Aromatase Inhibitors for Breast Cancer Treatment

Aromatase inhibitors are a hormone therapy (also called endocrine therapy). They are used to treat hormone receptor-positive early, locally advanced and metastatic breast cancers.

Learn about aromatase inhibitors and other hormone therapies for metastatic breast cancer.

How do aromatase inhibitors work?

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

Aromatase inhibitors lower estrogen levels in the body by blocking aromatase, an enzyme that converts other hormones into estrogen. This slows or stops the growth of the tumor by preventing the cancer cells from getting the hormones they need to grow.

Aromatase inhibitors include:

• Anastrozole (Arimidex)
• Exemestane (Aromasin)
• Letrozole (Femara)

To learn about a specific aromatase inhibitor, visit the National Institutes of Health’s Medline Plus website.

Aromatase inhibitors and treatment for early and locally advanced breast cancers

For women with hormone receptor-positive breast cancer, treatment with an aromatase inhibitor (alone or after several years of tamoxifen) lowers the risk of [88]:

• Breast cancer recurrence (a return of breast cancer)
• Breast cancer in the opposite breast
• Death from breast cancer

Among postmenopausal women with hormone receptor-positive breast cancer, aromatase inhibitors (alone or after tamoxifen) offer the same or slightly greater benefit compared to tamoxifen alone [88,105-108].

Anastrozole, exemestane and letrozole are equally effective and have similar side effects [88,105-108]. However, you may tolerate one drug better than another.

Let your health care provider know about any side effects you have.

Learn more about the side effects of aromatase inhibitors.

Learn about aromatase inhibitors and treatment for metastatic breast cancer.

Who can take aromatase inhibitors?

Aromatase inhibitors are used to treat breast cancer in women. In rare cases, they are used to treat breast cancer in men.

Menopausal status

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. Ovarian suppression is usually done with drug therapy, so menopause may be temporary.

How are aromatase inhibitors taken?

Aromatase inhibitors are pills. 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.

Find a list of questions on hormone therapy you may want to ask your health care provider.

Length of treatment with an aromatase inhibitor

Randomized clinical trials have compared outcomes for women who used aromatase inhibitors for 10 years versus 5 years [109,312]. Taking an aromatase inhibitor for 10 years [109,312]:

• Improves disease-free survival
• Lowers the risk of cancer in the opposite breast (contralateral breast cancer)

However, overall survival is the same whether a woman takes an aromatase inhibitor for 5 years or 10 years [109,312]. For most women, the benefit of the extra 5 years of treatment is small [109].

Women who take an aromatase inhibitor for more than 5 years continue to have side effects from the drug, including a higher number of bone fractures and a higher rate of osteoporosis [109-112].

Talk with your health care provider about how long you should take an aromatase inhibitor.

Learn about the importance of completing treatment with an aromatase inhibitor.

Importance of following your breast cancer treatment plan

Breast cancer treatment is most effective when all parts of the treatment plan are followed as prescribed.

Prescription drug assistance

Hormone therapy drug costs can quickly become a financial burden for you and your family.

Medicare and many insurance companies offer prescription drug plans. One may already be included in your policy, or you may be able to buy an extra plan for prescriptions.

Aromatase inhibitors are pills, so they’re covered under your health insurance plan’s prescription drug benefit rather than the plan’s medical benefit. This means there are usually out-of-pocket costs, which can add up over time.

You may qualify for programs that help with drug costs or offer low-cost or free prescriptions.

Aromatase inhibitors are all available in a generic form. Generic drugs cost less than name brand drugs but are just as effective.

Many cancer centers have patient financial counselors who can discuss insurance and cost coverage with you.

Learn more about insurance plans and prescription drug assistance programs.  

Learn about other financial assistance programs.

Aromatase Inhibitors – Work & Uses

By Erin Archer Kelser, RNMedically Reviewed by Robert Jasmer, MD

Reviewed: August 5, 2016

Medically Reviewed

This group of drugs lowers levels of estrogen in the body.

Aromatase inhibitors are a class of drugs that reduce the production of estrogen in the body.

They work by stopping an enzyme called aromatase from turning other hormones into estrogen.

Examples of aromatase inhibitors include:

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

Each drug comes as a pill that is typically taken once a day. All three medications are available in generic form.

Why Are Aromatase Inhibitors Given?

Even though both women and men need estrogen, estrogen can cause problems by promoting the growth of estrogen-receptor-positive cancers, especially breast cancer.

Aromatase inhibitors are often used in addition to other to cancer treatments (such as surgery, radiation, and chemotherapy) to starve these estrogen-receptor-positive cancers of estrogen.

These drugs are also sometimes used to help with certain fertility problems, and to block the effects of estrogen in men with a condition called gynecomastia, which causes enlarged breast tissue.

How Do Aromatase Inhibitors Work?

Men and women both have “masculine” androgen hormones and “feminine” estrogen hormones, but in different concentrations.

