“The take-home message is we can avoid unnecessary treatment and side effects by giving only 2 years of additional aromatase inhibitor therapy instead of 5 years.”

— Michael Gnant, MD

Tweet this quote

An additional 5 years of aromatase inhibitor therapy after 5 years of adjuvant endocrine therapy failed to improve disease-free survival compared with an additional 2 years of aromatase inhibitor therapy in postmenopausal women with hormone receptor–positive breast cancer, according to the results of the large Austrian Breast and Colorectal Cancer Study Group (ABCSG)-16 trial presented at the 2017 San Antonio Breast Cancer Symposium (SABCS).¹ Two years of additional aromatase inhibitor therapy was equally effective as 5 additional years for overall survival, disease-free survival, time to contralateral breast cancer, and time to second primary cancer. 

It can be difficult to adhere to aromatase inhibitor therapy due to side effects, especially arthralgia, so the investigators also looked at a subgroup of women who were adherent, and results were the same: 2 additional years of aromatase inhibitor after 5 years of hormone therapy did not improve outcomes compared with 5 additional years. The rate of clinical fractures was increased in the 5-year arm vs the 2-year arm. 

“We can now conclude that after 5 years of adjuvant endocrine therapy, 2 more years of aromatase inhibitor is sufficient. There is no benefit from 5 additional years of aromatase inhibitor, and 5 more years led to more clinical fractures and should be avoided,” said lead author Michael Gnant, MD, of the Medical University of Vienna, Austria. “The take-home message is we can avoid unnecessary treatment and side effects by giving only 2 years of additional aromatase inhibitor therapy instead of 5 years.” 

Dr. Gnant said it is not possible as yet to identify a subgroup of women who may benefit from an additional 5 years of treatment. “Some patients may benefit, but we haven’t been able to identify them. There was no benefit in the highest risk subgroups or for those who were adherent. For the vast majority of patients with luminal breast cancer, the most common type of breast cancer, a total of 7 years of endocrine therapy is sufficient.” 

In the future, he added, translational research may identify molecular characteristics of a subgroup that could benefit from prolonged extended aromatase inhibitor therapy. 

Study Rationale 

HORMONE RECEPTOR–POSITIVE breast cancer is associated with a significant risk of long-term relapse, with a substantial proportion of relapses occurring after the first 5 years of follow-up. Extended adjuvant therapy beyond 5 years is appealing in this setting because of the persistent risk of recurrence. Although studies have shown that aromatase inhibitor therapy for 5 years reduces risk of recurrence more than tamoxifen for 5 years, use of tamoxifen or sequencing of tamoxifen and aromatase inhibitor therapy are alternatives, especially for women who have trouble coping with the side effects of aromatase inhibitor. Studies have shown that 5 years of additional tamoxifen after an initial 5 years of tamoxifen reduces risk of recurrence in pre- and postmenopausal women, and adding an additional aromatase inhibitor is beneficial after early tamoxifen in postmenopausal women. 

“The situation is less clear after adjuvant aromatase inhibitor for how long to extend endocrine therapy,” Dr. Gnant noted. The ABCSG investigators sought to determine the optimal duration of extended adjuvant aromatase inhibitor in the ABCSG-16 trial. 

Study Details 

FOLLOWING LOCAL therapy (surgery plus or minus radiation therapy), 3,484 women with hormone receptor–positive breast cancer were treated with 5 years of endocrine therapy (tamoxifen, an aromatase inhibitor, or tamoxifen followed by an aromatase inhibitor) and then randomized to receive 2 more years of anastrozole vs 5 more years of anastrozole. Patients were recruited from 75 centers in Austria, and the median follow-up was 106.2 months. 

These results focused on 3,469 patients, with a median age of 64 years. The two treatment groups were well balanced. Twenty percent had high-grade disease; 77% had estrogen receptor–positive disease; 80% had breast-conserving surgery, and 20% had additional adjuvant chemotherapy. In the first 5 years, 51% received tamoxifen, and 49% received endocrine therapy that included an aromatase inhibitor. 

Key Findings 

THERE WAS NO DIFFERENCE in disease-free survival between the two groups of patients. Ten-year disease-free survival was 71.8% for 2 years and 70.3% for 5 years. A subgroup analysis failed to reveal any group with a preferential benefit from longer aromatase inhibitor, including patients at a higher risk of relapse and those receiving chemotherapy. There was also no difference in overall survival between the two arms: 10-year overall survival was 85.3% for the 2-year arm and 84.9% for the 5-year arm. Additionally, there was no difference between the two arms in the rate of contralateral breast cancer or second primary breast cancer. 

“Treatment adherence is a relevant issue,” Dr. Gnant said. The rate of nonadherence increased over time. Within 2 years of randomization, about 20% of patients were not taking their aromatase inhibitor, and by 5 years, the rate of nonadherence was 40%. 

An exploratory analysis of adherent patients supported the overall message of the trial: no further benefit with 5 years over 2 years of additional aromatase inhibitor therapy. Patients who had more aromatase inhibitor therapy in the first 5 years were more likely to comply, he noted. 

Five years after randomization, the rate of clinical fractures was higher in the 5-year arm than in the 2-year arm (6% vs 4.7%). 

DISCLOSURE: Dr. Gnant has a consulting/advisory role with Accelsiors; has received honoraria from Roche, Novartis, AstraZeneca, Celgene, GSK, Amgen, OBI-Pharma, Ipsen, and Nanostring Inc; research funding from AstraZeneca, Novartis, Roche, and Pfizer; and travel or accommodation expenses from Celgene, AstraZeneca, Novartis, Pfizer, Eisai, Amgen, and Ipsen; and has an immediate family member employed by Sandoz. 

REFERENCE 

1. Gnant M, Steger G, Greil R, et al: A prospective, randomized, multi-center, phase-III trial of additional 2 years of anastrozole versus additional 5 years of anastrozole after initial 5 years of adjuvant endocrine therapy—Results from 3,484 postmenopausal women in the ABCSG-16 trial. 2017 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 7, 2017.