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 SETER/PR 内分泌治疗敏感性指数测量内分泌受体相关转录 福尔马林固定石蜡包埋的肿瘤切片在实验室内部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以及内分泌治疗后的预后 姑息治疗和辅助治疗设置。其次，SET2,3指数调整SETER/PR的测量 基线预后因素指数，能够评估内分泌相关转录活性 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治疗的敏感性有更强的预测。 NSABP B-42 试验比较了来曲唑延长辅助内分泌治疗持续时间 5 次的效果 在完成 5 年辅助内分泌治疗的患者中，与安慰剂 5 年相比。 延长内分泌治疗证明随机分组后 10 年无病生存率有所提高， 尽管迄今为止，相关科学表明最初 4 年的治疗之间没有差异。 NSABP B-42 研究评估了 HOXB13/IL17BR 的乳腺癌指数 2 基因比率 表达、70 基因 MammaPrint 测定以及 21 基因的归一化 ESR1 基因表达评分 复发评分均未能在各自的主要分析中证明预测相互作用， 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。 我们追求 SETER/PR 指数将预测激素领域延长来曲唑治疗 (ELT) 的益处 具体而言，ELT 为患有 HER2 阴性乳腺癌的患者带来最大益处。 我们的主要分析计划是测试乳腺癌是否具有中等程度的内分泌敏感性。 SETER/PR 指数在 1.10 至 2.10（含）之间与较低的乳腺癌发病率有显着的交互作用 延长来曲唑治疗的游离间隔 (BCFI) 这代表了类似的四分位数范围。 NSABP B-42 人群的二次分析将评估其他终点、由节点定义的亚型。 状态或既往他莫昔芬治疗，以及 SETER/PR 指数的其他切点。其次，我们将评估 SET2,3 每个治疗组患者晚期复发的长期风险。 在临床上，延长内分泌治疗持续时间的获益的强有力预测因素将是有用的，因为 10 年 治疗时间太长，许多患者无法耐受，而且总体获益率很小 目前的证据表明 SETER/PR 指数是激素受体阳性乳腺癌人群的一个指标。 肿瘤对内分泌治疗敏感性以及相关预后的独立强预测因子 预测谁可能从较长时间的内分泌治疗中受益的强大潜力。 1