Abstract：
BACKGROUND: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk.
METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing.
RESULTS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]).
CONCLUSIONS: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor.
BACKGROUND: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.
METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing.
RESULTS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]).
CONCLUSIONS: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor.
BACKGROUND: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.
摘要：
背景：绝经后妇女患乳腺癌的风险增加与高血清雌二醇和睾酮浓度有关，但人们对这些激素如何影响乳腺癌预防或治疗内分泌治疗的反应知之甚少。我们旨在评估血清雌二醇和睾酮浓度对芳香化酶抑制剂阿那曲唑预防绝经后高危女性乳腺癌疗效的影响。
方法：在这项病例对照研究中，我们使用了IBIS-II预防试验的数据，一个随机的，控制,在40-70岁的绝经后女性中进行双盲试验，在18个国家的153个乳腺癌治疗中心进行。在审判中,女性被随机分配（1：1）接受阿那曲唑（1毫克/天，口服)或每天安慰剂，持续5年。在这项预先计划的病例对照研究中，主要分析是基线雌二醇与性激素结合球蛋白（SHBG）比值（雌二醇-SHBG比值）对所有乳腺癌发展的影响，包括导管原位癌（试验的主要终点）。病例是在进入试验后和2019年10月22日截止日期之前报告乳腺癌的参与者，并且在进入试验后3个月内或在试验期间有有效的血液样本且未使用激素替代疗法。对于每种情况，随机选择了两个没有乳腺癌的对照，与治疗组相匹配，年龄（2年内），和随访时间(至少是匹配情况的时间)。对于每个治疗组，我们应用多项logistic回归似然比趋势检验,以评估何种病例比例的变化与激素比值的1四分位数变化相关.对照仅用于确定四分位数截断值。轮廓似然95%CI用于指示估计的精度。二次分析还研究了基线睾酮-SHBG比率对乳腺癌发展的影响。我们还评估了阿那曲唑与安慰剂的相对益处（计算为1-阿那曲唑组乳腺癌病例与安慰剂组乳腺癌病例的比率）。该试验在ISRCTN（编号ISRCTN31488319）注册，并于2012年1月31日完成招募，但长期随访仍在进行中。
结果：在2003年2月2日至2012年1月31日之间招募了3864名女性参加试验，并随机分配接受阿那曲唑（n=1920）或安慰剂（n=1944）。中位随访时间为131个月（IQR106-156），在此期间,阿那曲唑组乳腺癌85例(4·4%),安慰剂组乳腺癌165例(8·5%).没有性别数据，种族,或种族被收集。排除后，病例对照研究包括来自阿那曲唑组的212名参与者(72例，140名对照）和416名来自安慰剂组（142例，274个控件）。在安慰剂组中发现随着雌二醇-SHBG比率的增加而增加乳腺癌风险的趋势（每四分位数1·25的趋势[95％CI1·08至1·45]，p=0·0033)，但非阿那曲唑组（1·06[0·86至1·30]，p=0·60）。安慰剂组的睾酮-SHBG比值效应较弱（趋势1·21[1·05至1·41]，p=0·011)，但同样不是阿那曲唑组(趋势1·18[0·96至1·46]，p=0·11）。阿那曲唑的相对益处见于四分位数2(0·55[95%CI0·13至0·78])，四分位数3(0·54[0·22至0·74]，雌二醇-SHBG比的四分位数4(0·56[0·23至0·76])，但不在四分位数1(0·18[-0·60至0·59])中。
结论：这些结果表明，应更常规地测量血清激素，并将其纳入风险管理决策。测量血清激素浓度是廉价的，并且可能有助于临床医生区分哪些女性将从芳香化酶抑制剂中受益最大。
背景：英国癌症研究中心，国家健康和医学研究委员会（澳大利亚），乳腺癌研究基金会,和DaCosta基金。
方法：在这项病例对照研究中，我们使用了IBIS-II预防试验的数据，一个随机的，控制,在40-70岁的绝经后女性中进行双盲试验，在18个国家的153个乳腺癌治疗中心进行。在审判中,女性被随机分配（1：1）接受阿那曲唑（1毫克/天，口服)或每天安慰剂，持续5年。在这项预先计划的病例对照研究中，主要分析是基线雌二醇与性激素结合球蛋白（SHBG）比值（雌二醇-SHBG比值）对所有乳腺癌发展的影响，包括导管原位癌（试验的主要终点）。病例是在进入试验后和2019年10月22日截止日期之前报告乳腺癌的参与者，并且在进入试验后3个月内或在试验期间有有效的血液样本且未使用激素替代疗法。对于每种情况，随机选择了两个没有乳腺癌的对照，与治疗组相匹配，年龄（2年内），和随访时间(至少是匹配情况的时间)。对于每个治疗组，我们应用多项logistic回归似然比趋势检验,以评估何种病例比例的变化与激素比值的1四分位数变化相关.对照仅用于确定四分位数截断值。轮廓似然95%CI用于指示估计的精度。二次分析还研究了基线睾酮-SHBG比率对乳腺癌发展的影响。我们还评估了阿那曲唑与安慰剂的相对益处（计算为1-阿那曲唑组乳腺癌病例与安慰剂组乳腺癌病例的比率）。该试验在ISRCTN（编号ISRCTN31488319）注册，并于2012年1月31日完成招募，但长期随访仍在进行中。
结果：在2003年2月2日至2012年1月31日之间招募了3864名女性参加试验，并随机分配接受阿那曲唑（n=1920）或安慰剂（n=1944）。中位随访时间为131个月（IQR106-156），在此期间,阿那曲唑组乳腺癌85例(4·4%),安慰剂组乳腺癌165例(8·5%).没有性别数据，种族,或种族被收集。排除后，病例对照研究包括来自阿那曲唑组的212名参与者(72例，140名对照）和416名来自安慰剂组（142例，274个控件）。在安慰剂组中发现随着雌二醇-SHBG比率的增加而增加乳腺癌风险的趋势（每四分位数1·25的趋势[95％CI1·08至1·45]，p=0·0033)，但非阿那曲唑组（1·06[0·86至1·30]，p=0·60）。安慰剂组的睾酮-SHBG比值效应较弱（趋势1·21[1·05至1·41]，p=0·011)，但同样不是阿那曲唑组(趋势1·18[0·96至1·46]，p=0·11）。阿那曲唑的相对益处见于四分位数2(0·55[95%CI0·13至0·78])，四分位数3(0·54[0·22至0·74]，雌二醇-SHBG比的四分位数4(0·56[0·23至0·76])，但不在四分位数1(0·18[-0·60至0·59])中。
结论：这些结果表明，应更常规地测量血清激素，并将其纳入风险管理决策。测量血清激素浓度是廉价的，并且可能有助于临床医生区分哪些女性将从芳香化酶抑制剂中受益最大。
背景：英国癌症研究中心，国家健康和医学研究委员会（澳大利亚），乳腺癌研究基金会,和DaCosta基金。
