Biomarker Approaches to Individualizing Systemic Therapy for High Risk Prostate Cancer

每年，全世界有超过100万新患者被诊断患有前列腺癌（PCa），并且超过30万人患有前列腺癌。 男人死于这种疾病。高风险PCa占PCa死亡的绝大多数。的护理标准 高危PCa由RTOG 92-02确定，这是一项III期试验，证明了疾病复发的减少 放射治疗加长期雄激素剥夺可改善前列腺癌特异性生存率 治疗（LTADT，28个月），与RT+短期ADT（施塔特，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这些患者群体中的严重临床问题。在这次试验中，50% RT + LTADT治疗无效的患者占80.0%。如果这部分患者被确定为 预后生物标志物，他们可以接受更适合他们的侵袭性疾病的治疗，包括 化疗和新型靶向药物。另一方面，30%的男性仅通过RT +施塔特治愈， 并可以避免24个月不必要的暴露于ADT及其毒副作用。令人惊讶的是， 前列腺癌是少数几种常见的癌症之一，其中分子生物标志物通常不用于指导 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的， 对于接受RT治疗的高危PCa患者，通过应用 临床级高密度寡核苷酸阵列对来自三个标志性阶段的一组独特的肿瘤样本进行检测 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，该分类器整合了接受治疗的PCa患者的基因组和临床病理学数据 与RT，允许选择高风险PCa的男性谁将受益于治疗强化在未来 试验，（2）推导并验证一个综合的基因组学-临床病理学预测因子， 施塔特，一种治疗持续时间特征，可区分需要LTADT的患者 vs.仅用施塔特可能治愈的患者，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前列腺癌患者进行个性化治疗的有效性 这些目标的成功完成将导致具有成本效益的预后和预测性临床等级 在符合CLIA的平台上开发的生物标志物，将对临床 高风险前列腺癌男性的管理，改变这些患者的当前治疗模式。

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.