The aromatase enzyme converts androgen hormones (testosterone and androstenedione) into estrogen hormones (estradiol and estrone).

Blocking the effects of aromatase reduces the amount of androgens converted into estrogens.

In women before menopause, most estrogen hormones are made in the ovaries.

Aromatase inhibitors don’t work to lower estrogen if your ovaries are still functioning. These drugs are only given to women who have gone through menopause, or who have had treatment to suppress the normal functioning of their ovaries.

You shouldn’t take aromatase inhibitors if you’re pregnant or breastfeeding.

Aromatase Inhibitors for Cancer Treatment

Aromatase inhibitors are given to postmenopausal women with estrogen-receptor-positive cancers, particularly of the breast.

They’re taken long-term, for 3 to 5 years or even longer.

Another class of drugs, called selective estrogen receptor modulators (SERMs), is used similarly. SERM drugs include Soltamox (tamoxifen) and Evista (raloxifene).

In postmenopausal women with estrogen-receptor-positive breast cancer, aromatase inhibitors have been found to be more effective and have fewer side effects than SERMs.

Other Uses for Aromatase Inhibitors

Aromatase inhibitors are also used for the following purposes:

Treating unwanted side effects of testosterone: Because some of the circulating testosterone is converted into estrogen by aromatase, men who take extra testosterone may develop breasts, experience undesired fat deposits, or have fertility problems.

Although they’re not approved for this purpose, aromatase inhibitors are sometimes also taken by anabolic-androgenic steroid (AAS) users to prevent certain side effects of their use.

Increasing fertility in polycystic ovary syndrome (PCOS): Some studies have shown that aromatase inhibitors may help premenopausal women with polycystic ovary syndrome carry a pregnancy to term.

Lowering the risk of breast cancer: Some studies have shown that taking aromatase inhibitors can lower the risk of breast cancer in women who are at high risk, but these drugs aren’t currently approved for this purpose in the United States.

Side Effects of Aromatase Inhibitors

Aromatase inhibitors can have certain unwanted side effects, including:

Weakening of the bones: These drugs may increase the risk of fractures and osteoporosis.

You may want to ask your doctor for a vitamin D level test and bone density scan (also called DEXA or bone densitometry) before taking these medications, and every 1 to 2 years while taking them.

Your doctor may want recommend performing weight-bearing exercises or taking calcium and vitamin D supplements to strengthen your bones.

If your bones do become weak, your condition may be treated with a class of drugs called bisphosphonates.

Joint pain and bone pain: This pain can be severe enough for some people to stop taking their medication.

If your pain persists, you may want to ask your doctor whether you need an X-ray to check for a broken bone.

Menopausal symptoms: These symptoms may include hot flashes, night sweats, and decreased libido. A group of antidepressants called selective serotonin reuptake inhibitors (SSRIs) may help with some of these symptoms.

For vaginal health issues like atrophy and dryness, talk to your doctor about your treatment options if personal lubricants don’t solve the problem.

By subscribing you agree to the Terms of Use and Privacy Policy.

Editorial Sources and Fact-Checking

• Aromatase Inhibitors; BreastCancer. org.
• J. A. Files, M. G. Ko, and S. Pruthi (2010). “Managing Aromatase Inhibitors in Breast Cancer Survivors: Not Just for Oncologists.” Mayo Clinic Proceedings.
• W. de Ronde and F. H. de Jong (2011). “Aromatase inhibitors in men: effects and therapeutic options.” Reproductive Biology and Endocrinology.
• R. S. Legro, R. G. Brzyski, M. P. Diamond, C. Coutifaris, W. D. Schlaff, P. Casson, G. M. Christman, H. Huang, Q. Yan, R. Alvero, D. J. Haisenleder, K. T. Barnhart, G. W. Bates, R. Usadi, S. Lucidi, V. Baker, J. C. Trussell, S. A. Krawetz, P. Snyder, D. Ohl, N. Santoro, E. Eisenberg, and H. Zhang (2014). “Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome.” New England Journal of Medicine.
• W. Y. Chen (2016). “Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention.” UpToDate.com.
• D. Sagoe, J. McVeigh, A. Bjørnebekk, M. S. Essilfie, C. S. Andreassen, and S. Pallesen (2015). “Polypharmacy among anabolic-androgenic steroid users: a descriptive metasynthesis.” Substance Abuse Treatment, Prevention and Policy.

Show Less

What Are Antacids? Uses, Warnings, Side Effects, and More

For occasional heartburn, indigestion, or acid reflux, antacids may help manage symptoms of pain and discomfort by neutralizing stomach acid.

