MOLECULAR PREDICTIVE TESTING IN OCULAR MELANOMA

描述(申请人提供)：大多数癌症死亡是由癌症转移或扩散到远处器官引起的。当转移进展到可以被检测到的程度时，体内的癌细胞数量已经翻了一番，翻了30倍，导致高度抵抗治疗的基因放松管制的细胞产生了巨大的肿瘤负担。最近的工作表明，在最初诊断时从原发肿瘤获得的分子信息或生物标记物可以识别哪些患者可能存在无法检测到的微转移。这将允许对这些高危患者进行辅助或先发制人的治疗，而不是等待癌症增加一倍，变得对治疗更具抵抗力。眼(葡萄膜)黑色素瘤就是这样一种癌症，需要一种高精度的微转移生物标志物。高达50%的眼部黑色素瘤患者发展为转移性疾病，尽管原发眼部肿瘤治疗成功，但转移性疾病总是致命的，这表明当原发眼部肿瘤接受治疗时，这些患者中已经存在微转移。转移性疾病通常在2-5年后可被发现，这为高危患者的辅助系统治疗提供了机会之窗。一种高度可预测的眼部黑色素瘤生物标记物来源于原发瘤，是在上一次资助期间开发的。这一生物标记物是一种测量12个标记基因和3个对照基因的协同表达的分析方法，即所谓的基因表达谱。识别单个肿瘤轮廓中的模式的计算机程序可以非常准确地区分哪些患者可能存在微转移。这项检测是迄今为止最准确的癌症转移预测指标，可用于指导高危患者的辅助治疗。在资助续期中，将通过多中心研究前瞻性地收集和分析大量肿瘤样本，对该分析进行提炼和优化，以供常规临床使用。此外，该分析将通过分析一大组有长期临床随访的存档肿瘤标本来评估和优化其在皮肤黑色素瘤中的预后价值。这项研究的结果可能会改善眼部黑色素瘤和皮肤黑色素瘤的患者护理，皮肤黑色素瘤是一种更常见的癌症。更广泛地说，这些研究为NIH目前主要强调个性化、预测性、先发制人的方法来管理复杂的慢性病(如癌症)提供了原则性证据。 与公共卫生相关：对于癌症等难以找到治疗方法的复杂疾病，越来越明显的是，一个更可实现和更现实的目标是通过将致命疾病转变为长期慢性病来延长生存时间和提高生活质量。实现这一目标的一个主要战略是对癌症护理采取个性化、预测性和先发制人的方法，即识别出有患病风险的个人，以便他们能够及早和积极地接受治疗，而不是等待疾病发展到更严重的形式。这项研究提案代表了这一策略的应用，并为其他癌症的类似方法提供了原则证明。

DESCRIPTION (provided by applicant): Most cancer deaths are caused by metastasis, or spread, of the cancer to distant organs. By the time that metastasis has advanced to the point where it can be detected, the number of cancer cells in the body has doubled as many as 30 times, resulting in a large tumor burden of genetically deregulated cells that are highly resistant to treatment. Recent work has shown that molecular information or "biomarkers" obtained from the primary tumor at the time of initial diagnosis can identify which patients are likely to harbor undetectable micrometastasis. This would allow adjuvant, or preemptive, treatment of these high-risk patients rather than waiting for the cancer to double many times and become more resistant to therapy. Ocular ("uveal") melanoma is one such cancer where a highly accurate biomarker of micrometastasis is needed. Up to 50% of ocular melanoma patients develop metastatic disease that is invariably fatal despite successful treatment of the primary eye tumor, indicating that micrometastasis was already present in those patients when the primary eye cancer was treated. Metastatic disease usually becomes detectable 2-5 years later, which provides a window of opportunity for adjuvant systemic therapy in high risk patients. A highly predictive biomarker for ocular melanoma derived from the primary tumor was developed during the previous funding period. This biomarker is an assay that measures the coordinate expression of 12 marker genes and 3 control genes, a so-called gene expression profile. Computer programs that recognize patterns in the profile from individual tumors can distinguish with great accuracy which patients are likely to harbor micrometastasis. This assay is the most accurate predictor of metastasis to date for this cancer and can be used to guide adjuvant therapy in high risk patients. In the grant renewal, the assay will be refined and optimized for routine clinical use by collecting and analyzing a large number of tumor samples prospectively through a multi-center study. Further, the assay will be evaluated and optimized for its prognostic value in cutaneous melanoma by analyzing a large set of archival tumor specimens with long clinical follow-up. The results of this research are likely to improve patient care in ocular melanoma and perhaps in cutaneous melanoma, which is a much more common cancer. More generally, these studies provide a proof of principle for the current major emphasis of the NIH on a personalized, predictive, preemptive approach to the management of complex chronic diseases such as cancer. PUBLIC HEALTH RELEVANCE: For complex diseases such as cancer, where cures have been difficult to find, it is becoming increasingly clear that a more achievable and realistic goal is to prolong survival and improve quality of life by converting a fatal disease into a long-term, chronic disease. A major strategy for achieving this goal is a personalized, predictive, preemptive approach to cancer care, in which individuals at risk for disease are identified so that they can be treated early and aggressively, rather than waiting for the disease to advance to a more severe form. This research proposal represents an application of this strategy and provides a proof of principle for similar approaches in other cancers.