Lancet：持续三苯氧胺治疗10年能降低雌激素受体阳性的乳腺癌患者的复发率和死亡率

对于雌激素受体阳性的早期乳腺癌患者，采用三苯氧胺治疗5年能显着减少患者确诊后15年内的死亡率。Christina Davies等旨在评估持续10年应用三苯氧胺治疗的效果。本研究的结果发表在Lancet 12月最新的在线期刊上。

在世界范围内进行的辅助三苯氧胺治疗：长期治疗或短期治疗（ATLAS）研究中，12894名早期乳腺癌女性患者在完成了5年的三苯氧胺治疗后被随机分入2组，一组继续接受三苯氧胺治疗至10年，另一组即停止治疗。采用电脑生成的最小值将患者按照1:1的比例分入两组。在患者入组后，从1996年至2005年，每年对患者进行评估，记录其复发、第二肿瘤、住院情况或死亡情况。研究者报道了在6846名雌激素受体阳性患者中治疗效果，同时报道了所有女性患者（雌激素受体阳性、阴性或未知）中副反应情况。长期的随访仍在继续。

在5-15年时复发累积危险度在继续治疗组为21.4%，而在对照组为25.1%，乳腺癌死亡率累积危险度分别为12.2%和15.0%。在雌激素受体阴性的女性乳腺癌患者中继续治疗似乎对乳腺癌临床结局无显着影响，在4800名雌激素受体状态不明的乳腺癌患者中重度有效。在所有的12894名女性中，乳腺癌复发以外造成的死亡受治疗影响较小（继续治疗组和停止治疗组分别为691人和679人），至于由其他疾病所造成的住院和死亡，其RR如下：肺栓塞1.87、卒中1.06、缺血性心脏病0.76以及子宫内膜癌1.74。子宫内膜癌在5-14年的累积危险度在继续治疗组为3.1，在对照组为1.6%。在雌激素受体阳性的患者中，继续三苯氧胺治疗能降低其乳腺癌复发风险（继续组和停药组的复发数分别为617人和711人）、降低乳腺癌死亡率（331人/397人）以及降低总体 死亡率（639人/722人），上述差异皆具有统计学意义。与10年后相比，乳腺癌副反应事件的降低在10年前更少，复发比率（RR）在5-9年和之后分别为0.90和0.75，乳腺癌死亡率RR分别为0.97和0.71。

研究结果指出，在雌激素受体阳性的早期女性乳腺癌患者中，继续三苯氧胺治疗至10年能进一步降低复发率和死亡率，尤其是10年之后的复发率和死亡率。结合既往三苯氧胺治疗5年和不治疗、以及本研究的结果，提示三苯氧胺治疗10年能减半患者在确诊后第二个10年的乳腺癌死亡率。

doi:10.1016/S0140-6736(12)61963-1
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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

Dr Christina Davies MBChB a , Hongchao Pan PhD a, Jon Godwin DPhil b, Prof Richard Gray MSc a, Prof Rodrigo Arriagada MD c, Prof Vinod Raina MD d, Mirta Abraham MD e, Victor Hugo Medeiros Alencar MD f, Atef Badran PhD g, Xavier Bonfill MD h, Joan Bradbury i, Prof Michael Clarke DPhil j, Prof Rory Collins FMedSci a, Prof Susan R Davis MBBS i, Antonella Delmestri PhD a, Prof John F Forbes MD k, Prof Peiman Haddad MD l, Prof Ming-Feng Hou MD m, Prof Moshe Inbar MD n, Prof Hussein Khaled MD g, Joanna Kielanowska MD o, Wing-Hong Kwan MD p, Beela S Mathew MD q, Bettina Müller MD r, Antonio Nicolucci MD s, Octavio Peralta MD r, Fany Pernas t, Prof Lubos Petruzelka MD u, Prof Tadeusz Pienkowski MD v, Balakrishnan Rajan MD w, Maryna T Rubach MD o, Sera Tort MD h, Gerard Urrútia MD h, Miriam Valentini MD s, Yaochen Wang MD a, Prof Richard Peto FRS a, for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group†

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.

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