – while you are taking an aromatase inhibitor. Ask your doctor which type of non-hormonal birth control would be best for you, as well as how long you should use this type of birth control after you stop taking an aromatase inhibitor.

The third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have largely replaced tamoxifen as the preferred treatment for hormone receptor – positive breast cancer in postmenopausal women. Approximately 185,000 new cases of invasive breast cancer are diagnosed yearly, and at least half of these women are both postmenopausal and eligible for adjuvant therapy with AIs.

In addition, AIs are currently being tested as primary prevention therapy in large randomised trials involving tens of thousands of women at increased risk for breast cancer. Given the volume of use, internists will increasingly see postmenopausal women who are taking or considering treatment with AIs. Physicians need to be able to: (i) briefly discuss the pros and cons of using a selective estrogen receptor modulator such as tamoxifen or raloxifene vs. an AI for risk reduction and (ii) recognise and manage AI-associated adverse events. The primary purpose of this review is to help internists with these two tasks.

The new non-steroidal and steroidal aromatase inhibitors are at least as effective as megestrol acetate (MA) as second-line hormonal agents in postmenopausal women with breast cancer. However, they are superior to MA in terms of tolerability and adverse effects. Letrozole and exemestane have been shown to be superior to MA in terms of efficacy. Furthermore, exemestane and anastrozole demonstrated a survival advantage over MA. These drugs are therefore considered established second-line hormonal agents.

There is a growing body of evidence supporting the role of third-generation aromatase inhibitors as first-line therapy for ER- and/or PgR-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor positive tumours unsuitable for breast conserving surgery. Studies comparing these drugs head-to-head and with adjuvant tamoxifen are currently in progress. The potential role of these drugs in breast cancer prevention is worth investigating.

Oestrogens play an important role in the development and growth of hormone-dependent breast tumours. The main sites of oestrogen biosynthesis in postmenopausal women are skin, muscle, adipose tissue, and benign and malignant breast tissue. In such tissues, oestrogen (a C18 steroid) is derived from androgens (C19 steroids) by the aromatase enzyme complex. The conversion of adrenal androstenedione to oestrone by aromatase is related to body weight.

In normal weight subjects, approximately 1% of androstenedione is converted to oestrone, whereas in obese subjects, this increases up to 10%. The increase in peripheral oestrogen synthesis with weight in postmenopausal women is the most likely explanation for the increased risk of breast cancer observed in obese postmenopausal women.

Aromatase activity seems also to increase with ageing. Anti-aromatase agents inhibit the cytochrome P-450 component of the aromatase enzyme complex by interfering with the electron transfer from NADPH. Examples of such agents include anastrozole (Arimidex) and letrozole (Femara). These drugs can be also classified into first-generation , second-generation and third-generation  compounds.

Anti-aromatase agents may also be divided into Type I and Type II inhibitors. The Type I inhibitors have a steroidal structure similar to androgens and inactivate the enzyme irreversibly by blocking the substrate-binding site, and are therefore known as aromatase inactivators. Examples of such drugs include formestane and exemestane (Aromasin). Type II inhibitors are non-steroidal and their action is reversible. Examples include anastrozole and letrozole. Figure 1 demonstrates the structures of important aromatase inhibitors.

What is an aromatase inhibitor and how does it work?

Aromatase inhibitors and inactivators interfere with the body’s ability to produce estrogen from androgens by suppressing aromatase enzyme activity. Before menopause, ovarian aromatase is responsible for the majority of circulating estrogen and is exquisitely sensitive to changes in luteinising hormone (LH). Following menopause, aromatase in fat and muscle may be responsible for much of the circulating estrogen.

Aromatase in highly estrogen-sensitive tissues, such as the breast, uterus, vagina, bone, brain, heart and blood vessels, provides local estrogen in an autocrine fashion . The aromatase gene promoter in breast tissue is less sensitive than the gene promoter in the ovary to fluctuations in LH but much more sensitive to increases in inflammatory cytokines. Circulating inflammatory cytokines increase with age, and breast tissue inflammatory cytokines increase with proliferative breast disease and breast cancer. Thus, it comes as little surprise that breast aromatase activity is increased in proliferative breast disease and many cases of breast cancer.

