MOLECULAR PREDICTIVE TESTING IN OCULAR MELANOMA

描述（由申请人提供）：大多数癌症死亡是由癌症转移或扩散到远处器官引起的。当癌细胞转移到可以被检测到的程度时，体内癌细胞的数量会增加一倍，达到30倍之多，导致大量基因失调的细胞成为肿瘤负担，这些细胞对治疗有很高的抵抗力。最近的研究表明，在最初诊断时从原发肿瘤中获得的分子信息或“生物标志物”可以识别哪些患者可能存在无法检测到的微转移。这将允许对这些高风险患者进行辅助或先发制人的治疗，而不是等待癌症翻倍并对治疗产生更大的耐药性。眼（“葡萄膜”）黑色素瘤就是这样一种需要高度精确的微转移生物标志物的癌症。高达50%的眼黑色素瘤患者会发展为转移性疾病，尽管原发性眼肿瘤得到了成功的治疗，但这种转移性疾病总是致命的，这表明这些患者在原发性眼癌接受治疗时已经存在微转移。转移性疾病通常在2-5年后被发现，这为高危患者提供了辅助全身治疗的机会。在之前的资助期间，开发了一种来自原发肿瘤的高预测性眼黑色素瘤生物标志物。这种生物标志物是一种测定12个标记基因和3个控制基因的坐标表达的方法，即所谓的基因表达谱。计算机程序可以识别单个肿瘤的轮廓模式，可以非常准确地区分哪些患者可能存在微转移。该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。在拨款续期中，通过多中心研究前瞻性地收集和分析大量肿瘤样本，将对该检测方法进行改进和优化，以用于常规临床应用。此外，通过分析大量档案肿瘤标本并进行长期临床随访，将评估和优化该检测方法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患者的护理，也可能改善皮肤黑色素瘤患者的护理，这是一种更常见的癌症。更一般地说，这些研究为目前NIH对复杂慢性疾病（如癌症）的个性化、预测性和先发制人的管理方法的主要重点提供了原则证明。

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.