By Frieda Wiley, PharmD, RPhFebruary 28, 2023

What Are Cephalosporins? Uses, Warnings, Side Effects, and More

Cephalosporins are a class of antibiotics used to treat a wide range of bacterial infections, including ear infections, pneumonia, meningitis, and gonorrhea…

By Frieda Wiley, PharmD, RPhDecember 6, 2022

What Are Sulfonamides? Uses, Warnings, Side Effects, and More

Sulfonamides are a group of medicines used to treat bacterial infections, urinary tract infections (UTIs), and other conditions.

By Julie Lynn MarksNovember 29, 2022

What Is a Diuretic? Uses, Warnings, Side Effects, and More

A diuretic, a type of drug also known as “water pills,” helps rid the body of extra water and lower blood pressure.

By Frieda Wiley, PharmD, RPhNovember 29, 2022

What Are COX-2 Inhibitors?

COX-2 Inhibitors are a type of nonsteroidal anti-inflammatory drug (NSAIDs) that treat inflammatory pain.

By Erin Archer Kelser, RNNovember 3, 2016

What Are Sedatives?

Sedatives are a category of drugs that slow brain activity. Also known as tranquilizers or depressants, sedatives have a calming effect and can also induce…

By Erin Archer Kelser, RNAugust 5, 2016

What Are Calcium Channel Blockers?

Calcium channel blockers are commonly prescribed medications for high blood pressure. The medications reduce blood pressure by helping blood vessels to…

By Diana RodriguezJanuary 15, 2016

What Are Tricyclic Antidepressants?

Tricyclic antidepressants, or TCAs, are a class of drugs that has been used for decades to treat depression, anxiety, and certain kinds of pain.

By Frieda Wiley, PharmD, RPhJanuary 6, 2016

The use of aromatase inhibitors in breast cancer patients in assisted reproductive technology programs

An integrated approach to the treatment of cancer can save the lives of many patients. However, polychemotherapy has a gonadotoxic effect and can lead to premature ovarian failure and infertility. Increasing survival rate after combined and complex treatment of oncological diseases, new reproductive technologies, as well as increasing attention to the quality of life of patients make it possible to maintain fertility in this group of patients.

Many countries have developed recommendations for the preservation of the reproductive material of patients receiving gonadotoxic treatment [1-3]. The criteria for selecting patients, the most acceptable and effective methods of preserving genetic material, as well as the timing of therapeutic measures were determined.

Cryopreservation of gametes and/or embryos in patients undergoing gonadotoxic treatment is now becoming more common and is performed in many countries around the world.

In a number of diseases, such as breast cancer, the use of standard schemes for stimulating superovulation is not entirely acceptable, as it leads to a pronounced increase in the level of sex steroids in the blood, which may have a potential risk to a woman’s health. Taking oocytes in a “natural” cycle avoids these risks, but gives a very small chance of having children in the future. With several embryos available for cryopreservation, the patient has a real chance of having a genetically related child. As a rule, there is not enough time for carrying out a program for the preservation of genetic material, due to the need to start treatment of the underlying disease. In this regard, the issue of using modified ovulation stimulation protocols that combine efficiency and safety is extremely relevant.

Aromatase inhibitors (AIs) are the most attractive in terms of providing these effects. This group of drugs has been discussed for many years as a means to stimulate ovulation, both in monotherapy and in combination with gonadotropins. However, the use of IAs in ART programs has not become so widespread, and their role in this area remains unclear today.

Some time ago, drugs belonging to the AI ​​group attracted the attention of specialists as agents that reduce the level of estradiol during ovulation stimulation in patients with breast cancer.

Aromatase is an enzyme complex of microsomes, a member of cytochrome P450, necessary in the body to complete the synthesis of estrogens through a unique aromatization reaction of C19 steroids, namely the biosynthesis of estrone from androstenedione, estradiol from testosterone. These reactions can occur in the ovaries, adipose tissue, placenta, mammary glands, muscles, brain, fibroblasts, osteoblasts, liver, i.e. aromatization is a universal reaction of the human body [4].

Essentially, AIs are antiestrogen. Blocking the aromatase reaction disrupts the synthesis of estrogen, namely the transition of estrone to estradiol, resulting in a decrease in the level of estradiol in the peripheral blood. This property of drugs is used to treat estrogen-positive breast cancer [5–7].

Letrozole and anastrozole are discussed as part of modified ovulation induction protocols. Both of these substances belong to the III generation of IAs, to the group of competitive inhibitors (their action is reversible).

Foreign studies show the effectiveness of AI in reducing the level of estradiol in the induction of superovulation in patients with breast cancer [8, 9]. This article presents our own experience of using this group of drugs in the program for the preservation of genetic material in young breast cancer patients.

Material and methods

This study included 20 women (mean age 29±3.6 years) of reproductive age with stage I-IIIA breast cancer. The patients were referred by oncologists of the Russian Cancer Research Center. N.N. Blokhin of the Russian Academy of Medical Sciences to address the issue of the possibility of preserving genetic material before the upcoming polychemotherapy. At the first stage, oncologists assessed the prognosis and the possibility of a favorable course of the disease based on data on the stage of the disease, the results of histological and immunohistochemical studies. At the time of application 8 out of 19patients underwent surgical treatment in the amount of mastectomy or radical resection of the breast (11). All women, with the exception of 1 patient, were scheduled for adjuvant polychemotherapy, in 1 case – non-adjuvant.

