Participant-reported symptoms as predictors of long-term adherence of endocrine therapy in the International breast cancer intervention studies 2 (IBIS-2)

Abstract

Background: Aromatase inhibitors (AIs) reduce the risk of breast cancer in women at increased risk and reduce recurrence in those with ductal carcinoma in situ (DCIS) (IBIS-2, MAP.3, NSABP B-33). The effectiveness of AIs depends on full adherence. We have previously reported adherence figures for the International Breast Cancer Intervention Studies 2 (IBIS-2) when 5 years of active treatment was not completed. Here, we assess reports of early symptoms on 5-year adherence with anastrozole in the prevention (versus placebo) and DCIS (versus tamoxifen) IBIS-2 after active treatment has been completed by all women.

Methods: In IBIS-2, 3864 postmenopausal women in the prevention study were randomised to placebo vs. anastrozole (1mg/day) and 2980 postmenopausal women with DCIS were randomised to tamoxifen (20mg/day) vs. anastrozole (1mg/day). Women were excluded from the analyses (n=491 [262 prevention; 229 DCIS]) due to breast cancer, death, major adverse events, or failure to initiate preventive therapy. Adherence (<4.5 years, ≥4.5 years) was calculated using the Kaplan-Meier method. The primary objective was to determine overall adherence to endocrine treatment in both studies separately. Secondary objectives were to estimate the effect of early symptoms (6 months visit) on adherence by study and by treatment arm separately.

Results: In the IBIS-2 prevention study (N=3615), overall adherence to treatment was 67.7% and was statistically not significantly different between anastrozole (66.5%) and placebo (69.0%) (OR=0.89 (0.78-1.03), P=0.11). Adherence was significantly lower regardless of treatment allocation for those who developed arthralgia (68.3% vs. 72.8%, P=0.008) or gynaecological symptoms (vaginal changes, irregular bleeding) (65.1% vs. 72.2%, P=0.007), but not for those who reported hot flushes (71.1% vs. 71.8%, P=0.92), compared with those who did not report these symptoms at 6 months. In the IBIS-2 DCIS study (N=2759), adherence to treatment was 70.1% overall (anastrozole (70.2%) or tamoxifen (70.0%) (OR=1.01 (0.86-1.19), P=0.92)). Women treated with anastrozole reported significantly more arthralgia (30.6% vs. 20.5%, P<0.001), but significantly fewer hot flushes (41.1% vs. 47.0%, P=0.002) and gynaecological symptoms (7.0% vs. 12.6%, P<0.001) compared with those on tamoxifen. However, none of these symptoms had an impact on adherence to either anastrozole or tamoxifen. In both studies, the majority of symptoms were of mild or moderate severity and we observed significant trends for lower adherence with increasing severity for all symptoms irrespective of allocated treatment arm.

Conclusions: In the IBIS-2 trials, we observed no significant differences in adherence between either anastrozole vs. placebo (prevention), or anastrozole vs. tamoxifen (DCIS). Significant associations between early symptoms and adherence were observed only in the prevention study, regardless of treatment allocation. Reporting symptoms in the first 6 months of preventive and adjuvant therapy is unlikely to explain non-adherence to medication. Further research is required to identify modifiable factors which may be altered by behavioural interventions to improve adherence.