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。当转移已经发展到可以检测到的程度时，体内癌细胞的数量已经增加了30倍，导致对治疗具有高度抗性的基因失调细胞的巨大肿瘤负担。最近的研究表明，在最初诊断时从原发肿瘤获得的分子信息或“生物标志物”可以识别哪些患者可能存在不可检测的微转移。这将允许对这些高风险患者进行辅助或先发制人的治疗，而不是等待癌症增加一倍并对治疗产生更大的抵抗力。眼部（“葡萄膜”）黑素瘤是一种需要高度准确的微转移生物标志物的癌症。高达50%的眼部黑色素瘤患者发展转移性疾病，尽管成功治疗了原发性眼部肿瘤，但转移性疾病总是致命的，这表明在治疗原发性眼部癌症时，这些患者中已经存在微转移。转移性疾病通常在2-5年后可检测到，这为高危患者的辅助全身治疗提供了机会之窗。在之前的资助期间，开发了一种高度预测性的原发性肿瘤来源的眼部黑色素瘤生物标志物。该生物标志物是测量12个标志物基因和3个对照基因的协调表达的测定，即所谓的基因表达谱。计算机程序识别个体肿瘤的模式，可以非常准确地区分哪些患者可能存在微转移。该检测是迄今为止该癌症转移的最准确预测因子，可用于指导高危患者的辅助治疗。在资助更新中，将通过多中心研究前瞻性地收集和分析大量肿瘤样本，对该检测方法进行改进和优化，以用于常规临床使用。此外，将通过分析具有长期临床随访的大量存档肿瘤标本，评价并优化该检测试剂盒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，皮肤黑色素瘤是一种更常见的癌症。更一般地说，这些研究为NIH目前的主要重点提供了原则证明，即采用个性化、预测性、先发制人的方法来管理复杂的慢性疾病，如癌症。 公共卫生相关性：对于像癌症这样难以治愈的复杂疾病，越来越清楚的是，一个更可实现和现实的目标是通过将致命疾病转变为长期慢性疾病来延长生存期和改善生活质量。实现这一目标的一个主要策略是个性化的，预测性的，先发制人的癌症护理方法，其中识别出有疾病风险的个体，以便他们可以早期和积极地进行治疗，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.