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TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer.
Breast Cancer Research ( IF 7.4 ) Pub Date : 2020-02-18 , DOI: 10.1186/s13058-020-01258-x
Christos Vaklavas 1, 2 , Brian S Roberts 3 , Katherine E Varley 3 , Nancy U Lin 4 , Minetta C Liu 5 , Hope S Rugo 6, 7 , Shannon Puhalla 8 , Rita Nanda 9 , Anna Maria Storniolo 10 , Lisa A Carey 11 , Mansoor N Saleh 12 , Yufeng Li 1 , Jennifer F Delossantos 1 , William E Grizzle 1 , Albert F LoBuglio 1 , Richard M Myers 3 , Andres Forero-Torres 1 ,
Affiliation  

BACKGROUND In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. METHODS Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. RESULTS Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. CONCLUSION In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. TRIAL REGISTRATION This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.

中文翻译:

TBCRC 002:II期随机,开放标签试验,对新诊断为2/3期激素受体阳性和HER2阴性乳腺癌的绝经后妇女进行术前来曲唑加或不加贝伐单抗治疗。

背景技术在临床前研究中,激素受体阳性乳腺癌中血管内皮生长因子(VEGF)的表达与雌激素非依赖性肿瘤的生长和对内分泌疗法的抵抗力有关。这项研究调查了在术前是否将贝伐单抗(一种抗VEGF的单克隆抗体)添加到来曲唑中是否增强了来曲唑的抗肿瘤活性。方法将新诊断为2或3期雌激素和/或孕激素受体阳性,HER2阴性的绝经后妇女随机分配(2:1)于来曲唑每天2.5 mg口服加贝伐单抗15 mg / kg静脉注射,每3周一次(让/ Bev),并在最终手术前24周每天服用来曲唑2.5 mg PO(Let)。主要目标是臂内病理完全缓解(pCR)率。次要目标是安全,客观反应和降级率。结果75例患者被随机分组​​(Let / Bev n = 50,n = 25)。在Let / Bev组可评估病理反应的45位患者中,有5位(11%; 95%CI,3.7-24.1%)达到了pCR,有4位(9%; 95%CI,2.5-21.2%)发生了微观残留病; 在Let臂上未发现pCR或微观残留病(0%; 95%CI,0-14.2%)。Let / Bev和Let武器的降级率分别为44.4%(95%CI,29.6-60.0%)和37.5%(95%CI,18.8-59.4%)。通常与来曲唑相关的不良事件(潮热,关节痛,疲劳,肌痛)在两组中的发生频率相似。高血压,头痛和蛋白尿仅在Let / Bev臂中可见。在Let / Bev和Let组中,3级和4级不良事件的发生率以及因不良事件导致的停药的发生率分别为18%,8%和16%,而无。一个独立的队列研究开发并证实了一个基于小RNA的分类器,可预测术前对Let / Bev的反应。结论在术前设置中,在来曲唑中加用贝伐单抗的患者的pCR率为11%。单用来曲唑未见pCR。贝伐单抗的掺入有附加毒性。可以根据预处理活检中5种小RNA的水平预测对Let / Bev的反应。试验注册该试验已在ClinicalTrials.gov(标识号:NCT00161291)上注册,该试验首次发布于2005年9月12日,并且已经完成。一个独立的队列研究开发并证实了一个基于小RNA的分类器,可预测术前对Let / Bev的反应。结论在术前设置中,在来曲唑中加用贝伐单抗的pCR率为11%。单用来曲唑未见pCR。贝伐单抗的掺入有附加毒性。可以根据预处理活检中5种小RNA的水平预测对Let / Bev的反应。试验注册该试验已在ClinicalTrials.gov(标识号:NCT00161291)上注册,该试验首次发布于2005年9月12日,并且已经完成。一个独立的队列研究开发并证实了一个基于小RNA的分类器,可预测术前对Let / Bev的反应。结论在术前设置中,在来曲唑中加用贝伐单抗的患者的pCR率为11%。单用来曲唑未见pCR。贝伐单抗的掺入有附加毒性。可以根据预处理活检中5种小RNA的水平预测对Let / Bev的反应。试验注册该试验已在ClinicalTrials.gov(标识号:NCT00161291)上注册,该试验首次发布于2005年9月12日,并且已经完成。贝伐单抗的掺入有附加毒性。可以根据预处理活检中5种小RNA的水平预测对Let / Bev的反应。试验注册该试验已在ClinicalTrials.gov(标识号:NCT00161291)上注册,该试验首次发布于2005年9月12日,并且已经完成。贝伐单抗的掺入有附加毒性。可以根据预处理活检中5种小RNA的水平预测对Let / Bev的反应。试验注册该试验已在ClinicalTrials.gov(标识号:NCT00161291)上注册,该试验首次发布于2005年9月12日,并且已经完成。
更新日期:2020-04-22
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