Characteristics of the Patients

Figure 1. Figure 1. Registration, Randomization, and Follow-up. All the patients who met the eligibility criteria and provided written informed consent were preregistered; a primary tumor specimen was subsequently obtained and sent to the Genomic Health laboratory for the 21-gene assay. On receipt of the assay report and recurrence-score result by the treating physician, the enrolling site then assigned patients to a treatment group. If the recurrence score was 10 or lower, the patient was assigned to receive endocrine therapy alone. If the recurrence score was 26 or higher, the patient was assigned to receive chemoendocrine therapy. If the recurrence score was 11 to 25, the patient underwent randomization and was assigned to receive either endocrine therapy or chemoendocrine therapy. The stratification factors that were used in randomization were tumor size (≤2 cm vs. >2 cm), menopausal status (pre- vs. postmenopausal), planned chemotherapy (taxane-containing vs. not), planned radiation therapy (whole breast and no boost irradiation planned vs. whole breast and boost irradiation planned vs. partial breast irradiation planned vs. no planned radiation therapy for patients who had undergone a mastectomy), and recurrence-score group (11 to 15 vs. 16 to 20 vs. 21 to 25), which was added midway through the trial.

Table 1. Table 1. Characteristics of the Patients in the Intention-to-Treat Population at Baseline.

A total of 10,273 women were registered between April 7, 2006, and October 6, 2010, of whom 10,253 were eligible for participation. Among the 9719 eligible patients with follow-up information who were included in the main analysis set, 6711 (69%) had a recurrence score of 11 to 25, 1619 (17%) had a recurrence score of 10 or lower, and 1389 (14%) had a recurrence score of 26 or higher (Figure 1). The median duration of follow-up in the cohort of patients with a recurrence score of 11 to 25 was 90 months for invasive disease–free survival and 96 months for overall survival. The characteristics of the trial population that was included in the main analysis are shown in Table 1, and in Table S1 in the Supplementary Appendix.

Adjuvant Therapy in the Cohort with a Recurrence Score of 11 to 25

The median duration of endocrine therapy was 5.4 years, with similar distributions of durations in the two randomly assigned treatment groups, including approximately 35% rates of adjuvant endocrine therapy extending beyond 5 years (Fig. S1 in the Supplementary Appendix). The most common chemotherapy regimens among the patients who were randomly assigned to and treated with chemotherapy were docetaxel–cyclophosphamide (56%) and anthracycline-containing regimens (36%). The endocrine therapy regimens among postmenopausal women most commonly included an aromatase inhibitor (91%); among premenopausal women, endocrine therapy regimens most commonly included either tamoxifen alone or tamoxifen followed by an aromatase inhibitor (78%), and suppression of ovarian function was used in 13% of premenopausal women (Table S2 in the Supplementary Appendix). The rate of nonadherence to the assigned treatment was 11.8% overall, including 5.4% among patients who were randomly assigned to receive endocrine therapy alone and 18.4% among those who were randomly assigned to receive chemoendocrine therapy (Table 1). In the as-treated population, some of the differences in baseline characteristics between the treatment groups were significant (Table S3 in Supplementary Appendix).

Invasive Disease–free Survival and Other End Points in the Cohort with a Recurrence Score of 11 to 25

Figure 2. Figure 2. Clinical Outcomes among Patients with a Recurrence Score of 11 to 25. Kaplan–Meier estimates of survival rates in the analysis according to the assigned treatment group are shown for the group that received endocrine therapy alone and the group that received chemoendocrine therapy in the intention-to-treat analysis of invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death) and freedom from recurrence of breast cancer at a distant site. The hazard ratios are for the endocrine-therapy group versus the chemoendocrine-therapy group.

There had been 836 events of invasive disease recurrence, second primary cancer, or death (the components of invasive disease–free survival, the primary end point) in the two randomly assigned treatment groups at the time of the final analysis, including 338 (40.4%) recurrences of breast cancer as the first event, of which 199 (23.8% of the total events) were distant recurrences (Tables S4 and S5 in the Supplementary Appendix). In the intention-to-treat population, endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval [CI], 0.94 to 1.24; P=0.26) (Figure 2A). Endocrine therapy was likewise noninferior to chemoendocrine therapy in the analyses of other end points, including freedom from recurrence of breast cancer at a distant site (hazard ratio for recurrence, 1.10; P=0.48) (Figure 2B), freedom from recurrence of breast cancer at a distant or local–regional site (hazard ratio for recurrence, 1.11; P=0.33), and overall survival (hazard ratio for death, 0.99; P=0.89). Additional details regarding these end points are provided in Figure S2 and Section 6B in the Supplementary Appendix.