Three generations of AIs have been developed. Each successive generation has been associated with higher specificity for the aromatase enzyme, fewer adverse events, and greater suppression of aromatase activity. The utility of first- and second-generation AIs was limited by adverse events, such as rash, fatigue, dizziness, ataxia, nausea and vomiting, as well as by a lack of enzyme selectivity.

Third-generation AIs are superior to earlier versions because they are associated with fewer adverse events and greater suppression of aromatase activity. There are two classes of third-generation AIs. Non-steroidal AIs reversibly bind to the aromatase enzyme and include anastrozole and letrozole. The steroidal AI exemestane binds to aromatase irreversibly. All third-generation AIs are administered orally on a daily basis. Adverse events include hot flushes, vaginal dryness, loss of libido, fatigue, arthralgias, joint stiffness and loss of bone mineral density with subsequent increased risk of fracture .

In premenopausal women, AIs have a limited ability to reduce circulating estrogen. Unlike postmenopausal women, premenopausal women have a large amount of aromatase substrate present in the ovary. The exquisite sensitivity of the ovarian aromatase promoter to gonadotrophins, which increase dramatically after AI administration, makes AIs less effective in inhibiting ovarian estrogen production. Thus, AIs are generally not given to premenopausal women for breast cancer treatment without the addition of a medication to suppress the rise in gonadotrophins and subsequent increase in hormone levels.

Hormone receptor-positive breast cancers need estrogen and/or progesterone (female hormones produced in the body) to grow.

Aromatase inhibitors are hormone therapy drugs that can slow or stop the growth of hormone receptor-positive tumors.

They lower estrogen levels in the body by blocking aromatase, an enzyme that converts other hormones into estrogen.

This prevents the cancer cells from getting the hormones they need to grow.

  • Aromatase inhibitors include:
  • Anastrozole (Arimidex)
  • Exemestane (Aromasin)
  • Letrozole (Femara)

Some breast cancers are stimulated to grow by the hormone oestrogen. In women who have been through the menopause, oestrogen is no longer produced by the ovaries. But some oestrogen is still made in body fat using an enzyme (a type of protein) called aromatase. Aromatase inhibitors stop this enzyme from working so there’s less oestrogen in the body.

An aromatase inhibitor will only be prescribed if your breast cancer has receptors within the cell that bind to the hormone oestrogen, known as oestrogen receptor positive or ER+ breast cancer. All breast cancers are tested for oestrogen receptors using tissue from a biopsy or after surgery. When oestrogen binds to these receptors, it can stimulate the cancer to grow.

When oestrogen receptors are not found (oestrogen receptor negative or ER- breast cancer) tests may be done for progesterone (another hormone) receptors. The benefits of hormone therapy are less clear for people whose breast cancer is only progesterone receptor positive (PR+ and ER-). Very few breast cancers fall into this category. However, if this is the case for you your specialist will discuss with you whether an aromatase inhibitor is appropriate.

If your cancer is hormone receptor negative, then an aromatase inhibitor will not be of any benefit.

Why do we need aromatase inhibitors?

For women with newly diagnosed hormone receptor positive ER+ cancers requiring systemic adjuvant therapy, 5 years of tamoxifen reduces the relative odds of recurrence by 40% and relative risk of death from breast cancer by 34%. At 15 years this equates to about a 12% absolute reduction in recurrence and a 9% absolute reduction in mortality, irrespective of nodal status.

However, about a third of women diagnosed with ER-positive breast cancer will ultimately relapse despite adjuvant tamoxifen with or without chemotherapy . Women with hormone receptor-positive disease that has metastasised to organ sites distant from the breast almost always relapse following first-line antihormonal therapy with tamoxifen. More effective antihormonal treatment for tamoxifen-resistant tumours are needed.

There is some evidence suggesting a worse outcome with tamoxifen for women with ER-positive tumours that lack progesterone receptor (PgR), and/or exhibit overexpression of growth factor receptors such as human epidermal growth factor receptors 1and 2 (EGFR and HER-2/neu) .

