In an Austrian Breast and Colorectal Cancer Study Group phase III trial (ABCSG-16/SALSA) reported in The New England Journal of Medicine, Michael Gnant, MD, of the Comprehensive Cancer Center, Medical University of Vienna, and colleagues found no difference in disease-free survival with 2 vs 5 years of anastrozole in postmenopausal women with early hormone receptor (HR)-positive breast cancer who had received 5 years of adjuvant endocrine therapy.1
Michael Gnant, MD
In the multicenter trial, 3,470 eligible women (intention-to-treat [ITT] population) who had received 5 years (± 12 months) of adjuvant endocrine therapy with tamoxifen, aromatase inhibitors, or both sequentially up until 12 months prior to randomization were randomly assigned between February 2004 and June 2010 to receive 2 years (n = 1,732) or 5 years (n = 1,738) of anastrozole at 1 mg/d. Randomization was stratified by pathologic tumor stage, pathologic node stage, primary adjuvant endocrine therapy, adjuvant chemotherapy, HR status, previous trial participation, and geographic region. The primary endpoint was disease-free survival in the primary analysis set of patients, including all patients still participating in the trial with no recurrence 2 years after randomization (when treatment in the 2-year group had ended).
The primary analysis set consisted of 3,208 patients, including 1,603 in the 2-year group vs 1,605 in the 5-year group. Among these patents, median age was 64 years (range = 38–84 years) vs 64 years (range = 29–80 years). Tumor stage was T1 in 73% vs 73% and T2 in 25% vs 25%. Nodal stage was N0 in 66% vs 67% and N1 in 31% vs 30%; 79% vs 77% were estrogen receptor (ER)- and progesterone receptor (PR)-positive and 21% vs 23% were either ER- or PR-negative; and 79% vs 81% had breast-conserving surgery and 21% vs 18% had mastectomy. Prior endocrine therapy was an aromatase inhibitor alone in 7% vs 7%, tamoxifen alone in 51% vs 51%, and both in 42% vs 42%. Overall, 14% vs 14% had prior anthracycline-containing chemotherapy and 5% vs 5% prior taxane-containing chemotherapy, and 80% vs 81% had prior radiotherapy.
Median follow-up from randomization was 118.0 months (interquartile range = 97.8–121.1 months). Recurrence within the first 2 years was observed in 62 patients in the 2-year group and in 65 patients in the 5-year group.
In the primary analysis set, disease-free survival events had occurred in 335 patients in each group at 8 years after the end of treatment in the 2-year group (10 years after randomization). Disease-free survival rates were 73.6% in the 2-year group vs 73.9% in the 5-year group (hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.85–1.15, P = .90). After adjustment for potential confounding factors, the hazard ratio was 1.00 (95% CI = 0.86–1.16). Among 1,665 vs 1,670 patients remaining on the study after 2 years, the 8-year overall survival rate was 87.5% vs 87.3% (HR = 1.02, 95% CI = 0.83–1.25).
In the disease-free survival subgroup analyses in the primary analysis set, hazard ratios were 1.01 (95% CI = 0.85–1.20) among 2,492 patients who were both ER- and PR-positive and 0.93 (95% CI = 0.69–1.26) among 712 who were negative for either ER or PR; 0.69 (95% CI = 0.40–1.19) among 235 patients with prior aromatase inhibitor treatment alone, 1.03 (95% CI = 0.83–1.26) among 1,635 with prior tamoxifen alone, and 1.02 (95% CI = 0.80–1.30) among 1,338 who received both; and 1.06 (95% CI = 0.87–1.29) among 2,146 patients with node-negative status and 0.89 (95% CI = 0.70–1.13) among 1,060 with node-positive status.
In the primary analysis set, contralateral breast cancer occurred in 2.2% vs 2.1% of patients (HR = 1.15, 95% CI = 0.75–1.77). A second primary cancer occurred in 6.2% vs 6.7% (HR = 1.06, 95% CI = 0.81–1.38). Local recurrence occurred in 3.0% vs 2.4%, distant recurrence occurred in 5.1% vs 4.9%, and death without recurrence occurred in 4.4% vs 5.0%.
In the ITT population, use of bone-targeted treatment included calcium/vitamin D in 69.4% vs 74.5%, bisphosphonates in 37.2% vs 39.8%, and denosumab in 4.8% vs 3.7%. The incidence of clinical bone fracture between 2 and 5 years after randomization was 4.7% vs 6.3% (HR = 1.35, 95% CI = 1.00–1.84). At 5 years, the number of patients who would need to be treated to result in harm to one patient was 63 (95% CI = 32–953).
Adverse events were consistent with the known toxicity profile of anastrozole. In the ITT population, serious adverse events occurred in 26.5% of the 2-year group and 40.2% of the 5-year group and were considered related to anastrozole in 2.3% vs 4.0%. The most common serious adverse event was osteoarthritis (1.7% vs 4.3%). Serious adverse events led to discontinuation of treatment in 1.6% vs 2.3% of patients (treatment-related in 0.3% vs 0.2%) and to death in 1.1% vs 1.6% (treatment-related in 0% vs 0%).
The investigators concluded: “In postmenopausal women with hormone receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture.”
DISCLOSURE: The study was funded by the Austrian Breast and Colorectal Cancer Study Group and AstraZeneca. Dr. Gnant has an immediate family member who has been employed by Sandoz; has received honoraria from Amgen, AstraZeneca, Eli Lilly, and Novartis; has served as a consultant or advisor to Daiichi Sankyo, Eli Lilly, LifeBrain, Pierre Fabre, and Veracyte.
1. Gnant M, Fitzal F, Rinnerthaler G, et al: Duration of adjuvant aromatase-inhibitor therapy in postmenopausal breast cancer. N Engl J Med 385:395-405, 2021.
Estrogen receptor–positive breast cancer is the most common type of breast cancer, diagnosed in more than 2.3 million women around the world each year, including more than 200,000 in the United States alone. Adjuvant endocrine therapy is a mainstay of treatment for these millions of women and is a...