新辅助化疗对乳腺癌患者激素受体及炎性标志物的影响及其与化疗疗效的相关性分析

发布时间：2018-05-17 23:03

本文选题：乳腺癌 + 新辅助化疗　；参考：《山东大学》2017年博士论文

【摘要】：研究背景:乳腺癌是最常见的女性恶性肿瘤和癌症相关死亡的主要原因之一,部分患者确诊时即为局部晚期乳腺癌(Locally advanced breast cancer, LABC)。新辅助化疗有利于保乳手术的进行以及降低术后复发风险,是局部晚期乳腺癌标准治疗的一部分。在临床中常常发现,分期或病理类型相同的患者接受相同的新辅助化疗化疗方案,其疗效和预后却不尽相同。近年来,随着乳腺癌分子生物学、组织学及系统生物医学研究的深入及进展,人们逐渐意识到肿瘤及其荷瘤宿主机体的“异质性”,是导致肿瘤患者预后及其对放/化疗治疗疗效差异的关键。如肿瘤组织学类型、分期及目前采用的临床病理分期等相同的癌症患者,其对化疗药物敏感性的不同,导致肿瘤即使接受了同样的化疗方案,其疗效和预后也不尽相同,因此,探索和建立临床可实时分析影响肿瘤治疗疗效的预测手段,仍然是肿瘤“精准”治疗领域的方向之一。虽然目前通过特定肿瘤的分子遗传信息的改变及肿瘤组织的分子病理变化,提高了乳腺癌的“精准”化疗,但由于其技术和标本类型等因素的限制,从临床角度仍希望找到更为简便和精确的系统评价指标。随着对炎症与肿瘤关系的研究进展,人们发现炎症在恶性肿瘤细胞的增殖和生存的肿瘤微环境中发挥着重要作用,同时发现用于评价炎性疾病进展及转归的系统标志,如粒/淋比(Neutrophil/lymphocyte ratio,NLR)和血/淋比(Platelet/lymphocyte ratio, PLR)等全身炎症反应标记物与多种恶性肿瘤的分期以及预后密切相关,大量的有关其对肿瘤预后预测的分析研究也证实了该类循环标志物的预测价值,而有关其是否能预测新辅助治疗的疗效的分析研究目前尚不多见,有待更多的分析探索研究。大量的研究已证实,作为一种激素依赖性肿瘤,乳腺癌的生长依赖于体内雌、孕激素水平,并受 ER (Estrogen receptor)、PR (Progesterone receptor)的调节,ER、PR的表达也是目前公认的唯一可以预测内分泌治疗疗效的生物标志物,影响其表达则影响其对内分泌治疗的敏感性。有研究发现髓系来源的细胞如巨噬细胞能影响ER的表达,也有研究证实新辅助化疗(Neoadjuvant Chemotherapy,NAC)能影响肿瘤ER、PR的表达状态或表达水平,但此种改变是否与化疗方案相关及其可能的医学意义目前研究甚少。乳腺肿瘤组织中ER、PR的表达与其病理特征、生物学行为、内分泌治疗敏感性、化学治疗敏感性以及预后等均密切相关,因此,监测新辅助化疗前后ER、PR的表达变化对于乳腺癌患者新辅助化疗疗效的评价及后续的个性化治疗具有重要的意义。循环系统中的NLR/PLR是否与乳腺癌组织中ER/PR表达状态或水平及其治疗疗效有关,目前知之甚少,了解其变化规律及其与临床特征的关联性,分析其与新辅助化疗疗效的关系对乳腺癌的治疗及制定个体化治疗方案具有一定的指导意义。研究目的:①分析乳腺癌患者新辅助化疗前NLR、PLR与ER、PR表达的相互关系;②分析新辅助化疗后的ER、PR、NLR、PLR的变化,探讨其与化疗方案的相关性;③分析探讨NLR、PLR在新辅助化疗后的变化与ER、PR的变化是否相关;④分析探讨新辅助化疗前ER、PR的表达状态与新辅助化疗疗效之间的关系;⑤分析探讨新辅助化疗前NLR、PLR与新辅助化疗疗效是否相关。研究方法:回顾性收集2011年1月至2015年8月泰安市中心医院乳腺外科及山东大学齐鲁医院乳腺外科行新辅助化疗的原发性乳腺癌患者132例,所有患者接受最多6个周期的以蒽环类药物为主的三周方案,具体如下:ET方案(表柔比星90mg/m2,多西紫杉醇75mg/m2),TEC方案(多西紫杉醇75mg/m2,表柔比星90mg/m2,环磷磷酰胺500mg/m2),CEF方案(环磷磷酰胺500mg/m2,表柔比星90mg/m2, 5-氟尿嘧啶500mg/m2)。根据免疫组化检测的标准化步骤以及判读标准,对新辅助化疗前后肿瘤组织中的ER、PR的表达状态或表达水平进行判读。收集所有患者治疗前的外周静脉血,同时为了比较新辅助化疗后的变化收集新辅助化疗1周期后即第2周期新辅助化疗前的外周静脉血。NLR数值=外周血中性粒细胞计数/外周血淋巴细胞计数,PLR数值=外周血血小板计数/外周血淋巴细胞计数,NLR、PLR预测ER/PR表达水平及新辅助化疗疗效的最佳临界点均通过ROC曲线计算得出。新辅助化疗前、后分别行超声检查测量乳腺肿块大小,根据实体瘤的疗效评价标准(Response Evaluation Criteria in Solid Tumors,RECIST)进行临床疗效的判断。关于新辅助化疗前的NLR、PLR和新辅助化疗前的ER、PR之间的相互关系应用卡方检验及独立样本t检验。新辅助化疗前后的ER、PR、NLR、PLR的变化采用配对t检验,ER、PR、NLR、PLR新辅助化疗前后的变化之间的关系以及ER、PR、NLR、PLR与化疗方案的关系均采用卡方检验。新辅助化疗前ER、PR、NLR、PLR与新辅助化疗疗效的关系应用卡方检验。研究结果:1.新辅助化疗前乳腺癌组织ER、PR表达状态与新辅助化疗前NLR、PLR无相关性(P0.05)。2. NLR2.05的乳腺癌患者组ER阳性表达比例均值显著高于NLR≥2.05的患者组(45.68%. vs 27.61%, p=0.012); PLR159.01 的乳腺癌患者组 ER 阳性表达比例均值显著高于PLR≥159.01的患者组(43.89% vs 28.99%,p=0.042);新辅助化疗前PLR159.01的乳腺癌患者组PR阳性表达比例均值显著高于PLR159.01的患者组(30.81%vs 17.94%,p=0.048);但PLR159.01的患者与PLR≥159.01的患者相比,其PR表达水平没有统计学差异3.新辅助化疗可致部分乳腺癌患者ER、PR表达状态或表达水平的改变。ER表达水平的改变在ET、TEC、CEF三种方案所占比例分别为46.88%(15/32)、57.89%(11/19)、43.33%(13/30); ER 表达状态的改变在 ET、TEC、CEF 三种方案所占比例分别为 15.63% (5/32)、21.05% (4/19)、10.00%(3/30); ER表达水平及/或表达状态的改变在TEC方案较为明显。PR表达水平的改变在ET、TEC、CEF三种方案所占比例分别为37.50%(12/32)、47.37%(9/19)、30.00%(9/30); PR 表达状态的改变在 ET、TEC、CEF 三种方案所占比例分别为 21.88% (7/32)、15.79% (3/19)、16.67%(5/30); PR表达水平的改变在TEC方案较为明显,而表达状态的改变在ET方案较为明显。4. ER、PR表达水平及表达状态的改变在ET、TEC、CEF三种化疗方案间无明显差别(P=0.498, 0.835)。5.新辅助化疗前后NLR的变化只在TEC方案有统计学意义(P=0.003),在ET、CEF方案无统计学意义(P0.05),但是这个结果不能排除人粒细胞集落刺激因子(G-CSF)的影响。