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

NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估，用于预测延长辅助内分泌治疗持续时间的益处

• 批准号: 10722146
• 负责人: William F Symmans
• 金额: $ 36.97万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722146
• 关键词: Adjuvant Therapy; Biological Assay; CLIA certified; Cancer Center; Cancer Control; Clinical; Data; Disease-Free Survival; Distant; ERBB2 gene; ESR1 gene; Endocrine; Estrogen Receptors; Evaluation; Formalin; Gene Expression; Genes; Genetic Transcription; Genomics; Laboratories; Letrozole; Ligand Binding; Malignant Neoplasms; Measurement; Measures; Molecular; National Surgical Adjuvant Breast and Bowel Project; Neoadjuvant Therapy; Nodal; Palliative Care; Paraffin Embedding; Pathologic; Patients; Performance; Pharmacodynamics; Placebos; Population; Primary Neoplasm; Probability; Progesterone Receptors; Prognosis; Prognostic Factor; Proliferating; Publications; Publishing; RNA; Randomized; Recurrence Score; Relapse; Reporting; Reproducibility; Residual state; Risk; Sampling; Science; Tamoxifen; Testing; Tissue Sample; Validation; adjuvant endocrine therapy; breast cancer diagnosis; chemotherapy; hormone receptor-positive; hormone therapy; improved; indexing; malignant breast neoplasm; molecular phenotype; molecular subtypes; patient subsets; predictive test; prognostic; prognostic index; randomized placebo controlled trial; receptor; response; secondary analysis; side effect; specific biomarkers; treatment arm; trial comparing; tumor; validation studies

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

摘要 内分泌治疗敏感性的SETER/PR指数衡量内分泌受体相关转录 福尔马林固定的石蜡包埋的肿瘤切片，在实验室内和实验室之间具有高度的重复性。 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物动力学反应和内分泌治疗后的预后 姑息和辅助治疗设置。其次，SET2、3指数对SETER/PR的测量进行调整 基线预后因素指数，使评估内分泌相关转录活动成为可能 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测信息 基因组测试，可能是因为对癌症对内分泌治疗的敏感性有更强的预测。 NSABP B-42试验将延长的辅助内分泌治疗与来曲唑进行了5次额外的比较 在完成了5年辅助内分泌治疗的患者中，服用5年的辅助性内分泌药物与5年的安慰剂相比。 扩展内分泌治疗显示，随机治疗后10年的无病生存率有所提高。 尽管在最初的4年中，不同的治疗方法之间没有差别。时至今日，相关科学 NSABP B-42的研究评估了乳腺癌指数2-HOXB13/IL17BR的基因比率 表达，70基因的MammaPrint试验，以及21基因的归一化ESR1基因表达分数 重复性分数。所有人在各自的初步分析中都未能证明预测性相互作用， 尽管探索性分析表明，使用更具体的生物标志物进行预测是可能的。 我们假设SETER/PR指数将预测延长来曲唑治疗(ELT)在激素方面的益处 受体阳性，HER2阴性的乳腺癌。具体地说，ELT为以下患者提供了最大好处 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和2.10之间(含)与较低的乳腺癌发病率有显著的交互作用- 延长来曲唑治疗的自由间期(BCFI)。这表示四分位之间的范围从类似的 居民请到NSABP B-42。二次分析将评估节点定义的其他端点、子类型 他莫昔芬治疗情况或治疗前，以及SETER/PR指数的其他临界点。其次，我们将评估SET2，3 用于每个治疗组患者晚期复发的长期风险。 在临床上，延长内分泌治疗疗程的可靠预测指标将是有用的，例如10年。 治疗的时间太长，许多患者无法忍受，总体上绝对受益率很小 患有荷尔蒙受体阳性乳腺癌的人群。目前的证据表明，SETER/PR指数是一个 独立地强烈预测肿瘤对内分泌治疗的敏感性，并与预后相关 预测谁可能从更长时间的内分泌治疗中受益的可能性很大。 1