In all patients, an analysis of the ovarian reserve was performed: the level of FSH, LH, estradiol, anti-Müllerian hormone (AMH) in the blood serum on the 2nd-3rd day of the menstrual cycle was studied, the volume of the ovaries and the number of antral follicles in them were assessed by ultrasound. In the patients of the study group, various schemes for managing the menstrual cycle were used, the protocol was selected based on the gynecological and oncological status (stage of the disease, clinical, pathomorphological and immunohistochemical characteristics of the tumor).

In 5 patients, oocyte retrieval was carried out in a “modified” natural cycle, which included the administration of a GnRH antagonist when the dominant follicle reached a size of 14 mm in order to prevent a parasitic LH peak and cancel the protocol. An ovulation trigger was administered when the follicle reached 18–19 mm in diameter. Transvaginal puncture was performed 36 hours later under short-term intravenous anesthesia and under ultrasound control. This protocol was used in patients referred to us in the middle of the menstrual cycle, as well as in women who do not want to resort to ovarian stimulation.

A GnRH antagonist protocol was used in 5 patients. The introduction of gonadotropins began from the 2nd-3rd day of the menstrual cycle. The criteria for prescribing GnRH antagonists and an ovulation trigger have been described previously.

In 5 women, oocyte sampling was carried out in the protocol with the depot form of the GnRH agonist. The GnRH agonist (zoladex 3.6 mg) was administered on the 2nd-3rd day of the menstrual cycle, gonadotropins were administered 2 days later. The ovulation trigger was administered according to generally accepted criteria.

In 6 cases, a modified protocol was used, including AI (anastrozole, letrozole) and gonadotropins. Oral administration of IA was started on the 2nd-3rd day of the menstrual cycle at a dose of 2 and 2.5 mg, respectively. The IA dose was adjusted during the stimulation cycle depending on the number of growing follicles and the level of estradiol in the blood serum. The maximum AI dose was 6 mg for anastrozole, 5 mg for letrozole. From the 3rd-6th day of the cycle, the administration of gonadotropins was started; when the leading follicle reached a diameter of 14 mm, the administration of GnRH antagonists was started. The ovulation trigger was administered based on generally accepted criteria. On the day of the ovulation trigger injection, the intake of IAs was stopped, resuming it on the day of the transvaginal puncture.

In all cases, transvaginal puncture was performed 36 hours after an intramuscular injection of an ovulatory dose of human chorionic gonadotropin (hCG). Fertilization in 8 cases was performed by ICSI, in 12 cases by IVF. Cryopreservation of embryos was carried out at the blastocyst stage (in 6 cases at the stage of 8 blastomeres) by slow freezing in 15 cases, vitrification was performed in 4 cases.

Statistical analysis. A non-parametric Mann-Whitney test for independent samples was used to compare quantitative data. At p<0.05 (95% confidence level), differences were considered statistically significant.

Results and discussion

The mean age of the patients was 29 years (23-40 years). Eight patients were diagnosed with stage I of the disease, 10 with stage II, and 2 with stage III. The patients were planned to undergo breast cancer treatment according to generally accepted standards, including polychemotherapy in non-adjuvant and/or adjuvant regimens. In one 40-year-old patient, chemotherapy was refused, and only hormonal treatment was planned for 5 years, however, given the patient’s older reproductive age, duration of treatment, and probable loss of fertility, it was decided to preserve the genetic material.

All patients underwent an IVF program followed by cryopreservation of the resulting embryos. In one patient, it was possible to take an oocyte in the natural cycle, immediately after treatment, and due to the possibility of delaying the start of treatment of the underlying disease in the next menstrual cycle, a second IVF attempt was made in a modified protocol with AI.

In the analysis of reproductive function and ovarian reserve in patients, no significant deviations from the norm were revealed. Only 2 patients showed a decrease in the level of AMH in the blood serum (0. 47 and 0.5 ng/ml, respectively), while the level of FSH and ultrasound data were within the normal range. In one of these patients, we failed to obtain oocytes in the protocol with GnRH depot agonists; in the second, 1 oocyte was obtained in a “modified” natural cycle.

It should be noted that 12 women had independent pregnancies, but only 2 patients had children, the rest planned to realize reproductive function in the future.

Detailed characteristics of reproductive function and ovarian reserve are presented in Table. 1, 2.

The menstrual management protocols used had different characteristics and efficacy (Table 3).

In our opinion, the most effective protocol was one that included AIs and gonadotropins, since it provided the possibility of obtaining a sufficient number of oocytes at a relatively low level of estradiol in the blood serum.

