Table 1. Table 1. Association of Tumor Size and Nodal Status and Grade with the Risk of Distant Recurrence in Years 5 to Less Than 10 and in Years 10 to 20.

Among women with ER-positive, early-stage breast cancer who were scheduled to receive only 5 years of adjuvant endocrine therapy, distant recurrences occurred at a steady rate for at least another 15 years after the end of the 5-year treatment period. Throughout this time, the original nodal status and tumor diameter remained remarkably strong determinants of the annual recurrence rate (Table 1). However, even among women with small, node-negative (T1N0), low-grade tumors, there was a risk of distant recurrence of approximately 10% during years 5 to 20. TN status was also a strong determinant of locoregional recurrence, although not of contralateral disease.

Given the TN status, the other risk factors were of limited additional prognostic relevance after the cessation of 5-year endocrine therapy. There was a strong association of tumor grade and Ki-67 status with the risk of distant recurrence during years 0 to 5 but only a moderate association during years 5 to 20. Data regarding tumor grade and Ki-67 status were sometimes from local institutions, so accuracy could be variable, but both factors were strongly predictive of 5-year risk, which suggests that these values were assessed with reasonable accuracy. Better assessments should better predict outcome but would probably not alter the observed pattern of substantially weaker associations with distant recurrence after 5 years than before 5 years. Likewise, tumors that were negative for progesterone receptor had a worse prognosis during years 0 to 5 but not thereafter, given the TN status. The data set did not include gene-expression assays,13-17 which may be shown to predict a very low risk of distant recurrence even without further therapy for some women when long-term follow-up data become available.18 However, decisions with respect to extending endocrine therapy will probably still depend on disease stage, so these findings will remain relevant.

Our main aim was to determine whether we could identify subgroups of women who stop endocrine therapy after 5 years in whom long-term risks are so small that any additional benefits from extended therapy would be unlikely to outweigh the additional side effects. However, even among women with T1N0 disease, the cumulative risk of distant recurrence was 13% during years 5 to 20. Although reliable trial evidence is not yet available on the long-term effects of extending endocrine therapy for 5 additional years on mortality,5-9,19-21 an absolute reduction of a few percentage points in the risk of distant metastases over the next 15 years might well be possible even for such low-risk women, with correspondingly greater absolute benefits for women with larger tumors or node-positive disease. Except for women who are older than 70 years of age or those in poor health, these probabilities will not be much attenuated by the risk of death from another cause, since in the absence of breast cancer, more than 80% of the women in the United States in reasonable health at the age of 65 years would be expected to survive beyond the age of 80 years.

Meta-analyses of data from individual patients will eventually reconcile any apparently conflicting findings from the trials of extending endocrine therapy beyond 5 years, especially after 5 years of aromatase inhibitor therapy.5-9,19-21 When these findings are available, the likely benefits of extending therapy will have to be weighed against uncommon but potentially life-threatening side effects, such as bone fracture for aromatase inhibitors3 and pulmonary embolus and (for women with a uterus) endometrial cancer for tamoxifen.2,5,6 The risks of such side effects increase with longer treatment, although the absolute risk of death from them is low (<0.5%).5-9

In addition, tamoxifen and aromatase inhibitors can cause bothersome but non–life-threatening side effects, including menopausal symptoms, arthropathy, and carpal tunnel syndrome, which adversely affect the quality of life. However, such symptoms are quite common even without endocrine therapy. In placebo-controlled trials7-10,22-24 that have systematically sought patient-reported outcomes, women in the placebo group have reported more than half as many episodes as those in the endocrine-therapy group, which highlights the importance of placebo control to assess many pharmacologic side effects. Trials have also shown little difference in discontinuation rates between endocrine therapy and placebo, although in clinical practice substantial numbers of women discontinue adjuvant endocrine therapy prematurely because of symptoms.25,26 However, women who have already completed 5 years of endocrine therapy are less at risk for unexpected symptoms than those who are initiating therapy.

