What is the role of aromatase inhibitors (AIs) in the treatment of breast cancer (breast ca)?

From the Guidelines

Aromatase inhibitors (AIs) are the preferred treatment for hormone receptor-positive breast cancer in postmenopausal women, due to their superior efficacy and different side effect profile compared to tamoxifen, as shown in the most recent study 1. The three main AIs used are anastrozole (1 mg daily), letrozole (2.5 mg daily), and exemestane (25 mg daily). These medications are typically prescribed for 5-10 years, either as initial therapy or following 2-3 years of tamoxifen. AIs work by blocking the aromatase enzyme, which converts androgens to estrogens in peripheral tissues, thereby reducing estrogen levels that can stimulate breast cancer growth. Key points to consider when prescribing AIs include:

• They are more effective than tamoxifen in postmenopausal women, with studies such as the ATAC trial showing fewer recurrences with anastrozole compared to tamoxifen 1.
• AIs have a different side effect profile, commonly causing joint pain, bone loss, and increased fracture risk rather than the blood clots and endometrial cancer risks associated with tamoxifen 1.
• To manage AI-related bone loss, patients should take calcium (1000-1200 mg daily) and vitamin D (800-1000 IU daily) supplements, with bone density monitoring and possibly bisphosphonate therapy.
• AIs are contraindicated in premenopausal women unless combined with ovarian suppression, as they are ineffective when ovarian estrogen production remains active 1. In terms of specific treatment strategies, the BIG 1-98 trial showed that letrozole alone for 5 years was superior to tamoxifen alone for 5 years in terms of disease-free survival 1. Additionally, the Italian Tamoxifen Anastrozole (ITA) trial found that switching to anastrozole after 2-3 years of tamoxifen was beneficial in terms of relapse-free survival 1. Overall, the use of AIs in postmenopausal women with hormone receptor-positive breast cancer is supported by strong evidence, and they should be considered a key part of treatment strategies for these patients, as recommended in the most recent guidelines 1.

From the FDA Drug Label

INDICATIONS AND USAGE Letrozole Tablets, USP are aromatase inhibitor indicated for: Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer ( 1.1) Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy ( 1.2) First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer ( 1.3)

INDICATIONS AND USAGE EXEMESTANE is an aromatase inhibitor indicated for: • adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to EXEMESTANE for completion of a total of five consecutive years of adjuvant hormonal therapy (14.1). • treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy (14.2).

INDICATIONS AND USAGE EXEMESTANE is an aromatase inhibitor indicated for: • adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to EXEMESTANE for completion of a total of five consecutive years of adjuvant hormonal therapy (14. 1). • treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy (14.2).

Aromatase inhibitors are used in the treatment of breast cancer. Specifically, letrozole and exemestane are indicated for:

• Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer 2 3 3
• Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy 2
• First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer 2
• Treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy 3 3

From the Research

Aromatase Inhibitors in Breast Cancer Treatment

• Aromatase inhibitors are a gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease 4.
• The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and the irreversible aromatase inactivator exemestane 4.
• Third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant, and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen 5.

Comparison of Aromatase Inhibitors

• Letrozole seems to be the best choice for the majority of breast cancer patients whenever a non-steroidal aromatase inhibitor has to be chosen in a clinical setting, based on available evidence 4.
• Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared to tamoxifen 5.
• Aromatase inhibitors provide an alternative to tamoxifen as adjuvant therapy for post-menopausal, hormone-receptor-positive breast cancer patients, with options including anastrozole and letrozole for five years, as well as anastrozole and exemestane following two to three years of tamoxifen, for a total five years of hormonal therapy 6.

Adverse Events and Prevention

• Patients receiving aromatase inhibitors should be monitored for changes in bone mineral density and for cardiovascular disease risk factors and outcomes 6.
• Aromatase inhibitors are currently being tested as primary prevention therapy in large randomized trials involving tens of thousands of women at increased risk for breast cancer 7, 8.
• Phase 3 trials of aromatase inhibitors for breast cancer prevention are ongoing, including IBIS-II, MAP.3, and STELLAR, which compare anastrozole, exemestane, and letrozole to placebo or other agents for primary prevention of breast cancer in high-risk postmenopausal women 8.