To assess the severity of the antiestrogenic effect of IAs, we compared standard stimulation cycles in 6 women of the same age and with comparable parameters of ovarian reserve and folliculogenesis and patients of the study group in whom IAs were included in the stimulation protocol.

The analysis showed that AI provided a decrease in serum estradiol levels by 6 times (p<0.05) compared with the standard stimulation protocol. At the same time, there was no violation of follicle and oogenesis, a decrease in the quality and quantity of the obtained oocytes and embryos (Table 4).

It was shown that the use of letrozole in the stimulation regimen provided a more pronounced decrease in the level of estradiol (by 3.5 times compared with anastrozole), however, these differences were not statistically significant, which is probably due to the small sample size. It should be noted that in patients receiving anastrozole, the dose of the drug 2 mg was ineffective, and in all cases it was required to increase the dose to 4 mg, up to a maximum of 6 mg. At the same time, the dose of letrozole 2.5 mg allowed to reduce the level of estradiol to normal values; in one patient, who had multifollicular growth, it was necessary to increase the dose of the drug to 5 mg.

As a clinical example, we present the following observation.

A 40-year-old female patient who had an oocyte retrieval in a modified natural cycle immediately after treatment. The level of estradiol on the day of hCG administration was 526 pmol/L. On the 2nd day of the next menstrual cycle, oral administration of letrozole was started at a dose of 2.5 mg per day. From the 4th day of the menstrual cycle, the introduction of gonadotropins at a dose of 150 IU per day was started. The level of estradiol on the day of the introduction of the ovulation trigger was 561 pmol / l, i.e. did not differ from that in the natural menstrual cycle. However, transvaginal ovarian puncture yielded 5 good quality oocytes. On the 3rd day after oocyte sampling, with continued administration of IA, the level of estradiol was 213 pmol/l.

This study shows that the use of AIs in superovulation induction protocols leads to a significant decrease in serum estradiol levels, while obtaining a sufficient number of oocytes and good quality embryos. The duration of stimulation with IA does not exceed 14 days, which allows the sampling of genetic material in a short time before the start of polychemotherapy.

Our data are consistent with the results of studies by foreign authors, who also showed the possibility of using this stimulation protocol in patients with breast cancer [10, 11]. Some authors [11] described a higher efficiency of letrozole in relation to anastrozole. In our work, reliable data in this regard were not obtained, due to the small number of patients, which makes it necessary to continue research in this area.

Discusses the safety of using AIs in superovulation induction cycles. According to several foreign authors [12, 13], the use of AI does not lead to an increase in the incidence of malformations in children. Experiments performed on mice showed that IAs do not cause chromosomal abnormalities in oocytes and do not lead to disruption of embryogenesis; the level of blastocyst formation is comparable with the control [14, 15]. In addition, when used in stimulation cycles, IAs are excreted from the body by the time of embryo implantation, since they have a short half-life (48 h), and when cultivated, in vitro embryos are not exposed to letrozole at all. Thus, at the moment there is no information about the possible teratogenic effects of AI.

An important issue is the safety of the use of IAs and gonadotropins to stimulate superovulation in patients with breast cancer in relation to the progression of the underlying disease. In the study by A. Amr et al. [16], which included 215 women of reproductive age, showed that the use of this stimulation scheme in order to preserve the genetic material does not lead to an increase in the frequency of disease recurrence. However, given the rather short follow-up period (average 2 years) and the small number of patients, final conclusions can only be made after the accumulation of evidence and clinical experience.

In conclusion, it should be noted that the preservation of genetic material in young patients before gonadotoxic treatment is included in the clinical recommendations of many countries around the world. The use of AIs in stimulation protocols makes it possible to collect a sufficient number of good quality oocytes and at the same time reduce the possible adverse effects on the woman’s body of high estrogen levels.

Breast Cancer Hormone Therapy – Methods 2023

What is hormone dependent breast cancer?

Hormone-positive breast cancer is a cancer whose IHC examination of the tumor showed a positive reaction to the estrogen and/or progesterone receptors (ER/ER, PR/PR). Most often, the degree of response is indicated as a percentage, for example: ER / ER-15%, PR / PR- 0%, etc.

To determine the hormone-dependent nature of the tumor, it is enough that one of the receptors is positive.

The hormones estrogen and progesterone are produced by the ovaries in premenopausal women, as well as by several other tissues (including fat and skin), both premenopausal and postmenopausal.

Estrogen promotes the development and maintenance of female sexual characteristics and bone growth.

Progesterone plays an important role in the menstrual cycle and pregnancy.

Men also produce estrogen and progesterone in body tissues and are therefore also diagnosed with hormone-dependent breast cancer.

In hormone-dependent breast cancer, malignant cells contain proteins called receptors (estrogen receptors (ER) and/or progesterone receptors (PR)), which are activated when they interact with hormones.

Activated receptors cause changes in the expression of certain genes that stimulate the growth of malignant cells.

