Aromatase Inhibitor as Adjuvant Therapy for Breast Cancer: Is Longer Treatment Better?

Commentary

Adjuvant endocrine therapy reduces the risk of recurrence and increases survival in women with hormone receptor–positive breast cancer. The use of tamoxifen as adjuvant therapy for women with early stage breast cancer has been extensively studied. A metanalysis performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTG) demonstrated that tamoxifen reduces breast cancer mortality by a third when given as adjuvant therapy for women with hormone positive breast cancer [1].

Two important studies published in the last decade demonstrated that extending therapy with tamoxifen beyond 5 years reduces the chance of recurrence and improves survival. In the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial, women with early stage breast cancer who had completed 5 years of adjuvant tamoxifen were randomized to stop therapy or to continue tamoxifen for 5 additional years. Among patients with estrogen receptor (ER)–positive disease, the results demonstrated an absolute recurrence reduction of 3.7% and an absolute mortality reduction of 2.8% in 15 years after diagnosis [2].The aTTom trial randomized 6953 women with ER-positive breast cancer to discontinue tamoxifen after 5 years or to continue to complete 10 years of treatment and confirmed a benefit in recurrence rates and breast cancer mortality with 10 years of adjuvant tamoxifen [3].

Although tamoxifen is active in both pre- and postmenopausal patients, therapy with an aromatase inhibitor either as first-line or following treatment with tamoxifen has been demonstrated to be superior to tamoxifen alone in hormone receptor–positive postmenopausal women. In the ATAC (The Arimidex, Tamoxifen, Alone or in Combination) trial, postmenopausal patients were randomized to receive 5 years of either tamoxifen or anastrozole as adjuvant therapy. The anastrozole group had higher disease-free survival, time to recurrence and time to distant recurrence [4].In the Breast Intergroup (BIG) 1-98 trial, postmenopausal women were assigned to 4 different arms: 5 years of letrozole, 5 years of tamoxifen, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. The 2 groups assigned to receive letrozole initially were compared to the 2 groups assigned to receive tamoxifen initially. Compared with tamoxifen, letrozole significantly decrease the risk of recurrence [5].The MA-17 trial demonstrated a disease-free survival advantage with 5 years of letrozole compared with placebo in women who had been treated with tamoxifen for 5 years [6].  Based on these data, current guidelines for adjuvant endocrine therapy for postmenopausal women recommend an aromatase inhibitor for 5 years as primary therapy or after 2 to 3 years of tamoxifen [7].  

Results from studies with extended endocrine therapy, either 10 years of tamoxifen or 5 years of aromatase inhibitor after up to 5 years of tamoxifen, provide rationale to study the effect of therapy with aromatase inhibitor beyond 5 years. The current study by Goss et al (the MA 17.R trial) addresses the relevant question of whether extended adjuvant therapy with an aromatase inhibitor in post-menopausal women beyond 5 years provides additional benefit. The design of this study has several strengths including being randomized, phase 3, placebo-controlled and double-blind. Another strength was the large number of patients enrolled. The choice of disease-free survival as the primary endpoint is in accordance with the natural course of ER-positive breast cancer, which has a prolonged rate of recurrence. The study results showed that patients who received 10 years of letrozole had a 34% lower risk of recurrence, with an absolute improvement of 4% in disease-free survival. However, no overall survival benefit was demonstrated at a median follow-up of 6.3 years. This might be a result of the fact that the highest proportional benefit was reduction in incidence of contralateral breast cancer. It is also possible that an overall survival benefit would be observed with a longer follow-up.

As highlighted by the authors, the benefit of extended adjuvant therapy is higher in the first years. Given that the majority of patients enrolled in this study had received prior tamoxifen, it is possible that patients who receive only an aromatase inhibitor for 5 years without prior tamoxifen would benefit even more from extended aromatase inhibitor therapy. On the other hand, the 1.1% numerical advantage observed in reducing distant recurrence is quite modest, with the majority of the disease-free survival advantage seen with extended aromatase inhibition being due to a reduction in local recurrence and contralateral new concerns.

The quality of life assessment enhanced this trial, since adherence to adjuvant endocrine therapy remains a challenge. It should be noted, however, that patients willing to participate in a trial of extended therapy are likely to be those who have tolerated therapy reasonably well. The increase in body pain and differences in the role-emotional subscale in the letrozole reflect side effects of aromatase inhibitors that are seen in clinical practice. The higher rates of new-onset osteoporosis and bone fractures underscore the need to balance potential benefits and risks with extended aromatase inhibitor therapy.

Results from other trials evaluating extended adjuvant therapy will be helpful. The NSABP B-42 study randomized ER-positive postmenopausal patients to receive 5 years of letrozole or placebo after completing 5 years of hormonal therapy with an aromatase inhibitor for 5 years or ≤ 3 years of tamoxifen followed by an aromatase inhibitor. This study has completed enrollment and should provide additional insight regarding duration of therapy with aromatase inhibitors.

Applications for Clinical Practice

These trial results showed a benefit with extended aromatase inhibitor therapy; however, the magnitude of benefit was relatively small, particularly with respect to impacting distant recurrence risk. Given that extended therapy has potential side effects, it is appropriate to have a detailed discussion with patients regarding potential benefits and risks. A reasonable clinical strategy is to discuss extended therapy with patients who have a higher chance of relapse and those who are motivated to continue therapy to reduce new breast cancer events.

—Leticia Varella, MD, and Halle Moore, MD,
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH