PRESURGERY STRESS--BIOLOGICAL IMPACT IN BREAST CANCER

以前的动物模型研究已经令人信服地证明：1)实验性暴露于各种应激源(例如，电击)对免疫系统有多种影响，包括自然杀伤(NK)细胞活性的降低；2)在静脉注射活的肿瘤细胞之前暴露于应激源会导致肿瘤清除减少、转移增加和死亡率增加；以及3)这些应激源暴露对转移风险的影响是通过应激诱导的NK细胞活性抑制来调节的。这一广泛的临床前研究文献与人类癌症的相关性目前尚不清楚。在这项探索性/发展拨款申请中提出的为期两年的研究研究的目标是调查手术前压力对两个被确定为癌症患者随后发生转移疾病的潜在预测因素的变量的影响：手术前NK细胞活性水平(和相关免疫变量)和与手术相关的肿瘤细胞在血流中的扩散。具体目的L：采用纵向受试者间研究设计，调查接受乳腺癌手术治疗的女性患者的术前应激水平的模式和预测因素。100名乳腺癌患者将在门诊手术前进行4次评估：第7天、第2天、第1天(在家)和第0天(手术用药前在诊所)。对压力的心理生物学评估将包括：自我报告、心血管和内分泌测量。将与两个匹配的对照组的反应进行对比：L)计划接受手术的良性乳腺疾病患者(n=50)，以及2)来自社区的健康女性(n=50)。具体目标2：采用纵向受试者间研究设计，检查计划接受乳腺癌手术治疗的女性患者术前NK细胞活性水平和相关免疫措施的模式和预测因素。在上述每一次术前评估中，都将采集血液样本以进行免疫措施的分析。具体目标3：采用纵向受试者间研究设计，探索计划接受乳腺癌手术治疗的女性患者手术前和围手术期血流中乳腺癌细胞水平的模式和预测因素。第6天和第0天的血液采集将包括用于评估循环中乳腺癌细胞数量的样本，使用具有新发现的高度特异性标记物(乳巨球蛋白)的极其灵敏的逆转录聚合酶链式反应(RT-PCR)。在第0天，将另外收集两个样本--一个在手术中，一个在手术后--以提供一些初步迹象，表明在手术前心理生物应激之外，物理应激对肿瘤细胞扩散的相对贡献。

Previous research with animal models has compellingly demonstrated that: 1) experimental exposures to various stressors (e.g., electric shock) have multiple effects on the immune system, including reductions in natural killer (NK) cell activity; 2) exposures to stressors prior to intravenous injection with live tumor cells results in reduced tumor clearance, increased metastases, and increased mortality; and 3) these effects of stressor exposure on metastatic risk are mediated by stress-induced suppression of NK cell activity. The relevance of this extensive preclinical research literature to human cancer is currently unknown. The goal of the two year research study proposed in this exploratory/development grant application is to investigate the impact of presurgery stress on two variables identified as potential predictors of cancer patients' subsequent risk of developing metastatic disease: presurgery levels of NK cell activity (and related immune variables) and surgery-related dissemination of tumor cells in the blood stream. Specific Aim l: To investigate the patterns and predictors of presurgical stress levels among women scheduled for surgical treatment of primary breast cancer, using a longitudinal between-subjects research design. Patients (n=100) with breast cancer will be assessed on 4 occasions prior to outpatient surgery: Day-7, Day-2, Day-1 (in their homes) and Day-0 (in the clinic prior to medication for surgery). Psychobiological assessments of stress will include: self-report, cardiovascular, and endocrine measures. Responses will be contrasted to those of two matched Comparison Groups: l) patients (n=50) with benign breast disease scheduled for surgery; and, 2) healthy women from the community not undergoing surgery (n=50). Specific Aim 2: To examine the patterns and predictors of presurgical levels of NK cell activity and related immune measures in women scheduled for surgical treatment of breast cancer using a longitudinal between-subjects research design. At each of the presurgery assessments described above, blood samples will be taken for assay of immune measures. Specific Aim 3: To explore the patterns and predictors of pre- and peri- operative levels of breast cancer cells in the blood stream of women scheduled for surgical treatment of primary breast cancer, using a longitudinal between-subjects research design. Blood collection on Day-6 and Day-0 will include samples for assessment of the numbers of breast cancer cells in circulation, using an extremely sensitive reverse- transcriptase polymerase chain reaction (RT-PCR) with a newly identified, highly specific marker (mammaglobin). On Day-0, two additional samples will be collected - one during and one after-surgery - to provide some preliminary indication of the relative contribution of physical stresses to tumor cell dissemination above and beyond preoperative Psychobiological stress.