Biomarker Approaches to Individualizing Systemic Therapy for High Risk Prostate Cancer

全世界每年有100多万新患者被诊断为前列腺癌，其中30多万人被诊断为前列腺癌 男性死于这种疾病。高风险的前列腺癌是绝大多数前列腺癌死亡的原因。关爱的标准 RTOG 92-02设置了高危PCA，这是一项III期试验，证明了疾病复发的减少 放射治疗(RT)加长期雄激素剥夺可改善前列腺癌患者的存活率 治疗(LTADT，28个月)，与RT加短期ADT(STADT，4个月)相比。尽管有了这样的进步， 过度治疗和治疗不足都是这一患者群体的严重临床问题。在这项试验中，50% 的患者最终未被RT+LTADT治愈。如果这部分患者被确认为 预后生物标志物，他们本可以接受更适合他们侵袭性疾病的治疗，包括 化疗和新型靶向药物。另一方面，30%的男性单独接受RT+STADT治疗后痊愈， 本可以避免不必要的24个月的ADT暴露及其毒副作用。令人惊讶的是， 前列腺癌是少数几种未常规使用分子生物标记物进行指导的常见癌症之一。 治疗决定。为了解决这些未得到满足的需求，我们建议开发和验证临床有用的和 接受RT治疗的高危PCa患者的成本效益预后和预测生物标记物，通过应用 临床级别高密度寡核苷酸阵列对来自三个标志性阶段的独特的一组肿瘤样本 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 预测性生物标志物签名识别和验证、生物信息学和决策分析将：(1) 优化整合基因组和临床病理数据的PCa治疗患者的预后分类器 通过RT，可以选择患有高危PCa的男性，他们将在未来的强化治疗中受益 试验，(2)推导和验证一个完整的基因组-临床病理预测LTADT与 STADT，一种治疗持续时间的标志，将允许区分哪些患者应该需要LTADT 与那些可能仅使用Stadt治愈的人进行比较，以及(3)确定健康益处和成本- 使用基因组-临床病理分类器对患有高危前列腺癌的男性患者进行个性化治疗的有效性。 成功完成这些目标将产生具有成本效益的预后和预测性临床级别 在符合CLIA的平台上开发的生物标记物将对临床产生直接影响 对患有高危前列腺癌的男性的管理，改变这些患者目前的治疗模式。

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.