Hormonal Therapy For Metaplastic Carcinoma

  • Natasha Kaur Biomedical Science – Bachelors of Science, University of Lincoln, UK

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Overview

Definition of metaplastic carcinoma

Metaplastic carcinoma or metaplastic breast cancer is a rare form of breast cancer that can become increasingly aggressive. This variant has no general treatment at present, and the long-term outlook for the variant is less hopeful than other breast cancer forms, such as triple-negative breast cancer.1  

Overview of hormonal therapy

Hormonal replacement therapy, also known as HRT, is where the hormones lost during the menopausal transition in women are replaced by supplementation. This helps relieve the symptoms often associated with menopause. Oestrogen and progesterone elements are included in HRT, mimicking hormones produced by the ovaries.2  

Women without any other major disease or illness who are in early menopause with moderate to more severe symptoms are eligible for hormonal therapy.For all patients with metaplastic carcinoma, hormonal therapy is mandatory.4

Understanding metaplastic carcinoma and hormone receptors

Characteristics of metaplastic carcinoma

Neoplasia is where an entire section of epithelium tissue has become made up of abnormal cells with no normal epithelial cells left. This is irreversible, and control of the regenerative process of the cells has been lost.The neoplastic epithelium of metaplastic breast cancer turns into squamous or mesenchymal-looking cells.5 Metaplastic carcinoma is a type of malignant neoplasm. The abnormal growth of tissue in metaplastic carcinoma is malignant, meaning it is cancerous and could spread.

Importance of hormone receptor status

An immunohistochemistry test (IHC test) is performed to find out if your cancer cells have oestrogen (ER) and progesterone (PR) receptors.6 The results from the test give your hormone receptor status. If 1% or more of cells that have been tested have oestrogen and or progesterone receptors, then it means a tumour is hormone receptor-positive. If below 1%, the result will show hormone receptor-negative for the tumour.

Hormone-receptor positive result

These cells have either or both ER and PR receptors.

  • It can be treated with hormone therapy drugs, which lower oestrogen levels/ block oestrogen receptors.
  • These types of cancers often grow more slowly than those which are hormone-negative.

Hormone-receptor negative result

No oestrogen or progesterone receptors.

  • These cancers grow faster than hormone-positive cancers.
  • More common in women who have not experienced menopause.
  • Hormone therapy treatment is not helpful in these cases.

Triple-negative result

  • Breast cancer cells don’t have oestrogen or progesterone receptors but also don’t make as much HER2 protein.
  • More common in women under 40.
  • These grow and spread faster than most other cancers.
  • Due to a lack of receptors, hormone therapy is not helpful.
  • HER2 target drugs are also not useful as they don’t contain much HER2 protein.
  • Chemotherapy can still be useful.

Triple-positive result

  • ER is positive, PR is positive, and HER2 is positive.
  • It can be treated with both hormone therapy and HER2 target drugs.

Types of hormonal therapy

Selective oestrogen receptor modulators (SERMs)

Mechanism of action

Selective oestrogen receptor modulators interact with the oestrogen receptor on cancer cells using their tissue-selective oestrogen receptor agonist/ antagonist activity.7 Oestrogen receptors on cancer cells have α and β chains, and SERMs interact with either one of these chains, causing SERM action. This effect is always tissue-specific and can have physiological effects. SERMs can either mimic oestrogen components in some tissues or block oestrogen action in others.8

Examples and side effects

The SERM tamoxifen acts as a partial agonist in the uterus – this is a molecule which attaches to a target, for example, the oestrogen receptor, but doesn’t activate the receptor fully as a result of attachment.

Raloxifene – another selective oestrogen receptor modulator – behaves as a full antagonist in the uterus. This means that once raloxifene attaches to an oestrogen receptor in uterine tissue, it prevents any other molecule binding and, therefore, blocks oestrogen receptors.

Side effects of SERMs:

  • Hot flashes.
  • Nausea.
  • Vaginal discharge.9

Each SERM has different possible side effects; you should discuss these with your doctor.

Aromatase inhibitors (AIs)

Mechanism of action

Aromatase inhibitors prevent the action of aromatase, which is an enzyme that converts androgens into oestrogens. This means AIs are complete antagonists. Since breast tissue growth is stimulated by oestrogens, reducing the production of oestrogen is a method of suppressing breast tumour tissue recurrence.

Examples and side effects

Letrozole is an aromatase inhibitor specifically used in breast cancer treatment. It works by blocking the active site on the oestrogen in breast tissue, preventing the conversion of androgens to oestrogen.10

Common side effects of letrozole include but are not limited to:

  • Hot flushes and sweating.
  • Difficulty sleeping.
  • Feeling very tired.
  • Mild muscle and bone aches.
  • Numb or tingling hands.
  • Hair loss.
  • Depression.

