20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

Abstract

Background: The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment.

Methods: In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan-Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients' outcomes during the period from 5 to 20 years.

Results: Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1-3), and 34% with four to nine nodes involved (T1N4-9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1-3, and 41% with T2N4-9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively.

Conclusions: After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.).

Figure 1. Selection of Women with Breast Cancer from 88 Trials of Adjuvant Breast-Cancer Therapy.

The analyses combine individual patient data from 88 trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) database of randomized trials. All the women who were included in the study were scheduled to receive adjuvant endocrine therapy for only 5 years, regardless of actual adherence, after a diagnosis of estrogen-receptor (ER)–positive breast cancer before the age of 75 years. A total of 74,194 women who were enrolled in 78 trials at the time of diagnosis were included in the analyses that began at year 0. A total of 62,923 women who were enrolled in 88 trials either at the time of diagnosis or later (having already received 2 to 5 years of endocrine therapy) were scheduled to stop therapy at 5 years and were included in the analyses that began at year 5.

Figure 2. Association between Pathological Nodal Status and the Risk of Distant Recurrence or Death from Breast Cancer during the 20-Year Study Period.

Shown are data regarding the risk of distant recurrence (Panel A) and death from breast cancer (Panel B) among 74,194 women with ER-positive T1 or T2 disease who were enrolled in 78 trials at year 0 and were scheduled to receive 5 years of endocrine therapy. (Data for another 10,200 women who enrolled in 10 trials after year 0 are not shown here.) The risk was calculated according to the patients’ pathological nodal status at the time of diagnosis: N0, N1–3, or N4–9. The number of events and annual rate are shown for the preceding period (e.g., data for years 0 to 4 are shown at 5 years). The I bars indicate 95% confidence intervals. The dashed lines indicate that the event rate is for the whole 5-year period, rather than for individual years, as is otherwise shown. The annual rate of death from breast cancer was estimated by subtracting the death rate in women without recurrence from the rate in all women.

Figure 3. Association between Pathological Nodal Status and the Risk of Distant Recurrence during Years 5 to 20 of the Study, According to Tumor Stage.

Shown are the data for 62,923 women with ER-positive disease who were enrolled in 88 trials of breast-cancer therapy and who initiated therapy either at year 0 or within the first 5 years, according to whether they had T1 disease (Panel A) or T2 disease (Panel B). All the women were scheduled to receive 5 years of endocrine therapy and were event-free and still being followed at year 5. The I bars indicate 95% confidence intervals. The dashed lines indicate that the event rate is for the whole 5-year period, rather than for individual years, as is otherwise shown. Data for the number of events and annual rate begin at 5 years, since the analysis of the risk of distant recurrence starts at year 5.

Figure 4. Association of Tumor Diameter and Tumor Grade with the Risk of Distant Recurrence or Any Breast-Cancer Event during Years 5 to 20 of the Study.

Shown are data for 19,402 women (13,941 of whom had a known tumor grade) with ER-positive breast cancer with a tumor size of 2 cm or less with no spread to lymph nodes (T1N0). All the women were scheduled to receive 5 years of adjuvant endocrine therapy and then discontinue therapy and were event-free and being followed at year 5. The findings were categorized according to tumor diameter (T1a or T1b [≤1.0 cm] vs. T1c [>1.0–2.0 cm]) and tumor grade. Panels A and C show the risk of distance recurrence during years 5 to 20 according to tumor diameter and tumor grade, respectively; Panels B and D show the risk of any breast-cancer event (distant or local recurrence or contralateral onset) during years 5 to 20 according to tumor diameter and tumor grade, respectively. The I bars indicate 95% confidence intervals. The dashed lines indicate that the event rate is for the whole 5-year period, rather than for individual years, as is otherwise shown.