Most estrogen-positive breast tumors are also progesterone-positive.

Breast cancer that lacks ER is called ER-negative, and if it lacks both ER and PR receptors, this type of cancer is called hormone-independent.

Approximately 70-80% of breast cancers in women are ER-positive. Around 90% of breast cancers in men are ER-positive and about 80% are PR-positive.

What is hormone therapy?

Hormone therapy for the diagnosis of breast cancer, slows or stops the growth of hormone-dependent breast tumors by blocking the body’s ability to produce hormones, or by interfering with the effect of hormones on malignant breast cells.

Hormone insensitive tumors do not have hormone receptors and do not respond to hormone therapy.

Under no circumstances should hormone therapy for breast cancer be confused with menopausal hormone therapy (MHT), treatment with estrogen alone or in combination with progesterone to relieve menopausal symptoms.

These two types of therapy have exactly the opposite effect: hormone therapy for breast cancer blocks the progression of hormone-dependent breast cancer, while MHT can stimulate its growth.

For this reason, when hormone-dependent breast cancer is diagnosed in a woman taking MHT, it is most often recommended to discontinue MHT therapy.

The main indication for hormone therapy in breast cancer is a positive reaction of ER and/or PR receptors on histological examination of the tumor. In some cases, with hormone-dependent breast cancer, hormone therapy can be prescribed instead of chemotherapy in the initial stages of breast cancer, but this usually requires one of the existing molecular studies, such as: Oncotype, Mammaprint or Prosigna.

Types of hormone therapy for breast cancer in 2023?

In the treatment of hormone-dependent breast cancer in 2023, it is customary to use a number of hormone therapies described below: women in premenopause, its level can be reduced by elimination or suppression of ovarian function.

Blocking of ovarian function is also called ovarian ablation.

Ablation of the ovaries can be done surgically during surgery to remove the ovaries (so-called oophorectomy, this technique is not used in developed countries if there is no genetic predisposition to ovarian cancer) or with drug therapy.

Examples of ovarian suppressants approved in Israel are: Goserelin (Zoladex) and Leuprolide (Lupron) .

Aromatase inhibitor blocking

Drugs called aromatase inhibitors are used to block the activity of an enzyme called aromatase, which is used by the body to make estrogen in the ovaries and other tissues.

Aromatase inhibitors are used primarily in postmenopausal women because the premenopausal ovaries produce too much aromatase and aromatase inhibitors are unable to effectively block them.

However, these drugs can be used in premenopausal women when given with an ovarian suppressant drug.

Examples of aromatase inhibitors approved by the Israeli Ministry of Health for 2023 are: Anastrozole (Arimidex) and Letrozole (Femara) , both of which temporarily inactivate aromatase, and Exemestane (Aromasin) inactivate aromatase forever.

Estrogen blocking

Several types of drugs that interfere with estrogen’s ability to stimulate breast cancer cell growth:

• Selective estrogen receptor modulators (SERMs) bind to estrogen receptors, preventing estrogen from bonding. Examples of similar drugs approved for the treatment of breast cancer in Israel are: Tamoxifen and Toremifene (Fareston).
  Because they bind to estrogen receptors, SERMs can potentially not only block estrogen activity by preventing estrogen from binding to its receptor, but also mimic the effects of estrogen, depending on where they are expressed in the body.

For example, T amoxifen blocks the action of estrogen in breast tissues, but acts like estrogen in the uterus and bones.

• Antiestrogen drugs with a different mechanism of action : Fulvestrant (Faslodex) SERD, acts on the estrogen receptor by a different mechanism. Like SER modulators, Fulvestrant binds to the estrogen receptor and blocks estrogen.

However, unlike SERMs, Fulvestrant does not mimic estrogen. For this reason, it is called a pure antiestrogen. Also, when Fulvestrant binds to the estrogen receptor, the receptor is destroyed. In February 2023, approval of the first oral SERD drug is expected.

Tactics of using hormone therapy in hormone-dependent breast cancer in 2023

There are three main tactics of hormone therapy in the treatment of hormone-dependent breast cancer: th stage (with metastases to distant organs and fabrics).

Adjuvant therapy for breast cancer

In December 2022, additional data were published on the benefit of adding abemaciclib to hormone therapy, in the adjuvant regimen, in women with early hormone-positive and HER2-negative breast cancer, at a high risk of recurrence, reducing this risk by 25%, which is a significant result in oncology.

Tamoxifen is approved for adjuvant hormone therapy in premenopausal and postmenopausal women and men with early-stage ER-positive breast cancer.

Aromatase inhibitors: Anastrozole , Letrozole , and Exemestane are approved as adjuvant hormone therapy in women with hormone-dependent, early postmenopausal breast cancer.

