Overall, 3,142 patients were included, of whom 1,682 were aged <65 years (54%; median age, 58.4 years), 951 were aged 65–74 years (30%; median age, 69.7 years), and 509 were aged ≥75 years (16%; median age, 79.3 years). The median follow-up times from randomization were 5.0 years, 5.0 years, and 4.8 years, respectively. Baseline characteristics by age at diagnosis are shown in . Older age was associated with a different histological grade (p = .004) and larger tumor (p < .001); the nodal status, however, was similar among age categories. The presence of one or more cardiac, central nervous system, endocrine, gastrointestinal, genitourinary, and musculoskeletal comorbidity increased with older age (all p-values <.001). In addition, the proportion of patients treated with mastectomy was significantly greater with older age, whereas administration of radiotherapy and chemotherapy was significantly lower (all p-values <.001).
Baseline characteristics by age category
Overall, 256 patients (8.1%) discontinued the allocated endocrine therapy within 1 year of follow-up—116 (7.4%) in the exemestane arm and 140 (8.9%) in the sequential arm (p = .118). Nonpersistence within 1 year of follow-up was more common in the older age groups (<65 years, 7.0%; 65–74 years, 7.5%; ≥75 years, 13.2%; p < .001). As shown in , reasons for nonpersistence within 1 year of follow-up did not differ among the age categories (p = .561). In all age categories, the presence of adverse events was the most frequently reported reason for nonpersistence (85%, 83%, and 89%, respectively).
Reason for nonpersistence within 1 year of follow-up by age category
To gain insight into underlying mechanisms, we assessed predictive factors for nonpersistence within 1 year of follow-up in all age categories (supplemental online Table 1A, 1B, 1C). In patients aged <65 years, the presence of central nervous system, gastrointestinal, and genitourinary comorbidities, a mastectomy as the most extensive surgery, and the omission of radiotherapy were associated with nonpersistence within 1 year of follow-up. Multivariate analyses showed that gastrointestinal comorbidity and omission of radiotherapy were independent predictive factors for nonpersistence within 1 year of follow-up. In patients aged 65–74 years, no predictive factors for nonpersistence could be identified. In patients aged ≥75 years, larger tumor size, wide local excision as the most extensive surgical treatment, and omission of radiotherapy were independent predictive factors for nonpersistence within 1 year of follow-up. In cases of nonpersistence within 1 year of follow-up, older age was associated with less frequent administration of alternative endocrine treatment (78.8%, 80.3%, and 61.2%, respectively; p = .013) (data not shown).
At database lock, the numbers of deaths were 173 (10.3%) in patients aged <65 years, 133 (14.0%) in patients aged 65–74 years, and 154 (30.3%) in patients aged ≥75 years. The numbers of deaths resulting from breast cancer were 146 (8.7%), 88 (9.3%), and 60 (11.8%), respectively. depicts the cumulative incidence of deaths resulting from breast cancer and deaths resulting from other causes from the landmark by persistence status at 1 year of follow-up, stratified by age at diagnosis. As shown in , patients aged <65 years who were nonpersistent within 1 year of follow-up had a lower breast cancer–specific survival probability (multivariate hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.55–4.90; p = .001). For the overall survival probability, comparable results were observed (multivariate HR, 2.83; 95% CI, 1.65–4.85; p < .001)(). In contrast, nonpersistence within 1 year of follow-up was not associated with either the breast cancer–specific survival duration or the overall survival time in patients aged 65–74 years (multivariate p = .387 and .659, respectively) or in patients aged ≥75 years (multivariate p = .982 and .942, respectively).
Cumulative incidence of death resulting from breast cancer and from other causes by persistence status at 1 year follow-up, by age at diagnosis.
Breast cancer–specific and overall survival outcomes by age category and persistence status
Additional survival analyses including an interaction term between persistence status at 1 year of follow-up and age confirmed a significant interaction for the breast cancer–specific survival time (p = .031) but not for the overall survival time (p = .140). To assess the sensitivity of the landmark, we performed additional survival analyses using alternative landmark cutoffs (0.5 years and 1.5 years), which did not alter the results (data not shown). To account for a potential lack of power in patients aged ≥75 years, we performed additional survival analyses in which patients aged 65–74 years and patients aged ≥75 years were combined. Again, nonpersistence within 1 year of follow-up was not associated with the breast cancer–specific survival probability (univariate HR, 0.93; 95% CI, 0.49–1.77; p = .819; multivariate HR, 0.81; 95% CI, 0.39–1.69; p = .675). For the overall survival outcome, we observed comparable results (univariate HR, 1.29; 95% CI, 0.87–1.93; p = .206; multivariate HR, 1.19; 95% CI, 0.76–1.87; p = 0.440). Additional analyses were performed to evaluate the influence of alternative treatment in cases of nonpersistence (data not shown). In patients who were nonpersistent, alternative treatment was not associated with the breast cancer–specific or overall survival outcome in any age category (multivariate analyses for breast cancer–specific survival outcome: p = 0.401, .576, and .426, respectively; multivariate analyses for overall survival outcome: p = .314, .325, and .328, respectively).