Researchers have investigated the long-term effect of hormonal therapy in women with hormone-sensitive breast cancer

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Researchers at Karolinska Institutet in Sweden have investigated the long-term effect of hormonal therapy in women with the most common types of hormone-sensitive breast cancer.

The results, presented in the journal JAMA Oncology, show that the treatment has a protective effect against distant metastatic cancer for both so-called Luminal A and Luminal B breast cancer subtypes, and a long-term effect for women diagnosed with Luminal A cancer.

Estrogen receptor-positive (hormone sensitive) breast cancer is the most common form of breast cancer and means that the tumor grows in response to the female hormone estrogen.

Women who develop this form of breast cancer have a long-term risk of distant metastatic spread of the disease and dying from breast cancer.

There is however insufficient knowledge of how biological factors in the tumor and hormonal therapy affect this long-term risk.

Researchers at Karolinska Institutet have now investigated the long-term effect of hormonal therapy in women with the two most common types of estrogen receptor-positive breast cancer.

The researchers analyzed long-term data with follow-up for at least 20 years for patients in the Stockholm Tamoxifen trial (STO-3) randomised to receive either tamoxifen treatment or no hormonal therapy.

In summary, 336 women were diagnosed with so-called Luminal A breast cancer subtype and 126 women with Luminal B subtype.

The results show that patients with Luminal A breast cancer had a relatively small but prolonged risk increase for metastatic cancer, and that tamoxifen treatment significantly reduced this risk for as long as 15 years after diagnosis.

Patients with Luminal B subtype were at high risk for metastatic breast cancer during the first five years after diagnosis.

In these patients, tamoxifen treatment led to a significantly reduced risk during the first five years, but after that the protective effect of hormonal therapy decreased.

“Our conclusion is that tamoxifen treatment is beneficial for both groups of patients, but that it has a long-term protective effect for patients with Luminal A breast cancer,” says Dr. Linda Lindström, a research group leader at Karolinska Institutet’s Department of Biosciences and Nutrition, who coordinated the study.

“Patients with Luminal B breast cancer should also be offered hormonal therapy, and our results show a reduced risk of metastatic disease during the first years when the risk is the highest for these patients.

We will now proceed to investigate the long-term benefits of hormonal therapy in patients with Luminal A and Luminal B subtype who have been diagnosed with larger and aggressive tumours with spread to the lymph nodes.”

The study was funded by the Swedish Research Council, Forte, the Gösta Milton Donation Foundation, the California Breast Cancer Research Program Award, Iris, Stig and Gerry Castenbäck’s Foundation for Cancer Research and King Gustaf V’s Jubilee Foundation from Radiumhemmet Research Foundation. Co-author Laura van’t Veer holds a patent for “Mammaprint 70-gene risk signature” and is co-founder, shareholder and part-time employee at Agendia.


Tamoxifen is indicated for the treatment of breast cancer in a variety of settings. It should be noted that evidence suggests that patients with estrogen receptor positive tumors are more likely to benefit from tamoxifen.[1] Tamoxifen also has many off-labeled uses, and they may require additional data. 

FDA-Approved Indications

  • Treatment of breast cancer in both females and males[2]
  • Adjuvant treatment of breast cancer after patients have completed their primary treatment with surgery and radiation[3]
  • Treatment of female patients with ductal carcinoma in situ (non-invasive breast cancer) after surgery and radiation to reduce the risk of invasive breast cancer[4]
  • Breast cancer risk reduction in certain patients at high risk (5-year risk = 1.67% calculated by the Gail Model).[5]

Non-FDA-Approved Indications

  • Treatment of progressive or recurrent desmoid tumors in combination with sulindac[6]
  • Treatment of endometrioid histologies that are recurrent, metastatic, or at high-risk[7][8]
  • Treatment of primary or secondary gynecomastia along with breast pain associated with it[9]
  • Induction of ovulation in the treatment of infertility[10]
  • Treatment of oligospermia in combination with testosterone[11]
  • Prophylaxis of coronary arteriosclerosis in men with triple vessel[12]
  • Treatment of advanced or recurrent ovarian cancer[13][14]
  • Treatment of bladder cancer[15]
  • Treatment of lung cancer in addition to initial chemotherapy treatment[16][17]
  • Treatment of precocious puberty due to McCune-Albright syndrome in females[18]
  • Treatment of metastatic malignant melanoma in combination with other agents including carmustine, cisplatin, and dacarbazine[19][20][21][22]
  • Treatment of benign mammary dysplasia[23]
  • Treatment of bone metastasis[24]
  • Treatment of carcinoid tumor [25]
  • Treatment of cutaneous polyarteritis nodosa[26]
  • Treatment of hypertrophy of uterus[27]
  • Treatment of meningioma[28]
  • Treatment of primary breast pain, premenstrual mastodynia, or breast pain that originated from liver cirrhosis[29][30][31][32]
  • Prophylaxis of postmenopausal osteoporosis[33]
  • Improvement of length and quality of life in patients with retinoblastoma in addition to treatment protocols[34]
  • Treatment of Riedel’s thyroiditis[35]
  • Treatment of solid tumor secondary malignant neoplasms[36]

Mechanism of Action

Tamoxifen exhibits both estrogenic agonist and antagonist effects in different parts of the body. Because it has two actions, it is patient-specific as a selective estrogen receptor modulator (SERM). In the breast tissue, it competes with estrogen for binding sites and causes antiestrogenic and antitumor effects. Through downstream intracellular processes, it slows cell cycling which classifies it as cytostatic.

In the bone it stimulates estrogen receptors instead of blocking them, exerting an estrogenic agonist effect, and may prevent osteoporosis in postmenopausal women.[37]

Administration

Tamoxifen is available in a tablet (10 mg or 20 mg) or an oral solution (10 mg/5 mL). If it as administered as an oral solution, it is important to use the supplied dosing cup for adequate administration.

The American Society of Clinical Oncology (ASCO) guidelines for Adjuvant Endocrine Therapy of Hormone-Receptor Positive Breast Cancer recommends a dose of 20 mg daily for breast cancer prevention after completion of chemotherapy.

The duration of endocrine therapy depends on the patient’s menopausal status and can last 5 to 10 years.[38] For the treatment of metastatic breast cancer, 20 to 40 mg daily is recommended, although clinical benefit has not been shown for doses above 20 mg daily.[39] In some off-label clinical trials, 10 mg was used as the dose. It may be taken with or without food.

Adverse Effects

Tamoxifen has a black box warning for uterine malignancies, pulmonary embolism, and stroke in patients who are at high risk for cancer or who have ductal carcinoma in situ.[40] In patients who are female, tamoxifen is associated with an increased incidence of uterine or endometrial cancers, with some being fatal.

In patients who were already diagnosed with breast cancer, however, the benefits outweigh the risks.[41]

Like many cancer drugs, tamoxifen has many adverse effects associated with it, though serious and fatal ones are rare.

The most common adverse effects seen in treatment are hot flashes, irregular periods, and vaginal discharge. Other common adverse effects include peripheral edema, hypertension, mood changes, pain, depression, skin changes and skin rashes, nausea and vomiting, weakness, arthritis, arthralgia, lymphedema, and pharyngitis.

Less common adverse effects may include insomnia, dizziness, headache, weight gain, abdominal pain, diarrhea, indigestion, urinary tract infections, thrombocytopenia, back pain, alopecia, ostealgia, and cataracts among many more. Due to the extensive adverse effects of tamoxifen, it is important for patients to discuss all adverse effects they are experiencing with their doctor.[42]

Tamoxifen can also cause a local disease flare which may lead to increased bone and tumor pain. This can be associated with good tumor response and usually resolves quickly. In patients with bone metastasis, hypercalcemia may occur.

If hypercalcemia becomes severe and not manageable, discontinue tamoxifen.[43]

Contraindications

Tamoxifen should not be used in patients with a known allergy to it or any component in its formulation or concomitantly with warfarin.

For patients taking tamoxifen for breast cancer risk reduction who are at high risk for breast cancer or with ductal carcinoma in situ, it should be avoided if the patient has a history of deep vein thrombosis (DVT) or pulmonary embolism (PE).

In patients that have been diagnosed with breast cancer, the benefits outweigh the risks, but it should still be used in caution in patients with a history of thromboembolic events.

Tamoxifen also has many drug-drug interactions, so a comprehensive medication list in all patients receiving it is vital.[44]

Monitoring

All patients on tamoxifen should have routine lab work including a complete blood count with platelets, serum calcium, and liver function tests. Female patients should monitor for abnormal vaginal bleeding and receive a breast and gynecologic exam at baseline and routinely after. Patients should also watch for signs and symptoms of a DVT or PE.

Other monitoring parameters tend to vary, depending on patient-specific factors. In patients with pre-existing hyperlipidemia, triglycerides and cholesterol should be monitored.[45] 

Patients on vitamin K antagonists should have their INR and PT checked.[46] Reproductive female patients need a pregnancy test before treatment and should use reliable birth control methods during treatment.[47] 

Premenopausal women should receive a bone mineral density test. All patients should get an ophthalmic exam if vision problems or cataracts occur.[48]

Toxicity

There is currently no antidote available for tamoxifen.

Enhancing Healthcare Team Outcomes

Interprofessional teamwork and communication provide success for all patients, especially those undergoing cancer treatments.

Oncologists should thoroughly evaluate the patient and select an appropriate treatment regimen based on guidelines and patient-specific factors. For example, in estrogen receptor-negative breast cancer, tamoxifen may not be appropriate. Nurses should be aware of the more severe adverse effects tamoxifen may cause and look out for them in their patients.

Pharmacists should examine the patient’s current and complete drug regimen and make sure there are no interactions as tamoxifen has many. These are just a few examples, and roles tend to overlap in many different professions, but every healthcare professional provides a vital role that, in turn, benefits the patient greatly. (Level V)


More information: Nancy Y. Yu et al. Assessment of Long-term Distant Recurrence-Free Survival Associated With Tamoxifen Therapy in Postmenopausal Patients With Luminal A or Luminal B Breast Cancer, JAMA Oncology (2019). DOI: 10.1001/jamaoncol.2019.1856

Journal information: JAMA Oncology
Provided by Karolinska Institutet

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