Patel Sunita K, Wong Andrew L, Wong F Lennie, Breen Elizabeth Crabb, Hurria Arti, Smith Mackenzie, Kinjo Christine, Paz I Benjamin, Kruper Laura, Somlo George, Mortimer Joanne E, Palomares Melanie R, Irwin Michael R, Bhatia Smita
Department of Population Sciences (SKP, ALW, FLW, MS, CK, MRP), Department of Supportive Care Medicine (SKP), Department of Medical Oncology (AH, IBP, LK, GS, JM, MRP), Department of Surgery (IBP, LK), City of Hope Medical Center and Beckman Research Institute, Duarte, California; Institute of Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL (SB); Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA (ECB, MRI).
J Natl Cancer Inst. 2015 Jun 22;107(8). doi: 10.1093/jnci/djv131. Print 2015 Aug.
Neurocognitive dysfunction is reported in women with breast cancer even prior to receipt of adjuvant therapy; however, there is little understanding of underlying mechanisms. We tested the hypothesis that pretreatment neurocognitive dysfunction in newly diagnosed patients is related to immunological activation, as indexed by pro-inflammatory cytokines.
One hundred seventy-four postmenopausal patients with newly diagnosed breast cancer underwent a comprehensive neuropsychological evaluation (assessment of cognitive function, mood, and fatigue) and measurement of key cytokine levels prior to surgery. Age-matched control participants without cancer were evaluated concurrently. Multivariable regression analyses examined the contribution of circulating Interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and soluble TNF receptor type two (sTNF-RII) in predicting neurocognitive performance in patients after controlling for key factors thought to impact functioning. All tests of statistical significance were two-sided.
Memory performance was statistically significantly reduced, in patients compared with controls (P = .02). Of the three cytokines measured, only IL-1ra was statistically significantly elevated in cancer patients when compared with control participants (mean ± SD, 375 ± 239 pg/mL vs 291 ± 169 pg/mL, P = .007). After controlling for age, education, race, mood, fatigue, body mass index, and comorbidity, cytokines independently explained 6.0% of the total variance in memory performance (P = .01) in cancer patients but not control participants, with higher sTNF-RII associated with worse functioning. Exploratory analyses found that comorbidity statistically significantly explained variance in processing speed and executive functioning (P = .03 and P = .03, respectively).
An association of TNF with memory, previously reported in patients after exposure to chemotherapy, was found prior to initiation of any treatment, including surgery. This association requires further investigation as sTNF-RII was not higher in cancer patients relative to control participants.
据报道，乳腺癌女性在接受辅助治疗之前就存在神经认知功能障碍；然而，对其潜在机制了解甚少。我们检验了这样一个假设，即新诊断患者的治疗前神经认知功能障碍与免疫激活有关，以促炎细胞因子为指标。
174例新诊断的绝经后乳腺癌患者在手术前接受了全面的神经心理学评估（认知功能、情绪和疲劳评估）以及关键细胞因子水平的测量。同时对年龄匹配的无癌症对照参与者进行了评估。多变量回归分析在控制了被认为会影响功能的关键因素后，检验了循环白细胞介素-6（IL-6）、白细胞介素-1受体拮抗剂（IL-1ra）和可溶性肿瘤坏死因子受体II型（sTNF-RII）对预测患者神经认知表现的贡献。所有统计学显著性检验均为双侧检验。
与对照组相比，患者的记忆表现有统计学显著性降低（P = 0.02）。在测量的三种细胞因子中，与对照参与者相比，癌症患者中只有IL-1ra有统计学显著性升高（均值±标准差，375±239 pg/mL对291±169 pg/mL，P = 0.007）。在控制了年龄、教育程度、种族、情绪、疲劳、体重指数和合并症后，细胞因子独立解释了癌症患者记忆表现总方差的6.0%（P = 0.01），但对照参与者未出现这种情况，sTNF-RII越高，功能越差。探索性分析发现，合并症在统计学上显著解释了处理速度和执行功能的方差（分别为P = 0.03和P = 0.03）。
在包括手术在内的任何治疗开始之前，就发现了肿瘤坏死因子与记忆之间的关联，这与之前报道的化疗后患者的情况一致。由于癌症患者的sTNF-RII相对于对照参与者并不更高，这种关联需要进一步研究。
