Lifestyle Factors and Survival Outcomes for Colorectal Cancer Molecular Subtypes

结直肠癌分子亚型的生活方式因素和生存结果

• 批准号: 8618874
• 负责人: AMANDA IRENE PHIPPS
• 金额: $ 9.67万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-13 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618874
• 关键词: Address; Advisory Committees; Alcohol consumption; Area; BRAF gene; Biological; Body mass index; Cancer Biology; Cancer Patient; Cancer Prognosis; Carcinoma; Characteristics; Classification; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Colon Carcinoma; Colorectal; Colorectal Cancer; Complement; CpG Island Methylator Phenotype; CpG Islands; Data; Development; Diagnosis; Diagnostic; Disease; Disease-Free Survival; Drug usage; Educational Curriculum; Enrollment; Environment; Epidemiologic Methods; Epidemiologist; Epidemiology; Evaluation; Fred Hutchinson Cancer Research Center; Future; Goals; Grant; Heterogeneity; Home environment; Individual; Joints; Journals; K-Series Research Career Programs; KRAS2 gene; Knowledge; Laboratory Scientists; Malignant Neoplasms; Mentors; Mentorship; Methodology; Methylation; Microsatellite Instability; Molecular; Mutation; NCI Center for Cancer Research; Non-Steroidal Anti-Inflammatory Agents; North Central Cancer Treatment Group; Observational Study; Outcome; Outcomes Research; Pathology; Pathway interactions; Patients; Pharmacoepidemiology; Phase; Phenotype; Physical activity; Play; Population Study; Predictive Factor; Prognostic Factor; Public Health; Randomized Clinical Trials; Recurrence; Registries; Research; Research Activity; Research Personnel; Research Project Grants; Resources; Risk Factors; Role; Running; Science; Scientist; Seasons; Series; Smoking; Smoking History; Somatic Mutation; Source; Specialist; Staging; Teaching Materials; Testing; Training Activity; Translating; Tumor Markers; Universities; Vital Status; Washington; Work; adenoma; base; cancer diagnosis; cancer epidemiology; cancer risk; cancer therapy; career; career development; clinical epidemiology; clinical practice; clinically relevant; cohort; colon cancer family registry; design; disorder subtype; doctoral student; empowered; epidemiologic data; epidemiology study; experience; follow-up; interest; lifestyle factors; malignant breast neoplasm; mutant; oncology; outcome forecast; population based; pre-doctoral; prognostic; programs; randomized trial; skills; stem; tool; treatment trial; triple-negative invasive breast carcinoma; tumorigenesis; validation studies

DESCRIPTION (provided by applicant): The overarching goal motivating my research has been to characterize biological heterogeneity in cancer and its impact on cancer epidemiology. As an epidemiology doctoral student at the University of Washington (UW), I developed a research portfolio characterizing risk factors for triple-negative breast cancer - a poor prognosis poorly understood breast cancer subtype. Following my graduation from UW in 2010, my research transitioned from the study of breast cancer to the study of colorectal cancer (CRC), and from the study of cancer risk to the study of cancer survival. In extending my research to the study of CRC survival, the goal motivating my work has remained the same but my specific research interests have evolved to encompass areas in which I have not previously been involved. In particular, I have developed an interest in clinical epidemiology and in studies based in the clinical trial setting. The research and training activities proposed for this career development award will allow me to gain the skills, experience, and collaborations necessary to launch an independent academic career in cancer survival, and to transition my research into a more translational realm. Unifying my predoctoral, postdoctoral, and proposed research is an interest in the relationship between cancer biology and cancer epidemiology. Like breast cancer, CRC is a heterogeneous disease that can be classified into biologically distinct subtypes. Unlike breast cancer, however, molecularly-defined subtypes of CRC have not yet been widely characterized. Molecular classifications for CRC subtypes were recently proposed, using information