Studies have shown that women who received postoperative (adjuvant) hormonal therapy Tamoxifen, for at least five years, when diagnosed with early stage ER-positive breast cancer, the risk of recurrence was reduced, as well as the risk of cancer in the other breast was reduced , in addition, mortality decreased by a third in the first 15 years after the disease.

Just 10 years ago, Tamoxifen was the main type of hormone therapy for breast cancer.

However, with the introduction of new hormonal therapies (aromatase inhibitors) that have been compared in clinical trials with Tamoxifen , alternative hormonal therapy protocols based on aromatase inhibitors have emerged.

For example, some women may take an aromatase inhibitor instead of Tamoxifen daily for 5 years. Others, additional aromatase inhibitor treatment may be given after five years of use Tamoxifen .

Finally, some women may switch to an aromatase inhibitor after two or three years of Tamoxifen , for a total of five or more years of hormone therapy.

Studies have shown that for postmenopausal women who received adjuvant hormonal therapy with an aromatase inhibitor, the risk of relapse was reduced and overall survival improved compared with adjuvant Tamoxifen alone.

In some women, premenopausal, early stage estrogen positive breast cancer, drug ovarian suppression combined with an aromatase inhibitor has shown better relapse-free outcomes than drug ovarian suppression combined with Tamoxifen, or versus monotherapy Tamoxifen, without ovarian suppression.

Men with early-stage ER-positive breast cancer receiving adjuvant therapy receive 9 in the first stage0089 Tamoxifen . Those who are treated with an aromatase inhibitor also take a GnRH agonist (a substance that blocks the production of sex hormones by the testicles).

The choice of the type of hormonal therapy, as well as its duration, is a very complex task, and should be decided on an individual basis by a professional oncologist with a wealth of experience and knowledge, taking into account a number of factors such as: type of tumor, stage of the disease, age of the patient and the presence of chronic diseases, increased genetic (not always hereditary) and hereditary predisposition to breast cancer.

Neoadjuvant Hormone Therapy for Breast Cancer

The use of hormone therapy in the treatment of breast cancer to reduce tumor size before surgical removal (Neoadjuvant Therapy) has been studied in clinical trials.

Studies have shown that neoadjuvant hormone therapy, particularly aromatase inhibitors, may be effective in reducing breast tumor size in postmenopausal women, but in premenopausal women, the effectiveness of this approach is not yet clear.

Hormone therapy is sometimes used for neoadjuvant treatment of hormone-positive breast cancer in postmenopausal women, with severe side effects to chemotherapy, or when surgery needs to be delayed for health reasons.

Hormone therapy for recurrent or metastatic (stage 4) breast cancer.

In the treatment of metastatic hormone-dependent breast cancer in Israel, for 2023, several new types of drugs with different mechanisms of action are approved and used.

These drugs primarily include the AKT inhibitor – Capivasertib. During the third phase of the study, there was a positive trend in the use of the combination of capivasertib + fulvestrant among patients with hormone-positive locally advanced or metastatic breast cancer, after recurrence or progression against the background of hormone therapy with or without a CDK4/6 inhibitor.

For CDK 4/6 inhibitors by early 2023, clinicians agree that all 3 drugs (Palbociclib, Abemaciclib, and Ribociclib) have similar short-term efficacy, but there are differences in long-term, ongoing follow-up. There is still no consensus on which one to choose as the first line of treatment, due to the lack of a direct comparison. Thus, a group of premenopausal women with hormone-positive breast cancer who received ribociclib + hormone therapy showed better treatment and survival results compared to women who received chemotherapy. Another study is testing the differences between using the Abemaciclib+ Aromatase Inhibitor protocol versus Aromatase Inhibitors alone, with interim results showing a strong trend towards increased benefit of adding Abemaciclib, but research is ongoing.

As a rule, hormonal therapy is the first line of treatment for metastatic breast cancer, and can slow down the disease for several years, while not disturbing the patient’s normal life schedule.

With proper use of drugs, life expectancy exceeds the five-year survival limit among the vast majority of patients. Today, no one is surprised by the fact that patients with initially diagnosed stage 4 breast cancer live 10-12 years after diagnosis.

The benefits of hormonal therapy instead of chemotherapy as a first line treatment for stage 4 cancer are clear. Side effects are much less noticeable, no need for hospitalization, no hair loss and much more.

Hormone therapy may also be a treatment option for locally recurrent estrogen-positive breast cancer.

2 SERM drugs approved for 2023 in the treatment of hormone dependent stage 4 breast cancer: Tamoxifen and Toremifene .

Antiestrogen SERD Fulvestrant is approved for use in postmenopausal women with metastatic ER-positive breast cancer who have relapsed while being treated with other antiestrogen.

Fulvestrant is also approved for postmenopausal patients with hormone receptor positive and HER2 receptor negative, locally recurrent or metastatic breast cancer who have not previously received hormone therapy.

In recent years, there has been intensive development of new oral (tablet) SERD drugs, and in February 2023, the approval of the first such drug, Elacestrant, is expected, which showed greater effectiveness (30-45%) compared with standard hormone therapy, among women with positive ER .

