A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.
A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-20-3609
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发表时间：
2021-02-15
期刊：
影响因子：
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通讯作者：
Garber JE
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文献类型：
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作者：
Bhatia S;Palomares MR;Hageman L;Chen Y;Landier W;Smith K;Umphrey H;Reich CA;Zamora KW;Armenian SH;Bevers TB;Blaes A;Henderson T;Hodgson D;Hudson MM;Korde LA;Melin SA;Merajver SD;Overholser L;Pruthi S;Wong FL;Garber JE
低剂量他莫昔芬可降低乳腺癌风险，但在胸部照射癌症幸存者中仍未进行测试-乳腺癌风险与BRCA突变携带者相当。我们假设低剂量的他莫昔芬在降低放射相关的乳腺癌风险方面是安全有效的。我们在2010年至2016年期间在15家美国研究中心进行了一项药物启动的随机化IIb期双盲安慰剂对照试验（FDA IND 107367）。合格性包括40岁时胸部放射≥ 12 Gy和入组时年龄≥ 25岁。患者以1：1的比例随机接受低剂量他莫昔芬（5 mg/天）或相同的安慰剂片剂治疗2年。主要终点是基线、1年和2年时的乳腺摄影致密区。胰岛素生长因子-1（IGF-1）在乳腺癌发生中起作用;基线、1年和2年时的循环IGF-1和IGF-BP 3水平作为次要终点。72名参与者（低剂量他莫昔芬组：n=34，安慰剂组：n=38）入组，中位年龄为43.8岁（35-49岁），可评价。他们接受了胸部放射治疗，中位剂量为30.3戈伊。与安慰剂组相比，低剂量他莫昔芬组参与者的乳腺摄影致密区（P=0.02）和IGF 1水平（P<0.0001）显著降低，IGFBP-3水平升高（P=0.02）。治疗组之间的毒性生物标志物（血清骨特异性碱性磷酸酶、脂质和抗凝血酶III;尿N-端肽交联）无差异。我们没有发现任何与低剂量他莫昔芬相关的3-4级不良事件。在这项胸部照射癌症幸存者的随机试验中，我们发现低剂量他莫昔芬可有效降低乳腺癌风险的既定生物标志物，并可作为降低风险的策略。
Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors – a population with breast cancer risk comparable to BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 US sites. Eligibility included ≥12Gy of chest radiation by age 40y and age at enrollment ≥25y. Patients were randomized 1:1 to low-dose tamoxifen (5mg/day) or identical placebo tablets for 2y. The primary endpoint was mammographic dense area at baseline, 1y and 2y. Insulin growth factor-1 (IGF-1) plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1y and 2y served as secondary endpoints. Seventy-two participants (low-dose tamoxifen: n=34, placebo: n=38) enrolled at a median age of 43.8y (35-49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P=0.02) and IGF1 levels (P<0.0001), and higher IGFBP-3 levels (P=0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and anti-thrombin III; urine N-telopeptide crosslinks) between the treatment arms. We did not identify any grade 3-4 adverse events related to low-dose tamoxifen. In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.