The results of the as-treated analyses were consistent with those of the intention-to-treat analyses for invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.14; 95% CI, 0.99 to 1.31; P=0.06), freedom from recurrence of breast cancer at a distant site (hazard ratio for recurrence, 1.03; P=0.81), freedom from recurrence of breast cancer at a distant or local–regional site (hazard ratio for recurrence, 1.12; P=0.28), and overall survival (hazard ratio for death, 0.97; P=0.78) (Fig. S3 in the Supplementary Appendix). The estimated 9-year rates of invasive disease–free survival in the as-treated population were 83.1% for patients who received endocrine therapy alone and 84.7% for those who received chemoendocrine therapy. The outcomes were unlikely to have been affected by incomplete follow-up information (Section 6E in the Supplementary Appendix).

Survival Rates in All Recurrence-Score Cohorts and Treatment Groups

Table 2. Table 2. Estimated Survival Rates According to Recurrence Score and Assigned Treatment in the Intention-to-Treat Population.

The estimated survival rates at 5 and 9 years for all treatment groups and end points are shown in Table 2. At 9 years in the intention-to-treat population, among patients with a recurrence score of 11 to 25, the rate of invasive disease–free survival was 83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group; the corresponding rates were 94.5% and 95.0% for freedom from recurrence of breast cancer at a distant site, 92.2% and 92.9% for freedom from recurrence of breast cancer at a distant or local–regional site, and 93.9% and 93.8% for overall survival. When all recurrence-score cohorts (≤10, 11 to 25, and ≥26) and treatment-group assignments were considered, there were significant differences in the rates of invasive disease–free survival, recurrence, and death (P<0.001), driven largely by the higher likelihood of having an event in the cohort with a recurrence score of 26 or higher (Fig. S4 in the Supplementary Appendix). Distant recurrence was associated with recurrence score as a continuous variable between 11 and 25, but there was no significant interaction between chemotherapy treatment and recurrence score in this range (Figs. S5 through S10 in the Supplementary Appendix).

Interactions According to Subgroup in the Cohorts with a Recurrence Score of 11 to 25

Table 3. Table 3. Estimated Survival Rates According to Recurrence Score and Assigned Treatment among Women 50 Years of Age or Younger in the Intention-to-Treat Population.

We performed exploratory analyses to determine whether any subgroups might have derived some benefit from chemotherapy in the intention-to-treat population, with a focus on covariates that were prognostic or associated with greater benefit from chemotherapy, such as younger age (Section 6F and Fig. S11 in the Supplementary Appendix).6 There were no significant interactions between chemotherapy treatment and most of the prognostic covariates examined, including recurrence-score category (either 11 to 15 vs. 16 to 20 vs. 21 to 25, or 11 to 17 vs. 18 to 25), tumor size (≤2 cm vs. >2 cm), histologic grade (low vs. intermediate vs. high), clinical risk category (high vs. low), and menopausal status (pre- vs. postmenopausal). There were significant interactions between chemotherapy treatment and age (≤50 vs. 51 to 65 vs. >65 years) for invasive disease–free survival (P=0.03) and for freedom from recurrence of breast cancer at a distant or local–regional site (P=0.02) but not at a distant site (P=0.12). The effect of treatment also varied significantly over the six combinations of menopausal status and recurrence-score category (11 to 15 vs. 15 to 20 vs. 21 to 25) (P=0.02) and over the nine combinations of age and recurrence-score category (P=0.004) for invasive disease–free survival (Figs. S12 and S13 in the Supplementary Appendix) but not for freedom of recurrence of breast cancer at a distant site or distant or local–regional site. In women 50 years of age or younger, chemotherapy was associated with a lower rate of distant recurrence than endocrine therapy if the recurrence score was 16 to 20 (percentage-point difference, 0.8 at 5 years and 1.6 at 9 years) or 21 to 25 (percentage-point difference, 3.2 at 5 years and 6.5 at 9 years), although the rates of overall survival were similar (Table 3). Conversely, in the 40% of women 50 years of age or younger who had a recurrence score of 0 to 15, the rate of distant recurrence was approximately 2% at 9 years among those who had been assigned (either randomly or nonrandomly) to endocrine therapy alone.