Gonadotropin-releasing hormone (GnRH) Agonists

What is gonadotropin-releasing hormone?

A gland in your endocrine system called the pituitary gland uses gonadotropin-releasing hormone (GnRH) to trigger the production of follicle-stimulating hormone (FSH) and also luteinising hormone (LH). The gonadotropin hormones make the sex hormones oestrogen, testosterone and progesterone so it is significant to your sexual development.

Mechanism of action

GnRH gets released by the hypothalamus, travelling to the pituitary. Gonadotropin-releasing hormone then stimulates the  release of LH and FSH.11

Examples and side effects

Examples of gonadotropin-releasing hormones include leuprolide, triptorelin, goserelin and histrelin. Common side effects of both GnRH agonists and antagonists include:

  • Hot flashes.
  • Fatigue.
  • Weight gain.
  • Fluid retention.
  • Decreased libido.12

Hormonal therapy in metaplastic carcinoma treatment

Role of hormonal therapy

Hormonal therapy in metaplastic carcinoma treatment blocks or stops the effect of oestrogen in breast cancer cells. If the breast cancer is oestrogen receptor positive or in some cases, only progesterone positive, hormonal therapy can be beneficial, although very few breast cancers come under this category. If your breast cancer is oestrogen receptor-negative (ER-), it is not stimulated by oestrogen, and hormone therapy will not be beneficial.

Combination therapy

Combination therapy includes hormonal therapy and chemotherapy. This is available to those whose hormonal status test result is oestrogen receptor-positive.

Effectiveness and potential benefits

Research studies and clinical trials

Research shows the most common form of breast cancer is the oestrogen receptor-positive and HER2 protein-negative breast cancer. It is often detected early, and patients respond well to treatment, living without recurrence of the cancer 5 years after treatment.

Ribociclib is a common treatment for oestrogen receptor-positive and HER2 protein-negative breast cancer. This is because this form of breast cancer often requires treatment further than surgery and radiation therapy. Ribociclib is a target therapy that stops the processes by which cancer cells divide. The combination of ribociclib with hormonal therapy has become a standardised treatment in postmenopausal women with ER-positive and HER2-negative metaplastic breast cancer.

Limitations and challenges

Factors affecting effectiveness

The hormone receptor status test result informs whether hormonal therapy will be effective or not. Hormone receptor-negative breast cancer cells don’t have a receptor for either oestrogen or progesterone, meaning that treatment using hormones is not beneficial, and these cells are resistant to hormonal therapy. Chemotherapy or targeted therapies may be options if the tumour is HER2 protein-positive.

Monitoring and follow-up

Importance of regular monitoring

Monitoring and follow-up will always be a part of your treatment journey with metaplastic carcinoma, to track how well the hormonal therapy or combination therapies are working. This is vital in contributing to a more hopeful prognosis and a better outcome.

Ensure you are following up with your doctor after treatment and communicating any adverse effects you may be experiencing, as alternative treatments are available under each hormonal therapy option.

Imaging tests and biomarkers

Metaplastic carcinomas are picked up and monitored using mammography and ultrasounds, sometimes through biopsies too.13 HER2 protein status and hormone receptor status are the two biomarkers used in patients with breast cancer that can be used after imaging tests to perform a more detailed clinical analysis of the patient’s case.14

Patient support and resources

Supportive care options

You are never alone in your journey and whether it’s peer support, organisations, your doctors and nurses – there will always be someone to listen to you and answer any questions you may have.

Some organisations you can reach out to:

You can also visit your GP for referral to counselling services via the NHS and someone will help you identify the individual support you need.

FAQs

What are the disadvantages of hormone therapy for cancer?

Disadvantages of hormone therapy can range from mild physiological disruption (fatigue, weight gain/loss, hot flashes, difficulty sleeping) to more severe changes to your daily life and health (hair loss, vaginal bleeding, increased risk of blood clots). Your healthcare provider will talk you through the disadvantages of hormone therapy for cancer and whether hormone therapy is the most appropriate route for your individual case. 

Does hormone therapy stop cancer from spreading?

Some treatments, such as AI, can be used alone to try and control breast cancer cell growth. As many hormone therapies are used as a part of combination therapy (the combined effort of hormones, chemotherapy, or radiotherapy), treatment can be monitored over time with the aim of preventing cancer from spreading once identified. Some cancers, such as oestrogen-receptor-positive breast carcinomas, respond very well to hormone therapy in conjunction with other therapies. Others, such as hormone-receptor-negative cancers, are less likely to be prevented from spreading with hormone therapy.

How long can you live with metaplastic breast cancer?