Aromatase inhibitors Anastrozole and Letrozole are approved for postmenopausal women as first-line hormonal therapy for metastatic or local hormone-dependent breast cancer.

Both of the above, plus the aromatase inhibitor Exemestane , are approved for the treatment of postmenopausal women with recurrent breast cancer while taking Tamoxifen .

Men with recurrent breast cancer treated with an aromatase inhibitor also receive a GnRH agonist.

Combinations of hormonal therapy and targeted drugs

Women with metastases to distant organs and tissues (lungs, bones, liver, etc.) are usually prescribed a combination of hormonal therapy with one of several targeted drugs:

• Palbociclib (Ibrance) is approved for use in combination with Letrozole, as initial therapy in the treatment of hormone-dependent, HER2-negative recurrent or metastatic breast cancer in postmenopausal women. Palbociclib inhibits two cyclin-dependent kinases (CDK4 and CDK6) that promote the growth of hormone-dependent breast cancer cells.

Palbociclib also approved for use with Fulvestrant, in the treatment of postmenopausal women with hormone-positive and HER2-negative recurrent or metastatic breast cancer, against the background of disease progression during other hormone therapy.

• Abemaciclib (Verzenio) an additional CDK4 and CDK6 inhibitor approved in combination with HER2-negative recurrent or metastatic breast cancer, the disease of which has progressed against the background of hormone therapy treatment.

  Abemaciclib is also approved for use alone in women and men with hormone-dependent, HER2-negative recurrent or metastatic breast cancer who have progressed on hormonal therapy and/or chemotherapy for metastatic breast cancer.

  Abemaciclib is also approved, in combination with an aromatase inhibitor, as first-line hormone therapy in postmenopausal women with hormone-dependent, HER2-negative recurrent, or metastatic breast cancer.

• Ribociclib (Kisqali), an adjunctive CDK4 and CDK6 inhibitor, is approved in combination with an aromatase inhibitor in postmenopausal women with hormone-sensitive and HER2-negative metastatic breast cancer who have not previously received hormone therapy.

  Ribociclib is also used in combination with Fulvestrant in postmenopausal women with hormone-dependent and HER2-negative stage 4 breast cancer, as first-line therapy, or against the background of disease progression using another treatment.

• Lapatinib (Tykerb) is approved in combination with Letrozole for the treatment of HER2-positive metastatic breast cancer in postmenopausal women who are indicated for hormone therapy . It is a low molecular weight inhibitor of HER2 and EGFR tyrosine kinases.
• Alpelisib (Picray) is approved in the treatment of hormone-dependent breast cancer with HER2 negative and the presence of a mutation in the gene PIK3CA . The drug is used in combination with Fulvestrant in postmenopausal women and men whose breast cancer has progressed or has metastatic character and worsened during or at the end of hormone therapy.
• Some women with advanced hormone-dependent breast cancer and HER2 positive may be given hormone therapy in combination with Trastuzumab and Pertuzumab .

Ask an Israeli oncologist a question

Can hormone therapy be used to prevent breast cancer?

Yes. The majority of breast cancer cases are ER-positive, and a number of clinical studies have proven the feasibility of preventive hormonal therapy to prevent breast cancer in women with an increased risk of developing this disease.

A large international randomized clinical trial called the Breast Cancer Prevention Study found that Tamoxifen , taken for 5 years, reduces the risk of developing invasive breast cancer by approximately 50% in high-risk postmenopausal women.

Long-term follow-up, in another randomized study, showed that a 5-year course of treatment with Tamoxifen, reduced the incidence of breast cancer by at least 20 years.

Follow-up large randomized study, study Tamoxifen and Raloxifene showed that 5 years of Raloxifene reduced the risk of developing breast cancer in postmenopausal women by 38%.

Based on the results of these studies, Tamoxifen and Raloxifene have been approved by the FDA to reduce the risk of developing breast cancer in women at high risk of the disease. Tamoxifen is approved for this use regardless of menopausal status.

Raloxifene is approved for use only among postmenopausal women.

Additional studies have shown that the aromatase inhibitors Exemestane and Anastrozole reduce the risk of breast cancer in postmenopausal women at increased risk of the disease. After 3 years of follow-up in a randomized trial, women taking exemestane were 65% less likely to develop breast cancer than women taking placebo.

Following a 7-year follow-up in another randomized trial, the likelihood of developing breast cancer in women who took Anastrozole was 50% lower than in women taking placebo.

Exemestane and Anastrozole are both approved in Israel for the treatment of women with ER-positive breast cancer.

Hormone therapy and targeted therapy

Hormone therapy

• Aromatase inhibitors: 9018 8
• Arimidex (pharmacological name: Anastrozole)
• Aromasin (pharmacological name: Exemestane)
• Femara (pharmacological name: Letrozole)