The observation that prolonged administration of tamoxifen may increase rather than decrease late recurrence rates may be due to tamoxifen’s ability to act as a partial estrogen agonist in breast tissue under conditions of growth factor receptor up-regulation, which commonly occurs after prolonged tamoxifen use. AIs appear to be more effective than tamoxifen in ER-positive tumours regardless of PgR or growth factor receptor status .

Treatment with AIs produce frequent and durable responses in postmenopausal women previously treated with tamoxifen or endocrine ablative surgery, and AIs are more effective than tamoxifen in producing responses and delaying progression in first-line treatment of metastatic disease . A recent meta-analysis concluded that in women with metastatic breast cancer, AIs show a survival benefit when compared with other endocrine therapy.

Side effects of aromatase inhibitors

Aromatase inhibitors tend to cause fewer serious side effects than tamoxifen, such as blood clots, stroke, and endometrial cancer. But aromatase inhibitors can cause more heart problems, more bone loss (osteoporosis), and more broken bones than tamoxifen, at least for the first few years of treatment. If you and your doctor are considering an aromatase inhibitor as part of your treatment plan, you may want to ask your doctor about having a bone density test to see if a bone strengthening medicine might be necessary while you’re taking the aromatase inhibitor.

The most common side effects of aromatase inhibitors are joint stiffness or joint pain.

If you’re experiencing side effects from taking one aromatase inhibitor medicine, tell your doctor. You may be able to take a different medicine. Arimidex and Femara have similar chemical structures, while Aromasin has a different structure.

How are aromatase inhibitors currently used?

The third-generation AIs are currently the preferred first-line treatment for metastatic hormone receptor-positive tumours and have all been approved by the US Food and Drug Administration for adjuvant use in postmenopausal women before or after surgery for ER-positive and/or PgR-positive breast cancer. Although anecdotal responses have been observed in women with ER- and PgR-negative tumours, in current clinical practice, only postmenopausal women with ER-positive and/or PgR-positive tumours are selected for treatment with AIs.

There are several clinical studies evaluating the use of AIs in premenopausal women combined with ovarian suppression with a LH-releasing hormone (LHRH) analogue. AIs are generally not used off-label for premenopausal women except in special circumstances, such as prior tamoxifen failure or medical contraindications to tamoxifen. When AIs are used in premenopausal women they must be combined with surgical or medical ovarian ablation. Results with AIs in the adjuvant or neoadjuvant setting are detailed below

Who can take aromatase inhibitors?

In general, aromatase inhibitors are only used to treat breast cancer in postmenopausal women.

However, some premenopausal women may take an aromatase inhibitor when combined with ovarian suppression. Ovarian suppression prevents the ovaries from making estrogen, so a woman becomes postmenopausal. It’s usually done with drug therapy so the menopause is temporary.

Women with certain heart problems should not take anastrozole.

Aromatase Inhibitors and breast cancer treatment

  • Aromatase inhibitors come in pill form. You take one pill every day.
  • Postmenopausal women with hormone receptor-positive breast cancer can:
  • Begin hormone therapy with an aromatase inhibitor
  • Begin hormone therapy with tamoxifen and then after a few years, switch to an aromatase inhibitor
  • When an aromatase inhibitor is the only hormone therapy given, it’s taken for 5-10 years.
  • When an aromatase inhibitor is taken after tamoxifen, the drugs are taken for a combined total of 5-10 years.
  • Talk with your health care provider about how long you should take an aromatase inhibitor.

Information on different aromatase inhibitors

Anastrozole, exemestane and letrozole all work in similar ways to each other and share many of the same side effects, although there are some differences.

To find out more about each of these, including when they are prescribed, how long they are taken for and possible side effects, see our separate anastrozole, exemestane and letrozole web guides.

Use of aromatase inhibitors in premenopausal women

Responses have been observed in premenopausal women with concomitant goserelin and AI treatment following tamoxifen failure. This concept is also being tested in the adjuvant setting with the Suppression of Ovarian Function (SOFT) and Tamoxifen or Exemestane Plus Ovarian Ablation (TEXT) trials. In the SOFT trial, women who are premenopausal after any adjuvant chemotherapy and have ER-positive tumours are randomised to tamoxifen, tamoxifen plus an LHRH analogue or exemestane plus the LHRH analogue (other types of ovarian ablation are also allowed). In the TEXT trial, premenopausal women who may or may not have received chemotherapy are randomised to receive tamoxifen or exemestane, both with an LHRH analogue.