As metaplastic breast cancer can spread rapidly, it currently has a 5 year survival rate of around 54%.15 Despite displaying a bad prognosis when compared to other cancer types, it is a very rare type of carcinoma, and diagnosis with this type of carcinoma makes for only a small percentage (0.2-5%) of all breast cancer cases. Ongoing research into novel hormonal treatments aims to improve the lifespan of an individual with metaplastic breast cancer by finding new ways to target and kill cells before and during metastasis. 

Summary

Metaplastic carcinoma is a rare and malignant type of breast cancer that poses several challenges in terms of treatment. The diagnosis is typically made through immunohistochemistry tests that determine the status of your tumour receptors. Hormonal therapy is the primary form of treatment available when the tumour status is positive for ER and PR receptors. Hormonal medications with different mechanisms of action, such as SERMs, AIs, and GnRH, are available options and can offer promising outcomes when combined with chemotherapy. However, it's important to use them with caution as they may cause side effects. Navigating cancer treatment can be overwhelming, but regular monitoring, staying informed about available therapies, and seeking assistance from healthcare professionals or support groups can help you face this challenge with confidence.

References

  1. Reddy TP, Rosato RR, Li X, Moulder S, Piwnica-Worms H, Chang JC. A comprehensive overview of metaplastic breast cancer: clinical features and molecular aberrations. Breast Cancer Research [Internet]. 2020 Nov 4 [cited 2023 Oct 5];22(1):121. Available from: https://doi.org/10.1186/s13058-020-01353-z
  2. Harper-Harrison G, Shanahan MM. Hormone replacement therapy. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Oct 5]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK493191/
  3. Flores VA, Pal L, Manson JE. Hormone therapy in menopause: concepts, controversies, and approach to treatment. Endocr Rev. 2021 Nov 16;42(6):720–52.
  4. Drăgănescu M, Carmocan C. Hormone therapy in breast cancer. Chirurgia (Bucur). 2017;112(4):413–7.
  5. Thapa B, Arobelidze S, Clark BA, Xuefei J, Daw H, Cheng YC, et al. Metaplastic breast cancer: characteristics and survival outcomes. Cureus [Internet]. [cited 2023 Oct 5];14(8):e28551. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9517584
  6. Breast cancer hormone receptor status | oestrogen receptor [Internet]. [cited 2023 Oct 5]. Available from: https://www.cancer.org/cancer/types/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html
  7. An KC. Selective oestrogen receptor modulators. Asian Spine J [Internet]. 2016 Aug [cited 2023 Oct 5];10(4):787–91. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995266/
  8. Dutertre M, Smith CL. Molecular mechanisms of selective oestrogen receptor modulator (Serm) action. J Pharmacol Exp Ther [Internet]. 2000 Nov 1 [cited 2023 Oct 5];295(2):431–7. Available from: https://jpet.aspetjournals.org/content/295/2/431
  9. Serms what they are, how they work & their side effects [Internet]. [cited 2023 Oct 5]. Available from: https://www.breastcancer.org/treatment/hormonal-therapy/serms
  10. Nabholtz JMA. Long-term safety of aromatase inhibitors in the treatment of breast cancer. Ther Clin Risk Manag. 2008 Feb;4(1):189–204.
  11. Perrett RM, McArdle CA. Molecular mechanisms of gonadotropin-releasing hormone signaling: integrating cyclic nucleotides into the network. Front Endocrinol (Lausanne) [Internet]. 2013 Nov 20 [cited 2023 Oct 5];4:180. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834291/
  12. Gonadotropin-releasing hormone (Gnrh) analogues. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012 [cited 2023 Oct 6]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK547863/
  13. Langlands F, Cornford E, Rakha E, Dall B, Gutteridge E, Dodwell D, et al. Imaging overview of metaplastic carcinomas of the breast: a large study of 71 cases. Br J Radiol [Internet]. [cited 2023 Oct 6];89(1064):20140644. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124866/
  14. Fasching PA, Brucker SY, Fehm TN, Overkamp F, Janni W, Wallwiener M, et al. Biomarkers in patients with metastatic breast cancer and the praegnant study network. Geburtshilfe Frauenheilkd [Internet]. 2015 Jan [cited 2023 Oct 6];75(1):41–50. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318728/
  15. 15. Reddy, T.P., Rosato, R.R., Li, X. et al. A comprehensive overview of metaplastic breast cancer: clinical features and molecular aberrations. Breast Cancer Res2

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Natasha Kaur

Biomedical Science – Bachelors of Science, University of Lincoln, UK

Natasha is a dedicated full-time student with a significant background in all things health and biology related, acquired over several years, which is why sharing concise health-related knowledge to the public has developed into one of her strong passions. Her interest lies in cancer-related topics, including her final year degree dissertation project, and so educating people about the disease is of particular interest to her. She has established recent experience in medical writing with Klarity Health which has pointed her into a full-time writing career, post graduating.

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