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      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

      research-article
      a , * , a , b , a , c , d , e , f , g , h , i , j , a , i , a , k , l , m , n , g , o , p , q , r , s , r , t , u , v , w , o , h , h , s , a , a , for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group
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          Summary

          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.

          Related collections

          Most cited references26

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          Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

          The Lancet, 365(9472), 1687-1717
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            Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials

            Summary Background As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen. Methods We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21 457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment. Findings In oestrogen receptor (ER)-positive disease (n=10 645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0–4 and RR 0·68 [0·06] during years 5–9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10–14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10–19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0–4, 0·66 [0·05] during years 5–9, and 0·68 [0·08] during years 10–14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality. Interpretation 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen. Funding Cancer Research UK, British Heart Foundation, and Medical Research Council.
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              Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study.

              Initial findings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor-positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical significance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial findings. Women (n = 13,388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). Estimates of the net benefit from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided. After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically significant. The net benefit achieved with tamoxifen varied according to age, race, and level of breast cancer risk. Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer. Readily identifiable subsets of individuals comprising 2.5 million women could derive a net benefit from the drug.
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                Author and article information

                Journal
                Lancet
                Lancet
                Lancet
                Lancet Publishing Group
                0140-6736
                1474-547X
                9 March 2013
                9 March 2013
                : 381
                : 9869
                : 805-816
                Affiliations
                [a ]Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, UKClinical Trial Service Unit and Epidemiological Studies Unit (CTSU)University of OxfordUK
                [b ]Glasgow Caledonian University, Glasgow, UKGlasgow Caledonian UniversityGlasgowUK
                [c ]Institut Gustave-Roussy, Villejuif, FranceInstitut Gustave-RoussyVillejuifFrance
                [d ]Institute Rotary Cancer Hospital, All-India Institute of Medical Sciences, New Delhi, IndiaInstitute Rotary Cancer HospitalAll-India Institute of Medical SciencesNew DelhiIndia
                [e ]Instituto Cardiovascular Rosario (ICR), Rosario, ArgentinaInstituto Cardiovascular Rosario (ICR)RosarioArgentina
                [f ]Instituto do Cancer do Ceará (ICC), Fortaleza, BrazilInstituto do Cancer do Ceará (ICC)FortalezaBrazil
                [g ]National Cancer Institute, Cairo University, Cairo, EgyptNational Cancer InstituteCairo UniversityCairoEgypt
                [h ]Sant Pau Biomedical Research Institute (IIB Sant Pau-CIBERESP), Barcelona, SpainSant Pau Biomedical Research Institute (IIB Sant Pau-CIBERESP)BarcelonaSpain
                [i ]School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, AustraliaSchool of Public Health and Preventive MedicineMonash University, MelbourneMelbourneVictoriaAustralia
                [j ]Queens University, Belfast, UKQueens UniversityBelfastUK
                [k ]Australia and New Zealand Breast Cancer Trials Group, University of Newcastle, Newcastle, NSW, AustraliaAustralia and New Zealand Breast Cancer Trials GroupUniversity of NewcastleNewcastleNSWAustralia
                [l ]Cancer Institute, Tehran University of Medical Sciences, Tehran, IranCancer InstituteTehran University of Medical SciencesTehranIran
                [m ]Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ChinaKaohsiung Medical University HospitalKaohsiungTaiwanChina
                [n ]Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelTel Aviv Sourasky Medical CenterTel AvivIsrael
                [o ]The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, PolandThe Maria Sklodowska-Curie Memorial Cancer Center and Institute of OncologyWarsawPoland
                [p ]Comprehensive Oncology Centre, Hong Kong, ChinaComprehensive Oncology CentreHong KongChina
                [q ]Regional Cancer Centre, Trivandrum, IndiaRegional Cancer CentreTrivandrumIndia
                [r ]Chilean Cooperative Group for Oncologic Research (GOCCHI) Santiago, ChileChilean Cooperative Group for Oncologic Research (GOCCHI) SantiagoChile
                [s ]Consorzio Mario Negri Sud, S Maria Imbaro, ItalyConsorzio Mario Negri SudS Maria ImbaroItaly
                [t ]Instituto de Investigaciones Clinicas de Rosario, Rosario, ArgentinaInstituto de Investigaciones Clinicas de RosarioRosarioArgentina
                [u ]Medical Faculty 1, Charles University, Prague, Czech RepublicMedical Faculty 1Charles UniversityPragueCzech Republic
                [v ]European Health Centre Otwock (ECZO), Warsaw, PolandEuropean Health Centre Otwock (ECZO)WarsawPoland
                [w ]The National Oncology Centre, Royal Hospital, OmanThe National Oncology CentreRoyal HospitalOman
                Author notes
                [* ]Correspondence to: Dr Christina Davies, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Richard Doll Building, Old Road Campus, Oxford OX3 7LF, UK atlas@ 123456ctsu.ox.ac.uk
                [†]

                Members listed at end of paper

                Article
                LANCET61963
                10.1016/S0140-6736(12)61963-1
                3596060
                23219286
                b7bab394-1384-4aaf-b251-02fafdbb43f6
                © 2013 Elsevier Ltd. All rights reserved.

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