Hormonal Therapies For Secretory Carcinoma Of The Breast

Introduction 

Definition and prevalence

Secretory carcinoma (SC) is a rare type of breast cancer, accounting for under 0.15% of breast tumour cases. SC was originally referred to as “juvenile breast carcinoma” by McDivitt and Stewart in 1966, as the average age of their SC patients was only 9 years old. Although it is the most common paediatric breast cancer, we now know that SC can occur at any age. Most patients have a lump found near the areola (the pigmented area surrounding the nipple). SC is “secretory” because the tumour produces secretions both within and outside of the cancer cells. The prognosis and survival rate are generally very good.^1,2

Characteristics and histopathology

Secretory breast carcinoma usually involves a small mass with a median size of 1.9-2.4cm. The tumour tends to be tubular (tube-shaped) and microcystic, consisting of a cluster of small growths. 

Genetics of secretory carcinoma

This rare cancer subtype has been linked to a ‘chromosomal translocation’, where part of chromosome 12 is attached to a part of chromosome 13. This causes two genes to be fused, resulting in the ETV6-NTRK3 fusion gene. These genes influence an important pathway involved in cell growth and cell death, known as the MAP Kinase pathway. When the natural processes that regulate cell growth and cell death are disrupted, the result can often lead to cancer, as tumour cells grow out of control. Future research, for example, could pursue a treatment that acts on locating the ETV6-NTRK3 fusion gene, and dealing with the cell signalling disruption.^1,2

Hormone expression

Many breast cancer cells are ‘positive’ for certain hormone receptors, which means that their presence allows for hormones to bind to the cancer cells and help them to grow. For example, the sex hormones oestrogen and progesterone can sometimes activate tumour growth, and their actions can therefore be hijacked by medication to slow down cancer progression.

Some SC cases are not strongly hormone-linked, as the tumour cells do not express oestrogen receptors (ERs) or progesterone receptors (PRs). Moreover, the human epidermal growth factor receptor 2 (HER2) is not overexpressed, which is otherwise a successful treatment target in many other breast cancers. Because some SC cases do not have these three common features, SC has been referred to as a ‘triple-negative’, and therefore a slow-growing tumour.

However, a considerable amount of SC cases are hormone-positive, which means that these patients could benefit from hormonal treatment. A meta-analysis by Gong et al. reported that 58% of SC cases were oestrogen-positive, whilst 40% were progesterone-positive. This means that hormonal therapies would be helpful for these patients.³

Overview of hormonal therapy

Explanation and role in cancer treatment

The main treatments for breast cancers include the surgical removal of the tumour, and chemotherapy, which attempts to shrink tumour growth by halting the growth of fast-dividing cells. Hormonal therapy (or 'endocrine therapy') is used when the cancer is hormone-positive. For example, the hormonal drug treatment might block the ovaries from producing the hormones, selectively block oestrogen or progesterone production, or influence specific downstream effects. 

Hormonal treatments can be used at different stages of cancer progression:

• Cancer prevention for women at high risk due to familial history of cancer 
• Shrinking a tumour ahead of surgery to remove it
• Reducing the growth of a tumour after most of it has been removed through surgery 
• Shrinking secondary cancer breast tumours (cancer which has spread from another area of the body)
• Hormonal drugs can also be used instead of, or in addition to chemotherapy

It should also be noted that hormonal therapy may be an effective approach for any hormone-positive cancer, in both biological males and females

Mechanisms of action for secretory carcinoma

Evidence for the efficacy of hormonal therapy specifically for SC is quite low, due to the cancer usually described as being negative for oestrogen and progesterone. However, there is plenty of research demonstrating its effectiveness in hormone-positive cancers, and therefore this information can be potentially applied to hormone-positive SC cases, although further research is encouraged. Since most progesterone-positive cancers are also oestrogen-positive, and progesterone levels are controlled by oestrogen, all endocrine drugs (drugs targeting the endocrine system which circulates hormones along the bloodstream) generally target oestrogen. This then reduces both oestrogen and progesterone.

Hormonal therapy options

Selective oestrogen receptor modulators 

Definition and examples

Selective oestrogen receptor modulators (SERMs) bind selectively to oestrogen receptors, and their effects vary depending on where the modulators are located. SERMs can both block and mimic the effects of oestrogen, depending on the part of the body. SERMs are very useful in secretory breast cancer, as they block the oestrogen receptors in the breast, to prevent the hormone itself from binding to the tumour cell, and therefore preventing its effects. Examples of SERMs include tamoxifen and toremifene. These are oral drugs taken daily, usually as a 20 mg tablet.

Tamoxifen

Tamoxifen was first developed in the 1970s to treat breast cancer, and has also been explored as a preventative drug in women that have a high risk of developing breast cancer. Tamoxifen blocks the oestrogen receptor in breast tissue, but also promotes the oestrogen effects in other tissues, meaning that it can improve bone density and help protect against osteoporosis. Tamoxifen is highly effective at stopping cancer growth in hormone-positive breast cancer. Research showed that tamoxifen reduces the incidence of breast cancer in at-risk cancer-free women when taken for 16 years.^4,5

Toremifene

Toremifene is similar to tamoxifen, with a slight chemical difference (a difference of one chlorine atom). Again, toremifene blocks oestrogen receptors in breast cells, therefore slowing down the oestrogen-mediated growth of the carcinoma. Some studies show that tamoxifen and toremifene are equally effective, with a 94.3% chance of survival after 5 years for toremifene and a 93.5% chance for tamoxifen. In the meantime, other studies argue that toremifene may be slightly more beneficial. Tomerifene may have a lower risk of some severe side effects compared to tamoxifen, as a study has shown that its use has less risk of causing growths in the uterus (uterine neoplasms which could be cancerous or benign).^6,7

Benefits and limitations

The major benefit of SERMs is their high effectiveness in both preventing and shrinking hormone-positive breast cancers. There are also positive side effects, including a reduction in cholesterol, and an improvement in bone density. This consequently means that SERMs are also effective in managing osteoporosis, a condition involving the development of weak bones, which postmenopausal women are particularly at a heightened risk of. The SERM drug binds at the oestrogen receptor in bone tissue, mimicking oestrogen in a way that benefits bone health.

