Prolonged adjuvant anastrozole confers no DFS benefit in postmenopausal breast cancer
A longer duration of extended hormone therapy provided no benefit for postmenopausal women with hormone receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, according to randomized phase 3 study results.
The findings — published in The New England Journal of Medicine — showed no statistically significant difference in DFS between women who received 5 years vs. 2 years of extended hormone therapy.
In addition, women who received extended therapy demonstrated a higher risk for adverse effects and bone fracture.
“Seven years of adjuvant endocrine therapy is the optimal treatment duration. For most patients in this situation, there is no benefit in extending therapy beyond that,” Michael Gnant, MD, FACS, director and chairman of the department of surgery at the Comprehensive Cancer Center of Medical University of Vienna, and colleagues wrote. “In fact, side effects and risk [for] treatment-induced fractures increase.”
Prior studies showed extending adjuvant therapy with aromatase inhibitors after 5 initial years of tamoxifen therapy is beneficial for postmenopausal women with hormone receptor-positive breast cancer. However, the appropriate duration of extended adjuvant therapy had not been established.
Gnant and colleagues conducted the ABCSG-16 trial to compare the effect of an additional 2 years vs. 5 years of anastrozole after 5 years of adjuvant endocrine therapy.
The trial included 3,484 postmenopausal women (median age, 64 years) with hormone receptor-positive, early-stage breast cancer treated at 71 centers in Austria between February 2004 and June 2010.
“This is the most frequent subgroup of [patients with breast cancer] worldwide,” Gnant said.
Researchers randomly assigned women to one of the two extended treatment schedules. Prior to randomization, 51% of women had received 5 years of tamoxifen and 49% had received other aromatase inhibitor-containing regimens.
DFS among women who were still participating in the trial 2 years after randomization and had no disease recurrence served as the study’s primary endpoint. OS, contralateral breast cancer, fracture and toxicity served as secondary endpoints.
Median follow-up was nearly 10 years.
Most women (92%; n = 3,208) enrolled remained in the trial without disease progression after the first 2 years of extended anastrozole treatment.
At 8 years, 335 women in each treatment group had experienced disease progression or had died, translating to no significant DFS difference among women who received an additional 5 years of anastrozole vs. an additional 2 years (HR = 0.99; 95% CI, 0.85-1.15).
Researchers reported no differences between treatment groups with regard to most secondary endpoints and no differences in any key subgroups.
Adverse events appeared consistent with anastrozole’s known safety profile. A higher percentage of women in the 5-year group than 2-year group experienced at least one serious adverse event (40.2% vs. 26.5%). They also were more likely to experience serious adverse events determined by investigators to be related to anastrozole (4% vs. 2.3%).
More than twice as many women in the 5-year group developed osteoarthritis (4.3% vs. 1.7%), the most frequently reported adverse event.
Women in the 5-year group exhibited a greater risk for clinical bone fracture (6.3% vs. 4.7%; HR = 1.35; 95% CI, 1-1.84).
“The effect of extended aromatase inhibitor treatment on patients’ quality of life is not trivial [because] musculoskeletal symptoms — such as arthralgia and bone and joint pain — frequently occur, and these sequelae may persist for years,” Gnant and colleagues wrote. “Almost half of all patients in some studies have cognitive impairments, sexual dysfunction, mood changes or weight gain.
“Although, as expected, the prevalence of these side effects was similar in the two groups in our trial, it is evident that having these sequelae and being at risk for them for 3 additional years was a disadvantage for patients in the 5-year group,” they added. “Even though these side effects can be alleviated by pharmaceutical and lifestyle interventions, their occurrence often leads to a high rate of nonadherence to treatment.”
Gnant said further studies are needed to define molecular biomarkers to identify which patients may benefit from longer or shorter treatment durations.
As new approaches emerge to improve late outcomes of patients with hormone receptor-positive breast cancer, multiple factors must be considered when deciding on duration of aromatase inhibitor use, Pamela J. Goodwin, MD, professor of medicine at University of Toronto and senior investigator at Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, wrote in an accompanying editorial.
“Decisions regarding extended aromatase inhibitor therapy will continue to be individualized, with a combined assessment of recurrence risk, treatment tolerance and patient preference,” Goodwin wrote. “The data provided by Gnant [and colleagues] in patients with hormone receptor-positive breast cancer who are at low or average risk underscore the importance of avoiding iatrogenic complications when making these decisions.”
References:
Gnant M, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2104162.
Goodwin PJ. N Engl J Med. 2021;doi:10.1056/NEJMe2109356.
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Gnant M, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2104162.