美国弗雷德·哈钦森癌症研究中心Ross L. Prentice团队分析了绝经期女性使用激素治疗与乳腺癌发病率和死亡率的相关性。相关论文于2020年7月28日发表在《美国医学会杂志》上。

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确定。

在妇女健康倡议的临床试验中，为了评估先前随机使用雌激素加孕激素或仅使用雌激素与乳腺癌发病率和死亡率之间的关系，研究组进行了2项安慰剂对照的随机临床试验，1993-1998年，在美国的40个中心共招募了27347名年龄为50-79岁的绝经后女性，既往无乳腺癌，基线钼靶检查阴性。长期随访至2017年12月31日。

在涉及16608名子宫完整女性的试验中，将其随机分组，其中8506名接受共轭马雌激素（CEE）加醋酸甲羟孕酮（MPA）治疗，8102名接受安慰剂治疗。在涉及10739名接受过子宫切除术的女性的试验中，将其随机分组，其中5310名接受CEE治疗，5429名接受安慰剂治疗。CEE+MPA试验的中位干预期为5.6年，仅CEE试验为7.2年。对参与人群的乳腺癌发病率和死亡率进行分析。

27347名参与者的基线平均年龄为63.4岁，中位累积随访20年以上，98%以上可获得死亡信息。在10739名接受子宫切除术的女性中，CEE组的乳腺癌年发病率和年死亡率分别为0.30%和0.031%，均显著低于安慰剂组（0.37%和0.046%）。但在16608名子宫完整的女性中，CEE+MPA组的乳腺癌年发病率为0.45%，显著高于安慰剂组（0.36%）；但两组乳腺癌年死亡率相差不大，分别为0.045%和0.035%。

总之，对于绝经后的女性，若先前接受过子宫切除术，服用CEE可显著降低乳腺癌发病率和死亡率；若先前子宫完整，服用CEE+MPA则显著增加乳腺癌的发病风险，但乳腺癌死亡率差异不大。 

附：英文原文

Title: Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials

Author: Rowan T. Chlebowski, Garnet L. Anderson, Aaron K. Aragaki, JoAnn E. Manson, Marcia L. Stefanick, Kathy Pan, Wendy Barrington, Lewis H. Kuller, Michael S. Simon, Dorothy Lane, Karen C. Johnson, Thomas E. Rohan, Margery L. S. Gass, Jane A. Cauley, Electra D. Paskett, Maryam Sattari, Ross L. Prentice

Issue&Volume: 2020/07/28

Abstract: 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 27347 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 16608 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 10739 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 27347 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 10739 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 16608 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.

DOI: 10.1001/jama.2020.9482

Source: https://jamanetwork.com/journals/jama/article-abstract/2768806