Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial

摘要 内分泌治疗敏感性的SETER/PR指数测量了从1999年到2000年的内分泌受体相关转录。 福尔马林固定石蜡包埋的肿瘤切片，并且在实验室内和实验室之间具有高度可重复性。 SETER/PR值与雌激素受体和孕激素受体的配体结合活性相关， 预测内分泌治疗的早期药效学反应和内分泌治疗后的预后 姑息治疗和辅助治疗。其次，SET 2，3指标调整了SETER/PR的度量 基线预后因素的指数，使评估内分泌相关的转录活性， 基线预后风险的背景。这两个指数都独立地增加了当代的预后信息。 基因组测试，可能是由于更强的预测癌症的敏感性内分泌治疗。 NSABP B-42试验比较了来曲唑辅助内分泌治疗的持续时间延长， 在已完成5年辅助内分泌治疗的患者中，与安慰剂治疗5年相比， 扩展的内分泌治疗显示从随机化开始10年的无病生存率提高， 尽管在最初的4年中治疗之间没有差异。迄今为止，相关科学 来自NSABP B-42的研究评估了乳腺癌指数2-HOXB 13/IL 17 BR的基因比率 表达，70个基因的MammaPrint检测，以及来自21个基因的标准化ESR1基因表达评分。 复发评分。在其各自的主要分析中，所有研究均未能证明预测性相互作用， 尽管探索性分析表明用更特异的生物标志物进行预测是可能的。 我们假设SETER/PR指数可以预测来曲唑延长治疗（ELT）对激素依赖性心绞痛的疗效。 受体阳性HER2阴性乳腺癌。具体而言，ELT为以下患者提供最大益处： 乳腺癌具有中等程度的内分泌敏感性。我们的主要分析计划是测试 SETER/PR指数在1.10 - 2.10（含）之间与乳腺癌发病率较低具有显著的相互作用- 延长来曲唑治疗的自由间期（BCFI）。这代表了一个类似的四分位数范围 人群至NSABP B-42。次要分析将评价其他终点，由节点定义的亚型 状态或既往他莫昔芬治疗，以及SETER/PR指数的其他临界点。其次，我们将评估SET 2，3 每个治疗组患者晚期复发的长期风险。 临床上，延长内分泌治疗持续时间的获益的可靠预测因素将是有用的，因为10年 对于许多患者来说，治疗时间太长，无法耐受，并且总体上的绝对获益率很小 激素受体阳性乳腺癌患者。目前的证据表明SETER/PR指数是一个 肿瘤对内分泌治疗敏感性的独立强预测因子，以及相关的预后， 预测谁可能从更长时间的内分泌治疗中受益的潜力很大。 1

ABSTRACT The SETER/PR index of sensitivity to endocrine therapy measures endocrine receptor-related transcription from formalin-fixed paraffin-embedded tumor sections and is highly reproducible within and between laboratories. SETER/PR values correlate with the ligand binding activity of estrogen receptors and progesterone receptors, predict early pharmocodynamic response to endocrine therapy and prognosis following endocrine therapy in palliative and adjuvant treatment settings. Secondly, SET2,3 index adjusts the measurements of SETER/PR index for baseline prognostic factors, enabling the assessment of endocrine-related transcriptional activity in the context of baseline prognostic risk. Both indices add independently prognostic information to contemporary genomic tests, likely due to stronger prediction of the cancer’s sensitivity to endocrine therapy. The NSABP B-42 trial compared extended duration of adjuvant endocrine therapy with letrozole for 5 additional years, versus placebo for 5 years, in patients who had completed 5 years of adjuvant endocrine therapy. Extended endocrine therapy demonstrated improved disease-free survival at 10 years from randomization, although there was no difference between treatments during the initial 4 years. To-date, correlative science studies from NSABP B-42 have evaluated the Breast Cancer Index 2-gene ratio of HOXB13/IL17BR expression, the 70-gene MammaPrint assay, and normalized ESR1 gene expression scores from the 21-gene Recurrence Score. All failed to demonstrate predictive interaction in their respective primary analyses, although exploratory analyses suggest that prediction will be possible with a more specific biomarker. We hypothesize that SETER/PR index will predict benefit from extended letrozole therapy (ELT) in hormone receptor-positive HER2-negative breast cancer. Specifically, that ELT offers most benefit to patients whose breast cancer has a moderate degree of endocrine sensitivity. Our primary analysis plan is to test whether SETER/PR index between 1.10 and 2.10 (inclusive) has significant interaction with lower rate of breast cancer- free interval (BCFI) from extended letrozole treatment. This represents an inter-quartile range from a similar population to NSABP B-42. Secondary analyses will evaluate other endpoints, subtypes defined by nodal status or prior tamoxifen treatment, and other cutpoints of SETER/PR index. Secondly, we will evaluate SET2,3 for long-term risk of late relapse in patients from each treatment arm. Clinically, a robust predictor of benefit from extended duration of endocrine therapy will be useful, as 10 years of treatment is too long for many patients to tolerate and the absolute rate of benefit is small in the overall population with hormone receptor-positive breast cancer. Current evidence shows SETER/PR index to be an independently strong predictor of tumoral sensitivity to endocrine therapy, and associated prognosis, with strong potential to predict who is likely to benefit from longer duration of endocrine treatment. 1