新辅助化疗前后PLR的变化在ET、TEC、CEF方案均具有统计学意义(P0.05)。6.新辅助化疗后大多数患者PLR升高。7.新辅助化疗前后NLR、PLR的变化均与化疗方案相关(P=0.011,0.002)。8.新辅助化疗引起的ER/PR的变化与NLR/PLR的变化不相关(P0.05)。9.新辅助化疗前ER、PR的表达状态与新辅助化疗疗效不相关(P=0.555,0.748)。10.新辅助化疗前NLR1.67或者PLR151.27的患者其新辅助化疗疗效较好[(NLR1.67 vs. NLR 1.67, 67.3% vs. 47.1%,P0.05) (PLR151.27 vs.PLR≥151.27, 64.0% vs. 45.1%, P0.05)]。结论:本文从新辅助化疗前乳腺癌组织ER/PR的表达状态、表达水平及与新辅助化疗前中性粒细胞/淋巴细胞比值(Neutrophil/lymphocyte ration,NLR)、血小板/淋巴细胞比值(Platelet/lymphocyte ecoration,PLR)之间的相互关系切入,分析了新辅助化疗前后的ER、PR的表达变化与NLR/PLR的相关性及其与临床疗效的关系,研究发现:1.新辅助化疗前的ER、PR的表达状态与NLR、PLR水平无相关性,但ER、PR的表达水平与NLR、PLR有一定关联性,目前很少有类似的研究报道。2.新辅助化疗后乳腺癌患者的NLR、PLR会发生明显的改变,其中PLR会升高,这种变化与新辅助化疗方案具有明显的相关性,而且不同的方案效应不同;新辅助化疗会改变部分患者ER、PR的表达状态或表达水平,此变化与NLR、PLR的改变及化疗方案不相关。目前还没有类似的研究报道。3.对新辅助化疗前ER、PR、NLR、PLR与新辅助化疗疗效相关性的分析证明,ER、PR的表达状态与NAC疗效没有明显的相关性,但是新辅助化疗前NLRlloW、PLRlloW的患者其新辅助化疗疗效较好,提示NLR、PLR有望成为乳腺癌新辅助化疗疗效评价的有效预测因子。
[Abstract]:Background: breast cancer is one of the most common causes of cancer and cancer related deaths in women. Some patients are diagnosed as locally advanced breast cancer (Locally advanced breast cancer, LABC). Neoadjuvant chemotherapy is beneficial to breast conserving surgery and the reduction of postoperative recurrence risk. It is a standard treatment for locally advanced breast cancer. It is often found in the clinic that patients with the same stage or pathological type accept the same neoadjuvant chemotherapy and chemotherapy, and their efficacy and prognosis are not the same. In recent years, with the development of molecular biology, histology and systematic biomedical research on breast cancer, people are gradually aware of the tumor and the host body of the tumor bearing host. "Heterogeneity" is the key to the prognosis of cancer patients and the difference between chemotherapy and radiotherapy. For example, the type of tumor histology, the stages and the clinical pathological staging of the same cancer patients, which are different in sensitivity to chemotherapeutic drugs, cause the tumor to be treated with the same chemotherapy scheme, and its curative effect and prognosis are not complete. Therefore, it is still one of the directions in the field of "precise" treatment to explore and establish clinical real-time analysis that can affect the therapeutic effect of cancer treatment. Although the molecular genetic information of a specific tumor and the molecular pathological changes of the tumor tissue are now raised, the "precise" chemotherapy of breast cancer is raised, but it is due to its technique. With the limitations of factors such as surgery and specimen type, we still hope to find more simple and accurate systematic evaluation indicators from the clinical point of view. With the progress in the study of the relationship between inflammation and tumor, it is found that inflammation plays an important role in the proliferation and survival of malignant tumor cells, and is also found to be used to evaluate the progress of inflammatory diseases. Systemic markers such as grain / drenching ratio (Neutrophil/lymphocyte ratio, NLR) and blood / drenching ratio (Platelet/lymphocyte ratio, PLR) are closely