Integrative prediction models for metastasis risk in colon cancer

描述（由申请人提供）：虽然III期结肠癌的辅助化疗可带来总体生存获益，但即使没有辅助治疗，42 - 44%的III期患者也不会在5年内复发。相反，临床试验未能证明辅助化疗对II期结肠癌的总体益处;然而，一部分高危患者可能受益于辅助治疗。因此，非常需要一种确定复发风险和相应的全身治疗获益可能性的准确和可靠的方法。 我们最近开发了一种基于小鼠结肠癌细胞的转移生物学的新型基因表达标签（“34-基因标签”），能够将结肠癌患者组分为低复发风险和高复发风险。这样的基因签名可以允许更适当地选择接受或不接受辅助化疗的患者，从而使那些处于低风险的III期患者能够避免潜在的发病率、偶尔的死亡率和系统治疗的确定的经济费用，同时提高II期患者的生存率。 为了准确地识别个人风险，临床，人口统计学，病理和体细胞突变数据都必须与基因表达相结合;为了整合这些不同的数据，我们建议进行研究，以开发一种综合转移风险预测模型，允许整合不同类型的数据。我们将验证该模型的预测能力，并在未来五年内探索平台，前瞻性地应用该工具作为指导结肠癌患者治疗决策的方法。这项重点研究将在临床试验之前，在相对较短的时间内将我们的分子发现转化为临床应用。 该提案的长期目标是从不同类型的数据中开发临床有用的转移评分，其可以应用于II期和III期结肠癌患者，以降低死亡率、发病率和与结肠癌和结肠癌治疗相关的成本。为此，我们的具体目标如下：1）建立结肠癌转移风险综合预测模型; 2）确定34基因转移评分临床试验的最佳平台;和3）在存档组织上以盲法测试优化的预后标记，以确定测试的稳健性以及转移风险评分是否应提前到前瞻性临床试验中，以预测II期和III期患者的结局。 公共卫生相关性：虽然III期结肠癌的辅助化疗可带来总体生存益处，但即使没有辅助治疗，42%至44%的III期患者也不会在5年内复发。相反，临床试验未能证明辅助化疗对II期结肠癌的总体益处;然而，一部分高危II期结肠癌患者可能从全身治疗中获益。我们建议开发一个综合模型来预测结肠癌转移的风险，从而确定最有可能从辅助化疗中获益的患者，目标是使低风险患者避免潜在的发病率，偶尔的死亡率和系统治疗的明确经济费用，同时提高高风险患者的生存率。

DESCRIPTION (provided by applicant): While adjuvant chemotherapy for stage III colon cancer results in an overall survival benefit, 42 to 44% of stage III patients will not recur in five years even without adjuvant treatment. Conversely, clinical trials have failed to demonstrate an overall benefit of adjuvant chemotherapy for stage II colon cancer; however, a subset of high-risk patients may benefit from adjuvant treatment. Thus, an accurate and reliable method of determining risk of recurrence, and corresponding likelihood of benefit of systemic therapy, is greatly needed. We have recently developed a novel gene expression signature ("34-gene signature") based on the metastatic biology of mouse colon cancer cells, capable of segregating colon cancer patient groups into low and high risk of recurrence. A gene signature such as this may allow for more appropriate selection of patients to receive or not receive adjuvant chemotherapy, thus enabling those phase III patients at low risk to avoid the potential morbidity, occasional mortality, and definite financial expense of systemic therapy, while improving the survival of phase II patients. To accurately identify personal risk, clinical, demographic, pathologic, and somatic mutation data all must be incorporated with gene expression; to incorporate these various data, we propose to conduct research to develop an integrative metastatic risk prediction model that allows for integration of diverse types of data. We will validate the predictive power of this model and, over the next five years, explore platforms to apply this tool prospectively as an approach to guide treatment decisions in colon cancer patients. This focused study will translate our molecular findings to clinical application in a relatively short time, in advance of clinical trials. The long-term goal for this proposal is to develop a clinically useful metastasis score from diverse type of data that can be applied to stage II and III colon cancer patients for the purpose of reducing mortality, morbidity, and the cost associated with colon cancer and colon cancer treatment. To this end, our specific aims are as follows: 1) develop an integrative metastasis risk prediction model for colon cancer; 2) determine the optimum platform for the 34-gene metastasis score clinical test; and 3) test the optimized prognosis signature in a blinded fashion on archival tissue, to determine the robustness of the test and whether the metastasis risk score should be advanced to a prospective clinical trial to predict outcomes in stage II and III patients. PUBLIC HEALTH RELEVANCE: While adjuvant chemotherapy for stage III colon cancer results in an overall survival benefit, 42 to 44% of stage III patients will not recur in five years even without adjuvant treatment. Conversely, clinical trials have failed to demonstrate an overall benefit of adjuvant chemotherapy for stage II colon cancer; however, a subset of high-risk stage II colon cancer patients may benefit from systemic therapy. We propose to develop an integrative model for predicting risk of colon cancer metastasis and thereby identifying patients most likely to benefit from adjuvant chemotherapy, with the goal of sparing low-risk patients the potential morbidity, occasional mortality, and definite financial expense of systemic therapy, while improving the survival of high-risk patients.