on four tumor markers: microsatellite instability (MSI), CpG island methylation (CIMP), mutations in BRAF, and mutations in KRAS. Different combinations of these four markers are thought to reflect distinct pathways of CRC development. Biological distinctions between CRC subtypes defined by these markers also likely translate to differences in prognosis and prognostic factors, although such differences have not yet been well described. The research objectives of this proposal are to assess the prognostic significance of CRC molecular subtypes defined by joint MSI / CIMP / BRAF / KRAS status, and to assess the impact of modifiable lifestyle factors on clinical outcomes after CRC diagnosis for patients with these subtypes of disease. The ultimate goal of this research is to identify factors that will have clinical relevance in informing CRC survival. In pursuit of these research objectives, I will leverage data from two very rich but very different studies with which I have existing collaborations: the Seattle Colon Cancer Family Registry (S-CCFR) and a phase III randomized clinical trial of stage III colon cancer (N0147). Both studies are well annotated with epidemiologic data and information on MSI, CIMP, and BRAF and KRAS mutation status in CRC patients. Through the proposed research activities, I will use data from both studies to characterize differences in modifiable lifestyle factors (Aim 1a) and survival (Aim 1b) across four CRC subtypes defined by joint MSI / CIMP / BRAF / KRAS status. I will also use these data to assess the relationship between several lifestyle factors (e.g., smoking, alcohol consumption, physical activity) and survival in patients with these four subtypes of CRC (Aims 2-3). Conducting parallel analyses in an observational study (S-CCFR) and in a clinical trial (N0147) will provide opportunities for comparing and contrasting results across study settings with complementary strengths and limitations. This approach of parallel and complementary analyses will also provide me with experience in working with clinical outcomes data collected in different study settings and in working with clinical trials. In conducting the proposed research, will benefit from the rich resources and collaborative environment of the Fred Hutchinson Cancer Research Center (FHCRC). As one of the world's leading cancer research centers, the FHCRC is home to a large number of distinguished epidemiologists, clinical researchers, and laboratory scientists who can provide directed guidance. In particular, I will benefit from the mentorship of Dr. Polly Newcomb (primary mentor), who has considerable expertise in CRC epidemiology and observational studies of cancer survival and who is PI of the S-CCFR. I will also be mentored by Dr. Noel Weiss (co-mentor), who is a seasoned expert in epidemiologic methods and clinical epidemiology. For further guidance, I have enlisted the expertise of an external advisory committee, comprised of specialists in the conduct of oncology clinical trials (Dr. Steven Alberts, who is also the N0147 Study Chair), in the conduct of correlative science across study settings (Dr. Paul Limburg), in the epidemiology and treatment of CRC (Dr. Andrew Chan), and in CRC pathology (Dr. Christophe Rosty). To complement my research and further my career development, I will also work with Dr. Weiss to develop and implement materials for teaching a graduate-level epidemiologic methods course series. The hands-on experience and expertise gained through this project will be supplemented by formal coursework in outcomes research, pharmacoepidemiology, and clinical trial methodologies, and by regular research seminars offered through the FHCRC, the UW, and other programs. Both the FHCRC and the UW place particular emphasis on providing early career scientists with career development opportunities, offering formal mechanisms for mentoring, regular career development seminars, journal clubs, curriculum evaluation, and other networking resources. Thus, the environment of the FHCRC, and the closely affiliated UW, provides an excellent setting in which to launch my independent academic research career.

