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

Study Details

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.

Disease-Free Survival

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

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.

REFERENCE

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.