PDF(Pubmed)
Abstract：
BACKGROUND: Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271).
METHODS: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here.
RESULTS: ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16-0.91]).
CONCLUSIONS: Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies.
BACKGROUND: UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis.
METHODS: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here.
RESULTS: ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16-0.91]).
CONCLUSIONS: Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies.
BACKGROUND: UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis.
摘要：
背景：昼夜节律调节细胞生理学，并可能影响乳腺癌（BC）内分泌治疗（ET）的疗效。我们在UNIRAD佐剂III期试验(NCT01805271)中前瞻性地检验了这一假设。
方法：1278例高危激素受体阳性（HR+）/HER2阴性（HER2-）原发性BC患者被随机分配到安慰剂或依维莫司辅助ET组。患者前瞻性地在日记中报告了4个6小时插槽中ET摄入的每日时间（06:00-11:59（上午），12:00-17:59（下午）18:00-23:59（晚上）或24:00-05:59（夜间）。ET时间与无病生存期（DFS）之间的关联是该试验的预设次要终点，该观察性研究的结果在此报告。
结果：记录了855例患者（67.2％）的ET时间。宣布早晨（n=465，54.4％）或下午（n=45，5.4％）ET摄入量的患者比宣布晚上（n=339，39.6％）或夜间（n=5，0.6％）摄入量的患者年龄更大。中位随访时间为46.7个月，118例患者局部复发（n=30）或转移复发（n=84），41名患者死亡。在整个人群中，ET摄入时间与DFS无关（HR=0.77，95％CI[0.53-1.12]）。根据分层因素，ET摄入时间和DFS之间的关联揭示了与ET剂的相互作用（他莫昔芬与芳香化酶抑制剂（AI）在晚上/夜间与早上/下午他莫昔芬摄入组中DFS增加（HR=0.43，95％CI[0.22-0.85]），而AI摄入量没有发现相关性(HR=1.07，95%CI[0.68-1.69])。ET摄入时间和ET剂之间的相互作用保持在多变量分析中(HR=0.38[0.16-0.91])。
结论：高危HR+/HER2-BC患者在等待进一步ET时间研究的结果时，建议在晚上/晚上摄入他莫昔芬。
背景：UNIRAD得到了法国卫生部PHRC2012的资助，并获得了LaLiguecontreleCancer的资助，英国癌症研究中心,无数遗传学，还有诺华.
方法：1278例高危激素受体阳性（HR+）/HER2阴性（HER2-）原发性BC患者被随机分配到安慰剂或依维莫司辅助ET组。患者前瞻性地在日记中报告了4个6小时插槽中ET摄入的每日时间（06:00-11:59（上午），12:00-17:59（下午）18:00-23:59（晚上）或24:00-05:59（夜间）。ET时间与无病生存期（DFS）之间的关联是该试验的预设次要终点，该观察性研究的结果在此报告。
结果：记录了855例患者（67.2％）的ET时间。宣布早晨（n=465，54.4％）或下午（n=45，5.4％）ET摄入量的患者比宣布晚上（n=339，39.6％）或夜间（n=5，0.6％）摄入量的患者年龄更大。中位随访时间为46.7个月，118例患者局部复发（n=30）或转移复发（n=84），41名患者死亡。在整个人群中，ET摄入时间与DFS无关（HR=0.77，95％CI[0.53-1.12]）。根据分层因素，ET摄入时间和DFS之间的关联揭示了与ET剂的相互作用（他莫昔芬与芳香化酶抑制剂（AI）在晚上/夜间与早上/下午他莫昔芬摄入组中DFS增加（HR=0.43，95％CI[0.22-0.85]），而AI摄入量没有发现相关性(HR=1.07，95%CI[0.68-1.69])。ET摄入时间和ET剂之间的相互作用保持在多变量分析中(HR=0.38[0.16-0.91])。
结论：高危HR+/HER2-BC患者在等待进一步ET时间研究的结果时，建议在晚上/晚上摄入他莫昔芬。
背景：UNIRAD得到了法国卫生部PHRC2012的资助，并获得了LaLiguecontreleCancer的资助，英国癌症研究中心,无数遗传学，还有诺华.