related to the stages and prognosis of various malignant tumors. A large number of analysis and studies on the prognosis of tumor prognosis have also confirmed the prediction of this kind of circulating markers. The value, and the analysis of whether it can predict the efficacy of neoadjuvant therapy, is still rare and needs more analysis and research. A large number of studies have proved that as a hormone dependent tumor, the growth of breast cancer depends on the levels of female, progestin, and ER (Estrogen receptor), PR (Progesterone receptor). The expression of ER and PR is also recognized as the only biomarker that can predict the therapeutic effect of endocrine therapy, which affects its sensitivity to endocrine therapy. Studies have found that myeloid cells, such as macrophages, can affect the expression of ER, as well as new adjuvant chemotherapy (Neoadjuvant Chemotherapy, NAC). The expression status or expression level of tumor ER, PR, but whether this change is related to chemotherapy and its possible medical significance is rarely studied. The expression of ER, PR in breast tumor tissue is closely related to its pathological features, biological behavior, sensitivity of endocrine therapy, chemosensitivity and prognosis. The expression of ER, PR, before and after chemotherapy, is of great significance to the evaluation of the curative effect of neoadjuvant chemotherapy in breast cancer patients and the subsequent individualized treatment. Is NLR/PLR in the circulatory system related to the state or level of ER/PR expression in breast cancer and its therapeutic effect, and knows little about its change and its clinical characteristics Correlation, analysis of the relationship with the new adjuvant chemotherapy effect on the treatment of breast cancer and the formulation of individualized treatment plan has certain guiding significance. Objective: to analyze the relationship between NLR, PLR and ER, PR expression before neoadjuvant chemotherapy in breast cancer patients; secondly, to analyze the changes of ER, PR, NLR, PLR after neoadjuvant chemotherapy, and discuss its and chemotherapy. The correlation of the scheme; (3) to analyze the relationship between the changes of NLR, PLR after neoadjuvant chemotherapy and the changes of ER and PR; (4) to analyze the relationship between the expression of ER, PR and the therapeutic effect of neoadjuvant chemotherapy before neoadjuvant chemotherapy; and discuss the correlation between NLR, PLR and the efficacy of neoadjuvant chemotherapy before the neoadjuvant chemotherapy. From January 2011 to August 2015, 132 patients with primary breast cancer were treated with neoadjuvant chemotherapy in the breast surgery of Tai'an Central Hospital and Shandong University, Shandong University. All patients received a maximum of 6 cycles of three weeks with anthracycline, the following: the ET scheme (epirubicin 90mg/m2, docetaxel 75mg/m2), TEC prescription Cases (docetaxel 75mg/m2, epirubicin 90mg/m2, cyclic phosphate amido 500mg/m2), CEF scheme (cycloparidamide 500mg/m2, epirubicin 90mg/m2, 5- fluorouracil 500mg/m2). The