Clinical and Biological Predictors of Chemotherapy Toxicity in Older Adults

描述（由申请人提供）：根据PA 08-230（衰老癌症界面转化研究）的要求，本申请的总体目标是开发老年乳腺癌辅助化疗毒性的临床和生物学预测模型。这一点很重要，因为乳腺癌的最大风险因素是年龄的增长。此外，随着美国人口的老龄化，患乳腺癌的老年人数量预计将显著增加。几项研究表明，患有乳腺癌的老年人化疗毒性的风险增加；然而，目前还没有标准的方法来识别那些特别脆弱的人。此外，对临床因素、生物学因素或与规定的化疗方案的相对剂量强度降低相关的特定毒性知之甚少。本提案通过纳入老年易感性相关因素，并研究其对老年肿瘤人群的影响，将老年医学和肿瘤学领域结合起来。这项应用的具体目的是：1)建立一个由老年乳腺癌辅助化疗毒性的临床和生物学预测因子组成的预测模型；2)了解临床和生物学因素与处方化疗方案降低相对剂量强度（RDI）的关系；3)确定与处方化疗方案RDI降低相关的特定化疗毒性。这些目标将由一个具有老年病学、肿瘤学和生物统计学专业知识的多学科调查小组来完成。该研究小组将对500名年龄在70岁至70岁之间的I-III期乳腺癌患者进行前瞻性、多中心、纵向研究，这些患者将接受辅助化疗。化疗前将捕获临床因素（老年评估、社会人口统计学、肿瘤和治疗变量）和生物学因素（肾脏、肝脏和血液功能；炎症和凝血标志物；衰老分子标志物[p16INK4a]）。患者随后将接受治疗医师规定的标准护理辅助化疗。患者将在整个化疗过程中（从开始到完成后1个月）进行随访，以捕获NCI CTCAE (v4.0) 3-5级毒性。还将记录剂量延迟、剂量减少和停止治疗，以及这些事件与毒性的关系。关于预期结果，目前的项目将填补关于老年乳腺癌患者化疗毒性的临床和生物学预测知识的重要空白，这是肿瘤学家在为老年人开辅助化疗处方之前应该评估的领域。这一建议具有创新性，因为我们的数据最终将用于开发毒性的总体风险评分。最终，这些数据将作为未来干预研究的基础，旨在降低化疗毒性风险，维持老年乳腺癌患者的功能和健康。

DESCRIPTION (provided by applicant): The overarching goal of this application, in response to PA 08-230 (Translational Research at the Aging Cancer Interface), is to develop a "bedside to bench" model of clinical and biological predictors for toxicity to adjuvant chemotherapy in older adults with breast cancer. This is important because the greatest risk factor for breast cancer is increasing age. Furthermore, the number of older adults with breast cancer is predicted to increase significantly with the aging of the US population. Several studies have demonstrated that older adults with breast cancer are at increased risk for chemotherapy toxicity; however, no standard method currently exists for identifying those individuals who are particularly vulnerable. In addition, little is known about the clinical factors, biological factors, or specific toxicities associated with reduced relative dose intensity of the prescribed chemotherapy regimen. This proposal unites the fields of geriatrics and oncology by incorporating geriatric correlates of vulnerability, and studying their impact in an aging oncology population. The specific aims of this application are: 1) to develop a predictive model consisting of clinical and biological predictors of toxicity to adjuvant chemotherapy in older adults with breast cancer; 2) to understand the association between clinical and biological factors and reduced relative dose intensity (RDI) of the prescribed chemotherapy regimen; and 3) to identify the specific chemotherapy toxicities associated with reduced RDI of the prescribed chemotherapy regimen. These aims will be accomplished by a multi-disciplinary investigative team with expertise in geriatrics, oncology, and biostatistics. The team will perform a prospective, multicenter, longitudinal study of 500 adults age > 70 with stage I-III breast cancer who will receive adjuvant chemotherapy. Clinical factors (geriatric assessment, sociodemographic, tumor, and treatment variables) and biological factors (renal, hepatic, and hematologic function; markers of inflammation and coagulation; and a molecular marker of aging [p16INK4a]) will be captured before chemotherapy. Patients will subsequently receive standard of care adjuvant chemotherapy as prescribed by the treating physician. Patients will be followed throughout the course of chemotherapy (from start to 1 month post-completion) to capture NCI CTCAE (v4.0) grade 3-5 toxicities. Dose delays, dose reductions, and discontinuation of treatment will also be captured, along with the relationship of these events to toxicity. With regard to expected outcomes, the current project will fill vital gaps in the knowledge about clinical and biological predictors of chemotherapy toxicity for older adults with breast cancer, areas that an oncologist should assess prior to prescribing adjuvant chemotherapy for an older adult. This proposal is innovative, as our data will ultimately be used to develop an overall risk score for toxicity. Ultimately these data will serve as the basis for future intervention studies aimed at decreasing the risk of chemotherapy toxicity and maintaining the function and health of older adults with breast cancer.