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

抽象的 对内分泌疗法的敏感性的Seter/PR指数，来自内分泌接收器相关的转录 福尔马林固定的石蜡包裹的肿瘤切片，在实验室内和之间高度可重现。 Seter/PR值与雌激素受体和孕酮受体的配体结合活性相关， 预测内分泌治疗后对内分泌疗法和预后的早期药物学反应 姑息和调整治疗环境。其次，set2,3索引调整了seter/pr的测量值 基线预后因素的索引，以评估内分泌相关的转录活性 基线预后风险的背景。这两个指数都为当代添加了独立的预后信息 基因组测试，可能是由于对癌症对内分泌疗法的敏感性的强烈预测。 NSABP B-42试验比较了可调节的内分泌疗法的延长持续时间与LeTrozole持续5个 在完成5年调整内分泌疗法的患者中，与安慰剂相比已有5年。 扩展的内分泌疗法表明，随机化10年后，无疾病的生存率提高了， 尽管在最初的4年中治疗之间没有差异。迄今为止的相关科学 NSABP B-42的研究评估了HOXB13/IL17BR的乳腺癌指数2基因比 表达，70基因的乳房分析，并从21基因中归一化ESR1基因表达得分 复发分数。所有这些都无法在各自的主要分析中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可以进行预测。 我们假设Seter/PR指数将预测Homone中扩展的LeTrozole治疗（ELT）的好处 受体阳性HER2阴性乳腺癌。具体而言，ELT为患者提供了最大的好处 乳腺癌具有现代的内分泌敏感性。我们的主要分析计划是测试是否 1.10和2.10之间的二体/PR指数（包括）与乳腺癌率较低的相互作用显着相互作用 - 延长的letrozole治疗的自由间隔（BCFI）。这代表着从类似的四分之一范围 人口为NSABP B-42。次级分析将评估其他终点，亚型由节点定义 状态或先前的他莫昔芬治疗，以及Seter/PR指数的其他切口。其次，我们将评估SET2,3 每个治疗部门的患者的长期退休风险。 临床上，由于10年 许多患者的治疗时间太长，无法忍受，并且总体上的福利率很小 马龙受体阳性乳腺癌的种群。当前的证据表明，设置器/PR索引是 对内分泌疗法的肿瘤敏感性以及相关预后的独立强烈预测指标 预测谁可能受益于内分泌治疗持续时间的强大潜力。 1