Symptoms of endocrine treatment and outcome in the BIG 1-98 study

Abstract

Background There may be a relationship between the incidence of vasomotor and arthralgia/myalgia symptoms and treatment outcomes for postmenopausal breast cancer patients with endocrine-responsive disease who received adjuvant letrozole or tamoxifen. Patients and methods Data on patients randomized into the monotherapy arms of the BIG 1–98 clinical trial who did not have either vasomotor or arthralgia/myalgia/carpal tunnel (AMC) symptoms reported at baseline, started protocol treatment and were alive and disease-free at the 3-month landmark (n=4798) and at the 12-month landmark (n=4682) were used for this report. Cohorts of patients with vasomotor symptoms, AMC symptoms, neither, or both were defined at both 3 and 12 months from randomization. Landmark analyses were performed using Kaplan-Meier method for disease-free survival (DFS) and competing risk methodology for breast cancer free interval (BCFI). Median follow-up was 7.0 years. Results Reporting of AMC symptoms was associated with better outcome for both the 3- and 12-month landmark analyses (e.g. 12-month landmark, HR (95% CI) for DFS=0.65 (0.49–0.87), and for BCFI=0.70 (0.49–0.99)). By contrast, reporting of vasomotor symptoms was less clearly associated with DFS (12-month DFS HR (95% CI)=0.82 (0.70–0.96)) and BCFI (12-month DFS HR (95% CI)=0.97 (0.80–1.18). Interaction tests indicated no effect of treatment group on associations between symptoms and outcomes. Conclusions While reporting of AMC symptoms was clearly associated with better DFS and BCFI, the association between vasomotor symptoms and outcome was less clear, especially with respect to breast cancer-related events.

Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial

“…Recent findings support an inverse association between the reporting of early side effects under adjuvant endocrine treatment and breast cancer recurrence [38–40]. Vasomotor symptoms were associated with improved disease-free and overall survival in the TEAM trial [38] and reduced breast cancer recurrence in the ATAC trial [40], but not in the BIG 1–98 [41] and MA.27 trials [42]. Thus, we cannot exclude that the CYP19A1 rs10046 (T/T) genotype might be associated with reduced exemestane + OFS efficacy: women with this polymorphism possibly lack complete estrogen suppression, despite receiving concomitant OFS.…”

Endocrine Treatment-Related Symptoms and Patient Outcomes in Breast Cancer: A Meta-Analysis

“…The baseline characteristics of the included studies are described in Table 1 and Supplementary Table 2 . All included studies enrolled women 18 years or older diagnosed with stage I–III breast cancer, but five studies included only postmenopausal women [ 7 8 9 10 11 ]. All studies were exploratory retrospective studies of previous phase 3 trials.…”

“…Five studies were phase 3 randomized controlled trials comparing endocrine treatment regimens, and one study was a phase 3 randomized controlled trial of the effectiveness of a high-vegetable, low-fat diet [ 5 ]. Three studies used recurrence-free survival as a primary outcome [ 5 7 11 ], whereas the others used disease-free survival as a primary outcome, including death without disease relapse as an event [ 8 9 10 ].…”

“…An association between endocrine treatment-related symptoms and patient survival has been suggested previously, and was initially suggested to be associated with tamoxifen metabolism [ 5 6 ]. After the first report, several groups also reported results of exploratory analysis from previous trial data related to this issue [ 7 8 9 10 11 ]. However, the results of these studies have been conflicting, making it difficult to draw a conclusion.…”

Are we Ready to Change Clinical Practice after the ‘Soft and Text’ Results?

“…The BIG1.98, ATAC and IES trials had previously confirmed the efficacy of aromatase inhibitors compared with tamoxifen in the adjuvant treatment of postmenopausal women in terms of risk of recurrence (range: 15-25%) and distant metastases (∼27%) [7][8][9] and increased DFS, although no significant change in the OS and a small increase in cardiovascular risk were evidenced [7]. aromatase inhibitors: management considerations Aromatase inhibitors are classified into two groups: type 1 (enzyme inactivating), with irreversible action, and type 2 (nonsteroidal, enzyme inhibitor), with reversible action.…”