expression and expression level of ER, PR in neoadjuvant chemotherapy and tumor tissue were judged according to the standardization steps and criteria of immunohistochemical detection. The peripheral venous blood before treatment of all patients was collected, and the peripheral venous blood.NLR value before the second cycle neoadjuvant chemotherapy was collected for 1 cycles after neoadjuvant chemotherapy to compare the changes after the neoadjuvant chemotherapy. The peripheral blood neutrophils count / peripheral blood lymphocyte count, the value of PLR = peripheral blood platelet count / peripheral blood lymphatic fine, were collected. The cell count, NLR, PLR predicted the ER/PR expression level and the best critical point of the therapeutic effect of the neoadjuvant chemotherapy. The size of the breast lumps were measured before the new adjuvant chemotherapy, and the clinical efficacy was judged according to the evaluation criteria of the curative effect of solid tumor (Response Evaluation Criteria in Solid Tumors, RECIST). The relationship between NLR, PLR and ER, PR before neoadjuvant chemotherapy was applied to the chi square test and independent sample t test. The changes in ER, PR, NLR, and PLR before and after the neoadjuvant chemotherapy were examined by paired t test, ER, PR, and before and after the neoadjuvant chemotherapy. Chi square test. The relationship between ER, PR, NLR, PLR and neoadjuvant chemotherapy before neoadjuvant chemotherapy was applied to the chi square test. Results: 1. the expression of ER and PR in breast cancer tissues before neoadjuvant chemotherapy was significantly higher than that of breast cancer patients with no correlation (P0.05).2. NLR2.05 before neoadjuvant chemotherapy (P0.05) and PLR non correlation (P0.05).2. NLR2.05 was significantly higher than that of more than 2.05 In the group (45.68%. vs 27.61%, p=0.012), the mean ER positive expression ratio of the breast cancer patients in PLR159.01 was significantly higher than that of the patients with PLR > 159.01 (43.89% vs 28.99%, p=0.042). The mean value of PR positive expression in the breast cancer patients before the neoadjuvant chemotherapy was significantly higher than that in the PLR159.01 group (30.81%vs 17.94%,). There was no significant difference in PR expression level between 9.01 of patients and patients with PLR > 159.01. 3. neoadjuvant chemotherapy could induce ER, PR expression or expression level changes of.ER expression levels were 46.88% (15/32), 57.89% (11/19), 43.33% (13/30), respectively, and 57.89% (11/19), 43.33% (13/30), and ER expression status. The proportion of three schemes changed in ET, TEC, and CEF were 15.63% (5/32), 21.05% (4/19), 10% (3/30), and the change of ER expression level and / or expression state in TEC scheme was more obvious at.PR expression level in ET, TEC, and CEF three schemes, respectively, 47.37%, 30%. The proportion of three schemes in ET, TEC, and CEF accounted for 21.88% (7/32), 15.79% (3/19), 16.67% (5/30), and the change of PR expression level was more obvious in TEC scheme, and the change of expression