Biomarker Approaches to Individualizing Systemic Therapy for High Risk Prostate Cancer

高危前列腺癌个体化系统治疗的生物标志物方法

基本信息

批准号：
10524143
负责人：
Felix Yi-Chung Feng
金额：
$ 5.43万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10524143
关键词：
Acute Address Bioinformatics Biological Markers CLIA certified Cancer Patient Cardiovascular system Cessation of life Clinical Clinical Management Data Decision Analysis Decision Making Diagnosis Disease Event Exposure to Fracture Future Gene Expression Profile Genomics Goals Guidelines Health Benefit Impaired cognition Malignant Neoplasms Malignant neoplasm of prostate Mental Depression National Comprehensive Cancer Network Oligonucleotide Microarrays Operative Surgical Procedures Pathologic Patients Phase Prognostic Marker Prostate Publishing Radiation Therapy Oncology Group Radiation therapy Recurrence Research Sampling Sexual Dysfunction Systemic Therapy Therapeutic Tissues Toxic effect Use Effectiveness Validation androgen deprivation therapy arm base biomarker panel biomarker signature cancer biomarkers chemotherapy clinical predictors clinical translation cost cost effective cost effectiveness density genetic signature genomic signature high risk improved markov model men molecular marker new therapeutic target novel overtreatment patient population patient subsets personalized medicine phase III trial predicting response predictive marker predictive modeling predictive signature prognostic prognostic signature prognostic tool prognostic value prostate cancer risk randomized trial response side effect specific biomarkers standard of care targeted agent therapy duration treatment response treatment strategy tumor

项目摘要

Each year, over 1 million new patients are diagnosed with prostate cancer (PCa) worldwide, and over 300,000 men die of this disease. High risk PCa accounts for the vast majority of PCa deaths. The standard of care for high risk PCa was set by RTOG 92-02, a phase III trial that demonstrated a reduction in disease recurrence and an improvement in PCa-specific survival with radiation therapy (RT) plus long-term androgen deprivation therapy (LTADT, 28 months), compared to RT with short-term ADT (STADT, 4 months). Despite this advance, both overtreatment and undertreatment are acute clinical problems in this patient population. In this trial, 50% of patients were ultimately not cured with RT + LTADT. If this subset of patients had been identified with prognostic biomarkers, they could have received therapy more suited to their aggressive disease, including chemotherapy and novel targeted agents. On the other hand, 30% of men were cured with RT + STADT alone, and could have avoided 24 unnecessary months of exposure to ADT and its toxic side effects. Surprisingly, PCa is one of the few common cancers in which molecular biomarkers are not routinely used to guide therapeutic decisions. To address these unmet needs, we propose to develop and validate clinically useful and cost-effective prognostic and predictive biomarkers for high-risk PCa patients treated with RT, by applying a clinical-grade high-density oligonucleotide array on a unique set of tumor samples from three landmark phase III trials (RTOG 92-02, 99-02, and 94-13). Our research team, combining expertise in PCa, prognostic and predictive biomarker signature identification and validation, bioinformatics, and decision analysis, will: (1) Optimize a prognostic classifier that integrates genomic and clinicopathologic data for PCa patients treated with RT, allowing selection of men with high-risk PCa who would benefit from treatment intensification in future trials, (2) Derive and validate an integrated genomic-clinicopathologic predictor of response to LTADT vs. STADT, a therapeutic duration signature that would allow differentiation of patients who should require LTADT vs. those who are likely to be cured with STADT alone, and (3) Determine the health benefits and cost- effectiveness of using genomic-clinicopathologic classifiers to personalize therapy in men with high-risk PCa. Successful completion of these aims would result in cost-effective prognostic and predictive clinical-grade biomarkers developed on a CLIA-compliant platform that would have an immediate impact on the clinical management of men with high-risk PCa, transforming current treatment paradigms for these patients.

全球每年有超过 100 万新患者被诊断患有前列腺癌 (PCa)，并且超过 300,000 男性死于这种疾病。高风险 PCa 占 PCa 死亡的绝大多数。护理标准 RTOG 92-02 设定了高风险 PCa，这是一项 III 期试验，证明疾病复发率有所降低通过放射治疗 (RT) 加长期雄激素剥夺可改善 PCa 特异性生存治疗（LTADT，28 个月），与 RT 联合短期 ADT（STADT，4 个月）相比。尽管取得了这一进展，过度治疗和治疗不足都是该患者群体中严重的临床问题。在本次试验中，50% 的患者最终未能通过 RT + LTADT 治愈。如果这部分患者已被确定为预后生物标志物，他们本可以接受更适合其侵袭性疾病的治疗，包括化疗和新型靶向药物。另一方面，仅使用 RT + STADT 即可治愈 30% 的男性，并可以避免 24 个月不必要的 ADT 暴露及其毒副作用。出奇， PCa 是少数不常规使用分子生物标志物来指导的常见癌症之一治疗决定。为了解决这些未满足的需求，我们建议开发和验证临床上有用且通过应用一种方法，为接受 RT 治疗的高危 PCa 患者提供具有成本效益的预后和预测生物标志物临床级高密度寡核苷酸阵列，针对来自三个里程碑阶段的一组独特肿瘤样本 III 试验（RTOG 92-02、99-02 和 94-13）。我们的研究团队结合了 PCa、预后和预测性生物标志物特征识别和验证、生物信息学和决策分析将：(1) 优化预后分类器，整合治疗 PCa 患者的基因组和临床病理数据与 RT 一起，允许选择患有高风险 PCa 的男性，他们将在未来从强化治疗中受益试验，(2) 推导并验证 LTADT 与 LTADT 反应的综合基因组临床病理学预测因子。 STADT，一种治疗持续时间特征，可以区分需要 LTADT 的患者与那些可能仅通过 STADT 治愈的患者相比，以及 (3) 确定健康益处和成本- 使用基因组临床病理分类器对高危 PCa 男性进行个体化治疗的有效性。成功完成这些目标将带来具有成本效益的预后和预测性临床级别在符合 CLIA 标准的平台上开发的生物标志物将对临床产生直接影响对患有高危前列腺癌的男性进行管理，改变了这些患者目前的治疗模式。