Is There Benefit to Endocrine Therapy Beyond 5 Years?

It is well known that 5 years of adjuvant endocrine therapy with a drug such as tamoxifen reduces the risk for breast cancer recurrence, contralateral breast cancer, death from breast cancer, and death from any cause in women with estrogen receptor (ER)-positive early-stage breast cancer.¹ Although the benefits of extending endocrine therapy (with tamoxifen or an aromatase inhibitor) are recognized, the adverse events related to long-term use remain a source of concern. For example, treatment with tamoxifen has been associated with deep vein thrombosis, pulmonary embolism, and endometrial cancer, and treatment with aromatase inhibitors has been linked to bone fracture.¹

In a recent meta-analysis, researchers examined the influence of various characteristics of the original tumor on the 20-year incidence of breast cancer outcomes in women with ER-positive, early-stage disease. The meta-analysis combined patient data from 88 trials in the Early Breast Cancer Trialists’ Collaborative Group database of randomized trials. All patients included in the analysis had ER-positive breast cancer diagnosed at <75 years of age, had stage T1 (≤2 cm) or T2 (>2 cm–5 cm) disease (of varying grades) with <10 positive lymph nodes and no distant metastases, and were scheduled to receive 5 years of endocrine therapy and then stop (regardless of adherence).  

A total of 84,394 patients in the database met the criteria and were included in the analysis, with 62,923 continuing follow-up past year 5. From year 0, 63% were prescribed tamoxifen, 17% were prescribed an aromatase inhibitor, and 20% a sequence of tamoxifen and an aromatase inhibitor.

Results of this meta-analysis, which were recently published in The New England Journal of Medicine, showed that distant recurrences occurred steadily through the 20-year period. “The annual risk was strongly related (P <.001) to nodal status, with a 20-year risk of distant recurrence of 22% in women with no positive nodes [at diagnosis], 31% in those with one to three positive nodes, and 52% in those with four to nine positive nodes,” noted Pan and colleagues.¹

Additionally, the 20-year risk of death from breast cancer was 15% with N0 disease at diagnosis, 28% with N1-N3 disease at diagnosis, and 49% with N4-N9 disease at diagnosis. According to the researchers, “Although all of the women had been clinically disease-free for many years, the original tumor diameter and especially the original nodal status remained powerful determinants of late distant recurrence, even during the second decade after diagnosis.”

Importantly, in years 5 to 20 among patients with T1N0 disease at the onset, the cumulative risk for distant recurrence was 13%. Thus, it may be possible to reduce the risk for distant metastases by a few percentage points with extended endocrine therapy. In patients with larger tumors or node-positive disease, the benefit may be even greater.

“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,” Pan and colleagues concluded.

Reference

1. Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377:1836-1846.