The TEXT trial is nearing completion of accrual. It is not clear whether an AI with ovarian ablation will be as good as or better than tamoxifen with or without ovarian ablation at this time. If an AI is given to a premenopausal woman outside of these ongoing trials ovarian ablation with oophorectomy or ovarian suppression with an LHRH analogue must be given. If ovarian suppression with an LHRH analogue is chosen, serum estradiol levels must be monitored regularly to ensure that they remain in the postmenopausal range

Musculoskeletal effects 

Studies of tamoxifen in postmenopausal women have shown reduction in bone turnover markers and an increase in bone density and the opposite effects with AIs. These differential effects are not surprising because tamoxifen exerts partial estrogen agonist effects on bone in postmenopausal women, and osteoporosis has been strongly associated with the low serum estrogen levels that occur following AI administration.

Although a head-to-head comparison of the three third-generation AIs in the Letrozole, Exemestane, Anastrozole Pharmacodynamics study has shown a similar effect on markers of bone turnover for all three drugs , it has also been suggested that exemestane may be associated with less of a deleterious effect than is seen with the other third-generation AIs. Additional data are expected from a bone substudy in MA.27, an adjuvant trial comparing anastrozole with exemestane.

In adjuvant studies, all three third-generation AIs – anastrozole, letrozole and exemestane – have shown an increased risk of bone fracture compared with tamoxifen. The absolute differences, while statistically significant in the ATAC trial of anastrozole vs. tamoxifen and the BIG 1–98 trial of letrozole vs. tamoxifen, were only 1–4%. Most fractures were in the spine and not the hip.

The difference in fracture rate approached, but did not reach, statistical significance in the IES trial (3.1% for women switching to exemestane vs. 2.3% in women continuing on tamoxifen) . Letrozole given in MA.17 after 5 years of tamoxifen had a numerically higher fracture rate than placebo (5.3% vs. 4.3%), but like the IES trial, the absolute excess fracture rate was ≤ 1% and statistically insignificant. This would seem to indicate that tamoxifen taken before an AI provides some measure of bone mineral density protection in postmenopausal women.

Bisphosphonates can be used to prevent the bone mineral loss observed with AIs. This strategy was successfully used in the Zometa-Femara Adjuvant Synergy trials, and the Austrian Breast and Colorectal Cancer Study Group trial 12, in which an intravenous bisphosphonate, zoledronic acid, was administered every 6 months for the duration of AI therapy. Vitamin D supplementation is advisable in women with serum 25-OH vitamin D levels < 30 ng/ml because women with baseline vitamin D insufficiency are at an increased risk of bone loss when receiving AIs.

In randomised studies, arthralgias/myalgias have been reported significantly more frequently in women randomised to AIs than in those randomised to tamoxifen or placebo. The absolute frequency varies tremendously from trial to trial (5.4–37% for AIs vs. 3.6–26% for tamoxifen or placebo), which in turn probably reflects the method used to record the symptoms. The incidence of arthralgias and myalgias appear to be about two-thirds higher with an AI than with tamoxifen or placebo but usually improves with time.

Two small studies have shown that women taking AIs for cancer therapy often have deficient or suboptimal 25-OH vitamin D levels in their serum. Improvements in myalgias and arthralgias were observed in a high proportion of women with deficient or suboptimal levels of vitamin D who were given prescription-strength vitamin D for 12 weeks . Serum 25-OH vitamin D is used to assess adequacy of total body vitamin D stores and levels should be checked prior to starting AI treatment to make sure they are in the optimal range of 30–50 ng/ml .

In general, each additional 1000 IU of vitamin D3 can be expected to increase 25-OH-D serum levels by 10 ng/ml. The addition of celecoxib 400 mg bid to exemestane reduced arthralgias and improved response rates in a placebo-controlled trial in women with metastatic disease . Prospective trials are under way to assess the prevalence of vitamin D deficiency in women undergoing adjuvant therapy with AIs, correlation with the development of myalgias/arthralgias and the relief of symptoms with vitamin D replacement.

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