TERT epigenetic and genomic variants in stage II melanoma as biomarkers of outcome

II 期黑色素瘤中的 TERT 表观遗传和基因组变异作为结果的生物标志物

• 批准号: 10577949
• 负责人: DAVID POLSKY
• 金额: $ 23.77万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577949
• 关键词: Academy; Adjuvant; Adjuvant Therapy; American; Automobile Driving; BRAF gene; Biological Markers; Categories; Classification; Clinic; Clinical; Collaborations; Colon Carcinoma; Cutaneous Melanoma; DNA; Data; Data Set; Decision Making; Dermatology; Diagnostic Neoplasm Staging; Disease; Enrollment; Epigenetic Process; Event; Excision; Gene Mutation; Genes; Germ-Line Mutation; Goals; Guidelines; Histopathology; Immunotherapeutic agent; Immunotherapy; Infiltration; Inherited; Measurement; Measures; Metastatic Melanoma; Methods; Methylation; Mitosis; Modeling; Molecular; Multicenter Trials; Mutation; NF1 gene; National Comprehensive Cancer Network; Nucleic Acid Regulatory Sequences; Operative Surgical Procedures; Outcome; Pathogenicity; Patient Selection; Patient risk; Patients; Pharmaceutical Preparations; Placebos; Population; Primary Neoplasm; Probability; Prognostic Marker; Promoter Regions; Prospective cohort; Publications; Publishing; RNA-Directed DNA Polymerase; Recommendation; Recurrence; Recurrent tumor; Resected; Risk; Sampling; Site; Staging System; Standardization; Subgroup; Techniques; Telomerase; Testing; Therapeutic; Thick; Toxic effect; Treatment Effectiveness; Treatment-related toxicity; Tumor-Derived; Ulcer; Validation; Variant; anti-PD-1; biomarker validation; candidate marker; clinical biomarkers; cohort; cost; disease prognosis; follow-up; genetic variant; high risk; improved; interest; malignant breast neoplasm; melanoma; molecular pathology; mutational status; neoplastic cell; overtreatment; pembrolizumab; placebo group; predictive modeling; prevent; prognostic; prognostic tool; prognostic value; prognostication; promoter; prospective; randomized placebo-controlled clinical trial; randomized, clinical trials; relapse risk; standard of care; survival outcome; tool; tumor; validation studies

PROJECT SUMMARY In contrast to the dramatic progress in the treatment of metastatic melanoma, prognostication for localized melanoma has not advanced beyond the histomorphological measures of tumor thickness and ulceration that comprise the staging system. The prognostic accuracy of these measures for locally advanced, node-negative melanoma (Stage II) is generally poor. Post-surgical recurrence rates for stage II melanoma vary between 24% for stage IIA to 46% for stage IIC. In contrast to breast and colon cancers, where molecular pathology tests are routinely used to improve the accuracy of disease prognostication over routine histopathology, there are no validated molecular tests for primary melanoma, despite claims from commercial entities to the contrary. Recently, data from a randomized, placebo-controlled clinical trial of pembrolizumab, an anti-PD-1 immunotherapeutic agent, was used to support its approval as adjuvant therapy for surgically resected stage IIB and IIC melanoma. Although recurrence-free survival (RFS) at the 18-month post-surgical follow up showed a statistically significant benefit associated with permbrolizumab, 11 patients needed to be treated to prevent one recurrence. This is because the RFS in the placebo group is fairly high. Given the potential toxicity of immunotherapy, and its variable efficacy and high cost, we need more accurate tools to appropriately select patients for treatment who have a high probability of tumor recurrence, and spare surgically cured patients the risks of overtreatment. A major obstacle to this approach is the lack of validated biomarkers that accurately distinguish between high- and low-risk patients. Several publications as well as our own Preliminary Data support alterations of the upstream regulatory region of the telomerase reverse transcriptase gene (TERT) as potentially high-value prognostic biomarkers in melanoma. These alterations include hotspot mutations in the promoter region (possibly cooperating with an inherited germline variant), and/or methylation of an upstream regulatory region. In addition, data from large published studies suggest that NRAS, and possibly BRAF mutations may each be associated with decreased survival in stage II melanomas. In some datasets the effect is stronger if the mutations co-occur with TERT promoter mutations. The current proposal will test the hypothesis that adding molecular measurements of the upstream regulatory regions of TERT and mutations in NRAS or BRAF, either singly or in combination, will improve the accuracy of a recurrence prediction model for stage II melanoma. Successful creation of an improved model will generate interest from outside groups to collaborate on subsequent larger, multicenter validation and clinical utility studies where the biomarkers may eventually be used to assist in treatment decision-making.

项目概要 与转移性黑色素瘤治疗的巨大进展相反，局部黑色素瘤的预后 黑色素瘤尚未超出肿瘤厚度和溃疡的组织形态学测量范围 包括分期系统。这些措施对于局部晚期、淋巴结阴性的预后准确性 黑色素瘤（第二期）一般情况较差。 II 期黑色素瘤的术后复发率在 24% 之间 IIA 期为 46%，IIC 期为 46%。与乳腺癌和结肠癌相反，分子病理学测试 与常规组织病理学相比，常规用于提高疾病预测的准确性，但没有 尽管商业实体声称相反，但对原发性黑色素瘤的分子测试进行了验证。 最近，来自一项抗 PD-1 药物派姆单抗 (pembrolizumab) 的随机、安慰剂对照临床试验的数据 免疫治疗剂，用于支持其批准作为手术切除 IIB 期的辅助治疗 和 IIC 黑色素瘤。尽管术后 18 个月随访显示无复发生存率 (RFS) 与 permbrolizumab 相关的统计显着益处，11 名患者需要接受治疗才能预防一种 复发。这是因为安慰剂组的 RFS 相当高。鉴于潜在的毒性 免疫疗法的疗效多变且成本高，我们需要更准确的工具来适当选择 肿瘤复发概率高的患者接受治疗，避免手术治愈的患者 过度治疗的风险。这种方法的一个主要障碍是缺乏经过验证的生物标志物，可以准确地 区分高危和低危患者。 一些出版物以及我们自己的初步数据支持上游监管区域的变更 端粒酶逆转录酶基因（TERT）作为潜在的高价值预后生物标志物 黑色素瘤。这些改变包括启动子区域的热点突变（可能与 遗传性种系变异）和/或上游调控区域的甲基化。此外，来自大数据 已发表的研究表明，NRAS 和可能的 BRAF 突变可能均与下降有关 II 期黑色素瘤的存活率。在某些数据集中，如果突变与 TERT 同时发生，效果会更强 启动子突变。当前的提案将检验添加分子测量的假设 TERT 的上游调控区以及 NRAS 或 BRAF 的突变，无论是单独还是组合，都会 提高 II 期黑色素瘤复发预测模型的准确性。成功创建一个改进的 模型将引起外部团体的兴趣，以合作进行后续更大规模的多中心验证和 临床效用研究，生物标志物最终可用于协助治疗决策。