描述（由申请人提供）：我的研究的首要目标是表征癌症的生物异质性及其对癌症流行病学的影响。作为华盛顿大学 (UW) 的流行病学博士生，我开发了一个研究组合，描述了三阴性乳腺癌的危险因素——一种预后不良、人们对乳腺癌亚型知之甚少的疾病。 2010年从威斯康星大学毕业后，我的研究从乳腺癌研究转向结直肠癌（CRC）研究，从癌症风险研究转向癌症生存研究。在将我的研究扩展到结直肠癌生存的研究时，我工作的目标保持不变，但我的具体研究兴趣已经发展到涵盖我以前从未参与过的领域。特别是，我对临床流行病学和基于研究的研究产生了兴趣 在临床试验环境中。为该职业发展奖提议的研究和培训活动将使我获得必要的技能、经验和合作，以开展癌症生存方面的独立学术生涯，并将我的研究转变为更具转化性的领域。将我的博士前、博士后和拟议的研究统一起来是对癌症生物学和癌症流行病学之间关系的兴趣。与乳腺癌一样，结直肠癌是一种异质性疾病，可分为生物学上不同的亚型。然而，与乳腺癌不同的是，分子定义的 CRC 亚型尚未得到广泛表征。最近提出了 CRC 亚型的分子分类，使用四种肿瘤标志物的信息：微卫星不稳定性 (MSI)、CpG 岛甲基化 (CIMP)、BRAF 突变和 KRAS 突变。这四种标记的不同组合被认为反映了结直肠癌发展的不同途径。由这些标志物定义的 CRC 亚型之间的生物学差异也可能转化为预后和预后因素的差异，尽管这种差异尚未得到很好的描述。本提案的研究目标是评估由联合 MSI / CIMP / BRAF / KRAS 状态定义的 CRC 分子亚型的预后意义，并评估可改变的生活方式因素对患有这些亚型疾病的患者在 CRC 诊断后临床结果的影响。这项研究的最终目标是确定影响因素 告知 CRC 生存的临床相关性。为了实现这些研究目标，我将利用来自我现有合作的两项非常丰富但截然不同的研究的数据：西雅图结肠癌家族登记处 (S-CCFR) 和 III 期结肠癌的 III 期随机临床试验 ( N0147）。这两项研究都详细注释了 CRC 患者的流行病学数据和 MSI、CIMP、BRAF 和 KRAS 突变状态信息。通过拟议的研究活动，我将使用这两项研究的数据来描述四个方面可改变的生活方式因素（目标 1a）和生存率（目标 1b）的差异。 由联合 MSI/CIMP/BRAF/KRAS 状态定义的 CRC 子类型。我还将使用这些数据来评估几种生活方式因素（例如吸烟、饮酒、体力活动）与这四种 CRC 亚型患者的生存率之间的关系（目标 2-3）。在观察性研究 (S-CCFR) 和临床试验 (N0147) 中进行平行分析将为比较和对比具有互​​补优势和局限性的研究环境中的结果提供机会。这种并行和补充分析的方法还将为我提供处理在不同研究环境中收集的临床结果数据和临床试验的经验。在进行拟议的研究时，将受益于 Fred Hutchinson 癌症研究中心 (FHCRC) 的丰富资源和协作环境。作为世界领先的癌症研究中心之一，FHCRC 拥有大量杰出的流行病学家、临床研究人员和实验室科学家，他们可以提供直接指导。特别是，我将受益于 Polly Newcomb 博士（主要导师）的指导，他在 CRC 流行病学和癌症生存观察研究方面拥有丰富的专业知识，也是 S-CCFR 的 PI。我还将得到 Noel Weiss 博士（共同导师）的指导，他是流行病学方法和临床流行病学方面经验丰富的专家。为了获得进一步的指导，我聘请了外部咨询委员会的专业知识，该委员会由进行肿瘤学临床试验的专家（Steven Alberts 博士，也是 N0147 研究主席）组成，在跨研究环境中进行相关科学（ Paul Limburg 博士）、CRC 流行病学和治疗（Andrew Chan 博士）和 CRC 病理学（Christophe Rosty 博士）。为了补充我的研究并促进我的职业发展，我还将与 Weiss 博士合作开发和实施用于教授研究生水平流行病学方法系列课程的材料。通过该项目获得的实践经验和专业知识将得到成果研究、药物流行病学和临床试验方法方面的正式课程以及 FHCRC、华盛顿大学和其他项目提供的定期研究研讨会的补充。 FHCRC 和华盛顿大学都特别重视为早期职业科学家提供职业发展机会，提供正式的指导机制、定期职业发展研讨会、期刊俱乐部、课程评估和其他网络资源。因此，FHCRC 以及与之密切相关的威斯康星大学的环境为我开展独立学术研究生涯提供了良好的环境。