Aromatase inhibitors

Inhibition of aromatase prevents the synthesis of oestrogens.

Aminoglutethimide has been used in the past to produce a medical adrenalectomy, preventing the synthesis of adrenal oestrogens in patients post-oophorectomy. The clinically relevant activity of aminoglutethimide was aromatase inhibition. More recently specific inhibitors of aromatase have been developed which obviate the need for glucocorticoid replacement.

There are two classes of aromatase inhibitors:

• non-steroidal:
  • anastozole
  • letrozole
  • are potent aromatase inhibitors which may be used in advanced breast cancer
• steroidal:
  • formestane
  • exemestane
  • may be used in advanced breast cancer

Summary points (1,2,3):

• in contrast to tamoxifen, acts via inhibition of oestrogen synthesis
• leads to an improvement in disease free and metastatic free survival better than tamoxifen
• leads to a reduction in risk of recurrence when used as extended adjuvant therapy after five years of tamoxifen
• leads to a reduction in risk of contralateral breast cancer by a further 40-50% when given instead of, or after, tamoxifen
• may be more effective than tamoxifen against if human epidermal growth factor receptor 2 (HER2) positive tumours

A Drug and Therapeutics Bulletin review of aromatase inhibitors concluded (4):

• postmenopausal women with primary operable hormone-receptor-positive breast cancer
  • there is evidence that anastrozole is marginally more effective in prolonging disease-free survival, and is less likely to cause unwanted effects such as uterine cancer and thromboembolism, than tamoxifen in postmenopausal women with primary operable hormone-receptor-positive breast cancer; however anastrozole is associated with an increased likelihood of bone fractures in comparison with tamoxifen. It is unclear however whether anastrozole increases overall survival and .."in early disease tamoxifen remains the first-line adjuvant treatment...anastrozole is an alternative when tamoxifen is contraindicated or unsuitable because the woman is at risk for venous thromboembolims or has suspected endometrial abnormarlity"
• treatment before surgery in women with hormone-receptor-positive breast cancer
  • aromatase inhibitors should not, on present evidence, be used to treat women with hormone-receptor-positive breast cancer before surgery to reduce tumour size to allow breast-conserving surgery in preference to tamoxifen treatment
• in postmenopausal women with horone-receptor postive breaset cancer that is locally advancer or the patient has metastatic disease then aromatase inhibitors (anastrozole and letrozole) are a reasonable alternative first-line treatment option to tamoxifen

NICE have stated (5,6):

• aromatase inhibitors anastrozole, exemestane and letrozole, within their licensed indications, are recommended as options for the adjuvant treatment of early oestrogen-receptor-positive invasive breast cancer in postmenopausal women
  • postmenopausal women with oestrogen receptor (ER)-positive early invasive breast cancer who are not considered to be at low risk should be offered an aromatase inhibitor, either anastrozole or letrozole, as their initial adjuvant therapy. Offer tamoxifen if an aromatase inhibitor is not tolerated or contraindicated
  • offer an aromatase inhibitor, either exemestane or anastrozole, instead of tamoxifen to postmenopausal women with ER-positive early invasive breast cancer who are not low risk and who have been treated with tamoxifen for 2-3 years
  • offer additional treatment with the aromatase inhibitor letrozole for 2-3 years to postmenopausal women with lymph node-positive ER-positive early invasive breast cancer who have been treated with tamoxifen for 5 years

Chemoprevention for women with no personal history of breast cancer (7)

• should be discussed within a specialist genetic clinic
  • healthcare professionals within a specialist genetic clinic should discuss and give written information on the absolute risks and benefits of all options for chemoprevention to women at high risk or moderate risk of breast cancer
  • discussion and information should include the side effects of drugs, the extent of risk reduction, and the risks and benefits of alternative approaches, such risk-reducing surgery and surveillance
    
    
• recommendations about chemoprevention for women at high risk of breast cancer
  
  
  • tamoxifen should be offered for 5 years to premenopausal women at high risk of breast cancer unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer
    
    
  • anastrozole should be offered for 5 years to postmenopausal women at high risk of breast cancer unless they have severe osteoporosis.
    
    
  • for postmenopausal women at high risk of breast cancer who have severe osteoporosis or do not wish to take anastrozole:
    • offer tamoxifen for 5 years if they have no history or increased risk of thromboembolic disease or endometrial cancer, or
    • consider raloxifene for 5 years for women with a uterus if they have no history or increased risk of thromboembolic disease and do not wish to take tamoxifen
      
      
  • do not offer chemoprevention to women who were at high risk of breast cancer but have had bilateral risk-reducing mastectomy
    
    
• recommendations about chemoprevention for women at moderate risk of breast cancer (7)
  
  
  • tamoxifen should be considered for 5 years for premenopausal women at moderate risk of breast cancer, unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer
    
    
  • anastrozole should be considered for 5 years for postmenopausal women at moderate risk of breast cancer unless they have severe osteoporosis
    
    
  • for postmenopausal women at moderate risk of breast cancer who have severe osteoporosis or do not wish to take anastrozole:
    
    
    • consider tamoxifen for 5 years if they have no history or increased risk of thromboembolic disease or endometrial cancer, or
      
      
    • consider raloxifene for 5 years for women with a uterus if they have no history or increased risk of thromboembolic disease and do not wish to take tamoxifen
• do not continue chemoprevention beyond 5 years in women with no personal history of breast cancer
  
  
• inform women that they should stop tamoxifen at least:
  • 2 months before trying to conceive
  • 6 weeks before elective surgery

Breast cancer risk category

*This group includes known BRCA1, BRCA2 and TP53 mutations and rare conditions that carry an increased risk of breast cancer such as Peutz-Jegher syndrome (STK11), Cowden (PTEN) and familial diffuse gastric cancer (E-Cadherin)

Anastrozole is authorised for treating breast cancer in postmenopausal women and has been used off label in some cases for prevention, but it has now received official approval for prevention in postmenopausal women at moderate or high risk of developing the disease. In trials anastrozole has been shown to reduce the incidence of breast cancer in this population by almost 50% (9).

Notes:

• at the time of publication (June 2013), tamoxifen did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information.
• at the time of publication (June 2013), raloxifene did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information
• NHS England estimate that around 3.7% of the female population in England between 30-60 years old are eligible for preventative therapy for breast cancer (8)
• aromatase inhibitors and osteoporosis
  • because aromatase inhibitors reduce circulating oestrogen levels, a decrease in bone mineral density can be anticipated. Therefore, a warning has been included in the summaries of product characteristics of all three aromatase inhibitors that women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the beginning of treatment and, for anastrozole, at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and patients treated with an aromatase inhibitor should be carefully monitored (5)

Reference:

1. BMJ. 2006 Jan 28;332(7535):223-4.
2. BMJ 2006;332:34-37
3. BMJ 2006;332:101-103
4. Drug and Therapeutics Bulletin 2003; 41 (8) :57-59.
5. NICE (November 2006).Hormonal therapies for the adjuvant treatment of early oestrogen-receptor-positive breast cancer
6. NICE (February 2009).Early and locally advanced breast cancer - dagnosis and treatmentThurlimann B et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. NEJM 2005;33:2747-57
7. NICE (March 2017). Familial breast cancer: classifification, care and managing breast cancer and related risks in people with a family history of breast cancer
8. NHS. Pathway Transformation Fund 2020/21 Guidance for Tamoxifen Rapid Uptake Pathway (accessed 29/6/21)
9. Mahase E. Anastrozole: Repurposed drug could prevent thousands of breast cancer cases BMJ 2023; 383 :p2608 doi:10.1136/bmj.p2608