Modern choices of adjuvant endocrine therapy

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Breast cancer is usually a hormone dependant tumour. Response to hormonal treatment (also termed endocrine therapy) is determined by the oestrogen and progesterone receptor status of the breast cancer. This is tested either on the needle biopsy or surgical excision specimen of the breast cancer. Doctors have known for years that blocking oestrogen function prevents the growth and proliferation of breast cancer. Early drugs had rather non-specific suppressive effects on the steroid hormone axis and caused quite significant side-effects. Tamoxifen was a major development as a selective oestrogen receptor modulator and experience with tamoxifen in treating breast cancer exceeds 30 years. The latest overview of the Early Breast Cancer Trialist’s Group in 2000 showed that after 5 years of Tamoxifen, the additional benefit of staying on Tamoxifen having discontinued it is on-going compared with the placebo group over 15 years. More recent developments have seen the emergence of the aromatase inhibitors. The three commonest aromatase inhibitors available for use are anastrozole (trade name – Arimidex), Letrozole (Femara) and Exemestane (Aromosin). Tamoxifen and the aromatase inhibitors only work in patients whose tumours are oestrogen receptor positive and/or progesterone receptor positive. This constitutes 70% or so of patients with breast cancer. The benefit provided by endocrine treatment extends across node positive as well as node negative patients. Although tamoxifen works in pre-menopausal and post-menopausal women, the aromatase inhibitors only work in post-menopausal patients.

In post-menopausal patients with good prognosis breast cancer, chemotherapy is often not required and if hormone sensitive, patients are offered adjuvant endocrine therapy. In younger patients and in patients who have more aggressive disease, chemotherapy and endocrine therapy both confer a significant benefits and are used in conjunction. When used simultaneously, endocrine therapy can theoretically adversely block the benefits of chemotherapy and therefore endocrine treatment is usually prescribed after chemotherapy has finished.

Ten years ago, tamoxifen was the most common adjuvant endocrine therapy and was used for 5 years. Most trials have not shown a benefit of continuing Tamoxifen beyond 5 years. Continuing Tamoxifen after 5 years also has the disadvantage of increased rates of adverse-effects related to the medication.

There are a number of trials that have now compared tamoxifen with aromatase inhibitors. The ATAC trial shows that 5 years of anastrozole is superior to 5 years of tamoxifen when compare head to head as up-front use after surgery. In women with a higher risk of developing breast cancer progression, anastrozole is now often used as the first drug of choice rather than tamoxifen. The BIG I-98 trial compared 5 years of tamoxifen to 5 years of letrozole. Again, letrozole was shown to have a beneficial cancer reduction effect than tamoxifen. Neither of the trials has shown a survival benefit.

Several trials have shown that tamoxifen for 2 years followed by 3 years of an aromatase inhibitor superior to 5 years of Tamoxifen. The evidence of this for letrozole is in the BIG I-98 trial whilst the evidence for exemestane is in the IES study. The advantage of using 2 years of Tamoxifen followed by 3 years of an aromatase inhibitor is that there is a lower risk of loss of bone mineral density and lower rates of osteoporosis and therefore reduced fracture rates. Tamoxifen protects against losing bone mineral density (hence strengthens bones) whilst the aromatase inhibitors predispose to bone thinning (hence fracture risk). Patients on an aromatase inhibitor require to have their bone mineral density monitored very carefully. Other trials that have considered the use of an aromatase inhibitor after tamoxifen compared to Tamoxifen alone include ARNO-95 and ABCSG-8.

The MA-17 trial considered 5 years of tamoxifen followed by 5 years of letrozole. This has been shown to be associated with a reduction in the development of cancer events and may have a longer term survival benefit particularly in node positive breast cancer patients.

The optimum choice for you with regards to how to best benefit from adjuvant endocrine therapy is something that you should discuss with your doctor. Specific issues include: which agents, what duration, whether to switch and whether to use extended therapy.

Adjuvant endocrine therapy has side-effects. As one would expect, these effects often relate to oestrogen deprivation. The commonest of these relates to vasomotor (flushing and sweating) type symptoms. In general, patients who have had a difficult menopause are more likely to experience such symptoms. Flushing and sweating symptoms are slightly more common with tamoxifen than with the aromatase inhibitors.

Tamoxifen can cause vaginal discharge. It may also increase the thickness of the lining of the uterus, cause polyps to form within the wound and also induce or make fibroids grow. The aromatase inhibitors affect the uterus to a considerable lesser degree.

Tamoxifen can in the rare instants cause uterine cancer. Uterine cancer is rare, effecting 3 per 10,000 women. In women on Tamoxifen this risk goes up to 5 per 10,000. This risk is not significant in women on Aromatase Inhibitors.

Adjuvant endocrine therapy can induce deep vein thrombosis (DVT). The incidence of this complication is higher with tamoxifen than with the aromatase inhibitors. The risk is higher in post-menopausal women than in pre-menopausal women. Women on Tamoxifen should take the usual precaution for reduction of deep vein thrombosis risk when for example; taking long flights.

The aromatase inhibitors are more likely to induce bone and joint pains to a greater extent than tamoxifen. This is one of the more common reasons why women are intolerant of the aromatase inhibitors.

The aromatase inhibitors predispose to loss of bone mineral density. Tamoxifen, being a selective oestrogen receptor modulator, protects against bone loss. This is one of the advantages of using a switch combination therapy of tamoxifen followed sequentionally by an aromatase inhibitor. Women on an aromatase inhibitor need to be carefully monitored with X-rays of their bone density profile. Osteoporosis risk is easily managed. Bone density loss is often abrogated when the aromatase inhibitor is discontinued or the course of treatment completed.

Patients who have previously had a stroke or venous thrombosis are usually recommended to have an aromatase inhibitor rather than tamoxifen as there are lower arterial abnd venous clotting problems associated with the aromatase inhibitors.

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