What is the role of aromatase inhibitors (AIs) in the adjuvant therapy for breast cancer?

Updated: May 21, 2019
  • Author: Erin V Newton, MD; Chief Editor: Neetu Radhakrishnan, MD  more...
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Answer

Answer

Aromatase inhibitors (AIs) function by inhibiting aromatase, the enzyme (found in body fat, adrenal glands, and breast tissue, as well as tumor cells) responsible for converting other steroid hormones into estrogen. Aromatase is the sole source of estrogen in postmenopausal women and likely the underlying reason that obesity (larger volume of body fat produces more estrogen) has been associated with a higher risk of breast cancer in postmenopausal patients.

As the AIs have no effect on ovarian estrogen production, these agents are effective only in postmenopausal women. Common side effects of AIs include hot flashes (12-36%), arthralgia/arthritis (17%), headache (9-13%), vaginal dryness (2%), and mood changes (19%).

Several large randomized trials, including the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and the Breast International Group (BIG) 1-98 trials, have shown AIs to be superior to tamoxifen with regard to disease-free survival in postmenopausal women with early-stage breast cancer. [48] The ATAC trial results are most mature at more than 100 months of follow-up and show anastrozole (Arimidex) to be superior to tamoxifen in improving disease-free survival. [49]

Significant benefit was also seen in time-to-recurrence of contralateral breast cancer. However, none of the head-to-head comparison trials has yielded an improvement in overall survival compared with tamoxifen. Early switching trials in which AIs are initiated after 2-3 years of tamoxifen have also shown improved disease-free survival. However, in contrast to the upfront trials, an improved overall survival is observed when ER-negative patients are excluded and randomization occurs at the time of switching.

The Canadian-led MA.17 trial randomized patients to an additional 5 years of AI therapy with letrozole after completion of 5 years of tamoxifen therapy and resulted in improved disease-free survival in all patients randomized, as well as improved overall survival in the higher-risk lymph node–positive subset of patients. [50] This study was the first to suggest that prolonged hormone therapy may be more effective than 5 years of therapy.

The optimal duration and sequence for the use of AIs has not been defined clearly, but their benefits in terms of breast cancer recurrence and survival clearly support their use in all postmenopausal women. Ongoing trials are now comparing 5 and 10 years of AI therapy, including a continuation of the MA.17 trial, which will include patients receiving hormone therapies for up to 15 years, and evaluation of whether the sequence of hormone agent (ie, tamoxifen followed by AI vs AI followed by tamoxifen) affects efficacy.

The results of a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for 10 years were significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. [51]

The BIG 1-98 Collaborative Group found that disease-free survival was not significantly better between 2 sequential treatment groups with letrozole and letrozole monotherapy and that overall survival was not statistically different between monotherapy with letrozole and monotherapy with tamoxifen (when combined with previous trial data comparing efficacy in 4922 postmenopausal patients with endocrine-responsive breast cancer for letrozole). [52] In this randomized, double-blind, phase III trial to evaluate the optimal treatment strategy, 6182 patients were randomly assigned to the following treatment groups: 5 years of tamoxifen; 5 years of letrozole; letrozole for 2 years followed by tamoxifen for 3 years; and tamoxifen for 2 years followed by letrozole for 3 years.

A meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) of randomized trials in early breast cancer  found that early recurrence rates favored AIs over tamoxifen in a variety of regimens; for example, with 5 years of AIs versus 5 years of tamoxifen, the rate ratio (RR) for recurrence with 5 years of aromatase inhibitor versus 5 years of tamoxifen was 0.64 in years 0-1 and 0.80 in years 2-3, but was not significantly different thereafter. The 10-year breast cancer mortality rates were approximately 15% lower in patients who received 5 years of an aromatase inhibitor than in those treated with 5 years of tamoxifen. [53]


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