Importance The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. Objective To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials. Design, Setting, and Participants Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017. Interventions In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration. Main Outcomes and Measures The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer. Results Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11). Conclusions and Relevance In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

中文翻译：

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妇女健康倡议随机临床试验长期随访期间更年期激素治疗与乳腺癌发病率和死亡率的关联

重要性 由于观察性研究和随机临床试验的结果不一致，更年期激素治疗对乳腺癌的影响仍未得到解决。目的评估先前随机使用雌激素加孕激素或先前随机使用雌激素单独使用与妇女健康倡议临床试验中乳腺癌发病率和死亡率的关联。设计、设置和参与者 2 项安慰剂对照随机临床试验的长期随访，涉及 27 347 名 50 至 79 岁的绝经后妇女，既往无乳腺癌，基线筛查乳房 X 光检查阴性。从 1993 年到 1998 年，美国 40 个中心招募了女性，随访至 2017 年 12 月 31 日。 干预措施 在涉及 16608 名有子宫的女性的试验中，8506 名随机接受 0。625 毫克/天的结合马雌激素 (CEE) 加上 2.5 毫克/天的醋酸甲羟孕酮 (MPA) 和 8102，安慰剂。在涉及 10739 名既往子宫切除术的女性的试验中，5310 名随机接受 0.625 毫克/天的单独 CEE 和 5429 名安慰剂。CEE+MPA 试验在中位干预持续时间为 5.6 年后于 2002 年停止，仅 CEE 试验在干预持续时间中位数为 7.2 年后于 2004 年停止。主要结果和措施主要结果是乳腺癌发病率（方案预先指定的主要危害监测结果），次要结果是乳腺癌死亡和乳腺癌后死亡。结果 在两项试验中随机分配的 27 347 名绝经后妇女（基线平均 [SD] 年龄，63.4 岁 [7.2 岁]）中，经过超过 20 年的中位累积随访，超过 98% 的死亡率信息是可用的。在 10739 名接受过子宫切除术的女性中，单独使用 CEE 与安慰剂相比，与 238 例（年化率，0.30%）和 296 例（年化率，0.37%；风险比 [HR]，0.78； 95% CI，0.65-0.93；P = .005），并且与 30 例死亡（年化死亡率，0.031%）和 46 例死亡（年化死亡率，0.046%；HR，0.60；95 % CI，0.37-0.97；P = .04）。相比之下，在 16608 名有子宫的女性中，CEE 加 MPA 与安慰剂相比与统计学上显着更高的乳腺癌发病率相关，分别为 584 例（年化率，0.45%）和 447 例（年化率，0.36%；HR，1.28；95 % CI，1.13-1.45；P < . 001) 并且乳腺癌死亡率无显着差异，71 例死亡（年化死亡率，0.045%）与 53 例死亡（年化死亡率，0.035%；HR，1.35；95% CI，0.94-1.95；P = .11）。结论和相关性 在这项由 2 项随机试验组成的长期随访研究中，与安慰剂相比，在接受过子宫切除术的女性中，先前随机使用 CEE 与较低的乳腺癌发病率和较低的乳腺癌死亡率显着相关，而之前随机使用 CEE 加 MPA 与安慰剂相比，在具有完整子宫的女性中与较高的乳腺癌发病率显着相关，但在乳腺癌死亡率方面没有显着差异。人力资源，1.35；95% CI，0.94-1.95；P = .11）。结论和相关性 在这项由 2 项随机试验组成的长期随访研究中，与安慰剂相比，在接受过子宫切除术的女性中，先前随机使用 CEE 与较低的乳腺癌发病率和较低的乳腺癌死亡率显着相关，而之前随机使用 CEE 加 MPA 与安慰剂相比，在具有完整子宫的女性中与较高的乳腺癌发病率显着相关，但在乳腺癌死亡率方面没有显着差异。人力资源，1.35；95% CI，0.94-1.95；P = .11）。结论和相关性 在这项由 2 项随机试验组成的长期随访研究中，与安慰剂相比，在接受过子宫切除术的女性中，先前随机使用 CEE 与较低的乳腺癌发病率和较低的乳腺癌死亡率显着相关，而之前随机使用 CEE 加 MPA 与安慰剂相比，在具有完整子宫的女性中与较高的乳腺癌发病率显着相关，但在乳腺癌死亡率方面没有显着差异。