state in ET scheme was more obvious.4. ER, PR expression level and expression state were changed. There was no significant difference between three chemotherapeutic schemes (0.835). The changes of NLR before and after neoadjuvant chemotherapy were only statistically significant in the TEC scheme (P=0.003), and in ET, there was no statistical significance in CEF scheme (P0.05), but this result could not exclude the effect of human granulocyte colony stimulating factor (G-CSF). The changes of PLR before and after neoadjuvant chemotherapy were statistically significant in ET, TEC, CEF scheme (P0.05) after neoadjuvant chemotherapy In most patients, PLR increased the NLR in.7. neoadjuvant chemotherapy before and after neoadjuvant chemotherapy. The changes of PLR were related to the chemotherapy regimen (P=0.011,0.002).8. neoadjuvant chemotherapy was not related to the changes of NLR/PLR (P0.05).9. new adjuvant chemotherapy ER. The expression of PR was not related to the new adjuvant chemotherapy effect. Patients with PLR151.27 or PLR151.27 had better therapeutic effect [(NLR1.67 vs. NLR 1.67, 67.3% vs. 47.1%, P0.05) (PLR151.27 vs.PLR > 151.27, 64% vs. 45.1%, P0.05). Conclusion: the expression of the ER/PR expression of breast cancer tissue before neoadjuvant chemotherapy was expressed and the ratio of neutrophils / lymphocyte before neoadjuvant chemotherapy (Neut) Rophil/lymphocyte ration, NLR), the relationship between the platelet / lymphocyte ratio (Platelet/lymphocyte ecoration, PLR) and the correlation between the expression of ER, PR and NLR/PLR, and its relationship with the clinical efficacy before and after the neoadjuvant chemotherapy, and study the occurrence of ER, PR expression status and NLR, levels of ER before 1. new adjuvant chemotherapy. There is no correlation, but the expression level of ER, PR is associated with NLR, PLR, and there are few similar studies reported on the NLR of breast cancer patients after.2. neoadjuvant chemotherapy. PLR will change obviously, and PLR will rise. This change has obvious correlation with the new adjuvant chemotherapy scheme, and the different scheme effects are different; neoadjuvant is different. Neoadjuvant chemotherapy is different. Treatment will change the expression status or expression level of ER and PR in some patients. This change is not related to the changes of NLR, PLR and chemotherapy. There is no similar study on the correlation between ER, PR, NLR, PLR and neoadjuvant chemotherapy before the neoadjuvant chemotherapy, and there is no significant correlation between the expression of ER, PR and the efficacy of NAC, but there is no significant correlation between the expression of ER, PR and the efficacy of NAC. The new adjuvant chemotherapy for patients with NLRlloW and PLRlloW before neoadjuvant chemotherapy has a good effect, suggesting that NLR and PLR are expected to be an effective predictor of the evaluation of the efficacy of new adjuvant chemotherapy for breast cancer.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R737.9

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