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 - PubMed (original) (raw)
Randomized Controlled Trial
. 2013 Mar 9;381(9869):805-16.
doi: 10.1016/S0140-6736(12)61963-1.
Hongchao Pan, Jon Godwin, Richard Gray, Rodrigo Arriagada, Vinod Raina, Mirta Abraham, Victor Hugo Medeiros Alencar, Atef Badran, Xavier Bonfill, Joan Bradbury, Michael Clarke, Rory Collins, Susan R Davis, Antonella Delmestri, John F Forbes, Peiman Haddad, Ming-Feng Hou, Moshe Inbar, Hussein Khaled, Joanna Kielanowska, Wing-Hong Kwan, Beela S Mathew, Indraneel Mittra, Bettina Müller, Antonio Nicolucci, Octavio Peralta, Fany Pernas, Lubos Petruzelka, Tadeusz Pienkowski, Ramachandran Radhika, Balakrishnan Rajan, Maryna T Rubach, Sera Tort, Gerard Urrútia, Miriam Valentini, Yaochen Wang, Richard Peto; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group
Collaborators, Affiliations
- PMID: 23219286
- PMCID: PMC3596060
- DOI: 10.1016/S0140-6736(12)61963-1
Randomized Controlled Trial
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
Christina Davies et al. Lancet. 2013.
Erratum in
- Lancet. 2013 Mar 9;381(9869):804
- Department of Error.
[No authors listed] [No authors listed] Lancet. 2017 May 13;389(10082):1884. doi: 10.1016/S0140-6736(17)31004-8. Epub 2017 Apr 28. Lancet. 2017. PMID: 28457627 Free PMC article. No abstract available.
Abstract
Background: For 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.
Methods: In 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.
Findings: Among 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%).
Interpretation: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.
Funding: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.
Figures
Figure 1
Trial profile, showing the different populations analysed to assess the side-effects and the main effects of continuing tamoxifen to 10 years versus stopping tamoxifen at 5 years ER=oestrogen receptor. *39 patients were allocated twice in error, but stayed on their original allocation. Excludes 18 patients entered in error (17 with distant recurrence and one without ethics approval).
Figure 2
Treatment compliance (A) and proportion of patients in follow-up (B) by year since randomisation for 6846 women with ER-positive disease (54% node-negative) *>99% tamoxifen.
Figure 3
Recurrence (A) and breast cancer mortality (B) by treatment allocation for 6846 women with ER-positive disease Bars show SE. Recurrence rates are percentage per year (events/patient-years of follow-up). Death rates (overall rate – rate in women without recurrence) are percentage per year (SE). ATLAS=Adjuvant Tamoxifen: Longer Against Shorter.
Figure 4
Recurrence by treatment allocation for 6846 women with ER-positive disease, subdivided by patient or tumour characteristics and location or time of first recurrence *Europe, Australia, New Zealand, USA, Latin America, and South Africa (all predominantly of European origin). †Including multiple and unspecified sites.
Comment in
- Extended adjuvant tamoxifen for breast cancer--a new era?
Powles TJ. Powles TJ. Lancet. 2013 Mar 9;381(9869):782-3. doi: 10.1016/S0140-6736(12)62038-8. Lancet. 2013. PMID: 23219287 No abstract available. - 10 vs 5 years of adjuvant tamoxifen: exclusion of 1/402 centres in ATLAS.
Davies C, Pan H, Peto R. Davies C, et al. Lancet. 2017 May 13;389(10082):1884. doi: 10.1016/S0140-6736(17)31003-6. Epub 2017 Apr 28. Lancet. 2017. PMID: 28457628 No abstract available. - Rethinking Extended Adjuvant Antiestrogen Therapy to Increase Survivorship in Breast Cancer.
Abderrahman B, Jordan VC. Abderrahman B, et al. JAMA Oncol. 2018 Jan 1;4(1):15-16. doi: 10.1001/jamaoncol.2017.3510. JAMA Oncol. 2018. PMID: 29145574 No abstract available.
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