These findings underline the need to help women who are receiving endocrine therapy to discover whether any symptoms are actually caused or exacerbated by therapy. Such patients could try stopping treatment for short periods or switching from one agent to another.26 Switching between an aromatase inhibitor and tamoxifen, or among various aromatase inhibitors, is safer than discontinuing therapy prematurely.3 Adherence may also be helped by interventions that can mitigate some of the symptoms attributed to endocrine therapy,27 including nonhormonal interventions that reduce menopausal symptoms,28,29 musculoskeletal symptoms,30 sexual dysfunction,31,32 and osteoporosis.33

Our study has several limitations. First, the recurrence rates reported here are in women who were scheduled to receive 5 years of endocrine therapy, not in those who completed treatment. Only a few of the trials in our study provided detailed data with respect to adherence, but a substantial minority of women in trials of 5-year endocrine therapy did not complete their treatment.2 Because 5 years of therapy is more effective than only 2 years,1,2 the risks among women who actually completed 5 years of therapy would be somewhat lower than those in our study. However, an expected lower risk with greater adherence is to some extent counterbalanced by unreported breast-cancer events: the association between TN status and the rate of death without reported recurrence suggests that some of these deaths were from unreported breast cancer and that the rate of distant recurrence would have been higher by 5 to 10% with complete ascertainment. Although a persisting recurrence risk among women with ER-positive breast cancer is well recognized,13-17,34 our study quantifies the 20-year risk more reliably than previous studies, since it is large and has long follow-up. However, long follow-up means that most of the patients received the breast-cancer diagnosis well before 2000. Since then, the prognosis for women in particular TN categories has somewhat improved owing to earlier diagnosis, more accurate tumor staging, and better surgical, radiation, and systemic therapies. Gene-expression arrays have also been adopted to guide the use of chemotherapy in ER-positive disease, a factor that has somewhat affected the mix of patients receiving chemotherapy.35 However, it seems unlikely that such factors would have a substantive effect on the generalizability of our findings to current patients, since the use of chemotherapy in our cohort was similar to that in current practice (Table S2 in the Supplementary Appendix).36

Furthermore, we could not reliably assess the relevance of chemotherapy to prognosis after year 5, since the women who received chemotherapy and those who did not receive chemotherapy differed in the extent of nodal involvement, tumor size, tumor grade, and perhaps unrecorded selection factors. The relevance of chemotherapy to prognosis after year 5 is best assessed in meta-analyses of the trials of chemotherapy, since randomization balances known and unknown risk factors between treatment groups. Previous EBCTCG meta-analyses have shown that most of the reduction in the recurrence rate with chemotherapy occurred in the first 5 years, with similar proportional reductions among women with ER-positive and ER-negative disease, but also indicated further benefit in years 5 to 9 with more effective regimens.37 Thus, the risk of recurrence after 5 years may well be somewhat lower in women who receive contemporary chemotherapy than among those in our study.

In addition, only 2% of the women in our study received trastuzumab. Wider use of trastuzumab in women with HER2-positive disease might have improved prognosis after 5 years,38 although again such a hypothesis would be best evaluated by meta-analyses of trastuzumab trials. In trials without trastuzumab, the recurrence risk in years 0 to 4 was higher for HER2-positive tumors than for HER2-negative tumors, but HER2 status was of little relevance to prognosis thereafter. Hence, although HER2 status was unknown for many tumors, the overall findings are applicable to women with ER-positive, HER2-negative disease (i.e., to most women with ER-positive disease).

In conclusion, even after 5 years of adjuvant endocrine therapy, women with ER-positive, early-stage breast cancer still had a persistent risk of recurrence and death from breast cancer for at least 20 years after the original diagnosis. This finding has implications for long-term follow-up strategies and highlights the need for new approaches to reduce late recurrence. The risk could be somewhat reduced by extending the duration of endocrine therapy,5-11 with greater absolute benefits for those at highest risk for recurrence. A major predictor of risk is TN status, although even among women with large, strongly node-positive tumors, most who complete 5 years of endocrine therapy will remain free of distant recurrence 20 years after diagnosis. However, even low-grade T1N0 disease carries an appreciable risk of distant recurrence and contralateral breast cancer, a risk that is sufficient for at least the consideration of extended endocrine therapy. Recognition of the magnitude of the long-term risks of ER-positive disease can help women and their health care professionals decide whether to extend therapy beyond 5 years and whether to persist if adverse events occur.