However, there are also negative effects from SERM drugs, many of which link to reduced oestrogen and postmenopausal side effects. These include:

• Hot flushes 
• Vaginal discharge or vaginal irritation
• Feeling sick
• Fatigue
• Dry, itchy skin
• Increased blood clot risk

Additionally, tamoxifen has other serious side effects such as an increased risk of growths in the uterus which can cause endometrial (womb) cancer.^7,8

Aromatase inhibitors

Definition and examples

Aromatase inhibitors (AIs) block aromatase, an enzyme (an important protein that speeds up chemical reactions) responsible for the final step in the production of oestrogen. This means that you have less oestrogen being produced, so this can slow or completely stop the growth of oestrogen-positive hormones. Examples include anastrozole (brand name Arimidex), exemestane (Aromasin) and letrozole (Femara). Aromasin has a more permanent effect on aromatase function. These drugs are taken daily as pills, tablets or liquid.

However, it should be noted that these drugs are not effective at preventing oestrogen production in the ovaries before menopause, so they are generally only prescribed to postmenopausal women, or to men.⁹ 

Benefits and limitations

An issue with AIs is that many patients develop resistance to them, meaning that the treatment stops being effective after some time using the drug. Patients also experience symptoms from lowered oestrogen levels, such as osteoporosis due to a loss of bone strength, joint pain, and heart problems. They may also cause other low-oestrogen level effects such as hot flashes and vaginal irritation.

Gonadotropin-releasing hormone agonists

Definition and examples

Gonadotropin-releasing hormone (GnRH) is a hormone which regulates other reproductive hormones, such as oestrogen and progesterone. GnRH agonists are drugs which reduce the release of oestrogen and progesterone and slow down ovary function. By suppressing the ovaries, GnRH agonists prevent ovulation so they stop periods and the possibility of getting pregnant. As well as slowing hormone-positive cancer growth, this treatment protects your chances of fertility, by pausing the release of eggs while completing chemotherapy.

Examples of GnRH agonists used for breast cancer are goserelin (Zoladex), leuprolide (Lupron) and triptorelin (Trelstar). These are generally administered by injection, every month or every 3 months.¹¹

Benefits and limitations

GnRH agonists are effective at treating breast cancer, as well as protecting ovary function. The ovary suppression is temporary, therefore after the treatment is finished, the ovaries will eventually start to function again and continue ovulation.

GnRH agonists are often used in addition to an SERM such as tamoxifen. However, the suppression of ovary function causes negative side effects, similar to the other hormonal drugs. These include hot flashes, sweat, fatigue, vaginal dryness, and a reduction in libido. They also commonly result in disrupted sleep and headaches, weight changes and muscle weakness, as well as a risk of osteoporosis development.

Clinical efficacy and safety

Evidence from trials and studies

• SERMs such as tamoxifen and toremifene led to a 94% survival rate in breast cancer patients after 5 years, with an 87% disease-free survival for those taking toremifene, and an 85% disease-free survival for those taking tamoxifen.⁷
• Taking an AI (letrozole) led to 95% disease-free survival rate compared to 91% in the placebo group.¹⁰
• GnRH agonists protect ovary function, preserving the fertility of women receiving aggressive cancer treatment, as well as improving their cancer survival rate¹¹

Considerations for treatment

Patient selection criteria

Breast cancers are checked for hormone positivity to see if the patient is eligible for hormonal treatment. This is done by taking a biopsy and sending this to a lab. During this procedure, a small amount of the cancer tissue is surgically removed and is then analysed. If the tissue is positive for oestrogen or progesterone, the patient and their clinician then consider what hormonal therapies could be appropriate. For example, if postmenopausal, SERMs or AIs may be prescribed. If premenopausal, SERMs and/or GnRH agonists may be given.

Treatment duration and monitoring

Hormonal therapies are often fairly long-term as they are administered for several years. For example, SERMs can be given as a preventative treatment for 5 up to 16 years.⁵ AIs are often used for 5 years to reduce the risk of cancer growth.

Drug interactions and contraindications

There are some drug interactions and contraindications to be aware of.

• Many SERM tablets come with lactose, so this should be checked with your doctor if you have a lactose intolerance.
• Pregnant women should usually pause the use of hormonal therapies, or complete the hormonal treatment and wait at least two months before trying to get pregnant.
• SERMs such as tamoxifen increase the risk of blood clots, so they should not be combined with any other medication that can affect blood clotting such as anticoagulants
• Some antidepressants are suggested to reduce the effectiveness of SERMs such as tamoxifen.¹²
• AIs and GnRH agonists can increase bone loss and weakening, therefore these should be avoided by patients already experiencing osteoporosis

Summary

Hormonal therapies are a promising approach in the management of breast SC, a rare subtype of breast cancer which often affects young patients. Patients with SC should have a biopsy taken to check if they can be helped by any hormonal treatments.

There are several options which may be very effective, depending on whether the cancer patient is biologically male or female, and whether they have reached menopause yet. Whilst hormonal therapies do not fully cure the cancer, they may reduce the need for more aggressive treatments such as chemotherapy and may therefore improve survival rates.