Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

Abstract

SummaryBackgroundFor women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years.MethodsIn the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633.FindingsAmong women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%).InterpretationFor women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurren...

Adjuvant ovarian suppression for resected breast cancer: 2017 critical assessment

“…Those that tolerated EXE well on during the study may have continued EXE. Some probably got extended TAM after ATLAS was presented and published [18]. Some probably continued OFS, with or without an AI.…”

“…This treatment suffers from a paucity of data showing that further endocrine therapy is effective after 5 years of an AI. In contrast, we know that more TAM improves survival after 5 years of TAM [18,19], and an AI improves DFS after 5 years of TAM [9,17]. By the end of 2016, one study had been published [20] and 3 more had been presented at the 2016 San Antonio Breast Cancer symposium showing little or no benefit for extending AI therapy beyond 5 years except for continued suppression of new contralateral breast cancers [21][22][23].…”

“…On the other hand, women who got initial TAM can continue TAM with benefit as shown in Atlas and ATTOM [18,19], and then switch to an AI after their menopause, with a marked reduction in breast cancer events [9]. One notes that OFS ?…”

Antidepressant use and risk of central nervous system metastasis

“…In ER-positive disease, a 47% reduction in breast cancer recurrence occurred in years 0 to 4 and a 32% reduction for years 5 through 9, although this benefit is not apparent in ER-negative disease [63]. The general recommendation for tamoxifen use is 5 years after diagnosis, although, a recent study conducted by Davies et al [64] found continuing adjuvant tamoxifen for a total of 10 years, in comparison to stopping at 5 years, further reduced recurrence and mortality.…”

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

“…Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen of 5 years of Tamoxifen treatment vs none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis [1] .…”