本文選題：乳腺癌 + 新輔助化療�。� 參考：《山東大學》2017年博士論文

【摘要】：研究背景:乳腺癌是最常見的女性惡性腫瘤和癌癥相關死亡的主要原因之一,部分患者確診時即為局部晚期乳腺癌(Locally advanced breast cancer, LABC)。新輔助化療有利于保乳手術的進行以及降低術后復發(fā)風險,是局部晚期乳腺癌標準治療的一部分。在臨床中常常發(fā)現(xiàn),分期或病理類型相同的患者接受相同的新輔助化療化療方案,其療效和預后卻不盡相同。近年來,隨著乳腺癌分子生物學、組織學及系統(tǒng)生物醫(yī)學研究的深入及進展,人們逐漸意識到腫瘤及其荷瘤宿主機體的“異質(zhì)性”,是導致腫瘤患者預后及其對放/化療治療療效差異的關鍵。如腫瘤組織學類型、分期及目前采用的臨床病理分期等相同的癌癥患者,其對化療藥物敏感性的不同,導致腫瘤即使接受了同樣的化療方案,其療效和預后也不盡相同,因此,探索和建立臨床可實時分析影響腫瘤治療療效的預測手段,仍然是腫瘤“精準”治療領域的方向之一。雖然目前通過特定腫瘤的分子遺傳信息的改變及腫瘤組織的分子病理變化,提高了乳腺癌的“精準”化療,但由于其技術和標本類型等因素的限制,從臨床角度仍希望找到更為簡便和精確的系統(tǒng)評價指標。隨著對炎癥與腫瘤關系的研究進展,人們發(fā)現(xiàn)炎癥在惡性腫瘤細胞的增殖和生存的腫瘤微環(huán)境中發(fā)揮著重要作用,同時發(fā)現(xiàn)用于評價炎性疾病進展及轉(zhuǎn)歸的系統(tǒng)標志,如粒/淋比(Neutrophil/lymphocyte ratio,NLR)和血/淋比(Platelet/lymphocyte ratio, PLR)等全身炎癥反應標記物與多種惡性腫瘤的分期以及預后密切相關,大量的有關其對腫瘤預后預測的分析研究也證實了該類循環(huán)標志物的預測價值,而有關其是否能預測新輔助治療的療效的分析研究目前尚不多見,有待更多的分析探索研究。大量的研究已證實,作為一種激素依賴性腫瘤,乳腺癌的生長依賴于體內(nèi)雌、孕激素水平,并受 ER (Estrogen receptor)、PR (Progesterone receptor)的調(diào)節(jié),ER、PR的表達也是目前公認的唯一可以預測內(nèi)分泌治療療效的生物標志物,影響其表達則影響其對內(nèi)分泌治療的敏感性。有研究發(fā)現(xiàn)髓系來源的細胞如巨噬細胞能影響ER的表達,也有研究證實新輔助化療(Neoadjuvant Chemotherapy,NAC)能影響腫瘤ER、PR的表達狀態(tài)或表達水平,但此種改變是否與化療方案相關及其可能的醫(yī)學意義目前研究甚少。乳腺腫瘤組織中ER、PR的表達與其病理特征、生物學行為、內(nèi)分泌治療敏感性、化學治療敏感性以及預后等均密切相關,因此,監(jiān)測新輔助化療前后ER、PR的表達變化對于乳腺癌患者新輔助化療療效的評價及后續(xù)的個性化治療具有重要的意義。循環(huán)系統(tǒng)中的NLR/PLR是否與乳腺癌組織中ER/PR表達狀態(tài)或水平及其治療療效有關,目前知之甚少,了解其變化規(guī)律及其與臨床特征的關聯(lián)性,分析其與新輔助化療療效的關系對乳腺癌的治療及制定個體化治療方案具有一定的指導意義。研究目的:①分析乳腺癌患者新輔助化療前NLR、PLR與ER、PR表達的相互關系;②分析新輔助化療后的ER、PR、NLR、PLR的變化,探討其與化療方案的相關性;③分析探討NLR、PLR在新輔助化療后的變化與ER、PR的變化是否相關;④分析探討新輔助化療前ER、PR的表達狀態(tài)與新輔助化療療效之間的關系;⑤分析探討新輔助化療前NLR、PLR與新輔助化療療效是否相關。研究方法:回顧性收集2011年1月至2015年8月泰安市中心醫(yī)院乳腺外科及山東大學齊魯醫(yī)院乳腺外科行新輔助化療的原發(fā)性乳腺癌患者132例,所有患者接受最多6個周期的以蒽環(huán)類藥物為主的三周方案,具體如下: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,環(huán)磷磷酰胺500mg/m2),CEF方案(環(huán)磷磷酰胺500mg/m2,表柔比星90mg/m2, 5-氟尿嘧啶500mg/m2)。根據(jù)免疫組化檢測的標準化步驟以及判讀標準,對新輔助化療前后腫瘤組織中的ER、PR的表達狀態(tài)或表達水平進行判讀。收集所有患者治療前的外周靜脈血,同時為了比較新輔助化療后的變化收集新輔助化療1周期后即第2周期新輔助化療前的外周靜脈血。NLR數(shù)值=外周血中性粒細胞計數(shù)/外周血淋巴細胞計數(shù),PLR數(shù)值=外周血血小板計數(shù)/外周血淋巴細胞計數(shù),NLR、PLR預測ER/PR表達水平及新輔助化療療效的最佳臨界點均通過ROC曲線計算得出。新輔助化療前、后分別行超聲檢查測量乳腺腫塊大小,根據(jù)實體瘤的療效評價標準(Response Evaluation Criteria in Solid Tumors,RECIST)進行臨床療效的判斷。關于新輔助化療前的NLR、PLR和新輔助化療前的ER、PR之間的相互關系應用卡方檢驗及獨立樣本t檢驗。新輔助化療前后的ER、PR、NLR、PLR的變化采用配對t檢驗,ER、PR、NLR、PLR新輔助化療前后的變化之間的關系以及ER、PR、NLR、PLR與化療方案的關系均采用卡方檢驗。新輔助化療前ER、PR、NLR、PLR與新輔助化療療效的關系應用卡方檢驗。研究結(jié)果:1.新輔助化療前乳腺癌組織ER、PR表達狀態(tài)與新輔助化療前NLR、PLR無相關性(P0.05)。2. NLR2.05的乳腺癌患者組ER陽性表達比例均值顯著高于NLR≥2.05的患者組(45.68%. vs 27.61%, p=0.012); PLR159.01 的乳腺癌患者組 ER 陽性表達比例均值顯著高于PLR≥159.01的患者組(43.89% vs 28.99%,p=0.042);新輔助化療前PLR159.01的乳腺癌患者組PR陽性表達比例均值顯著高于PLR159.01的患者組(30.81%vs 17.94%,p=0.048);但PLR159.01的患者與PLR≥159.01的患者相比,其PR表達水平?jīng)]有統(tǒng)計學差異3.新輔助化療可致部分乳腺癌患者ER、PR表達狀態(tài)或表達水平的改變。ER表達水平的改變在ET、TEC、CEF三種方案所占比例分別為46.88%(15/32)、57.89%(11/19)、43.33%(13/30); ER 表達狀態(tài)的改變在 ET、TEC、CEF 三種方案所占比例分別為 15.63% (5/32)、21.05% (4/19)、10.00%(3/30); ER表達水平及/或表達狀態(tài)的改變在TEC方案較為明顯。PR表達水平的改變在ET、TEC、CEF三種方案所占比例分別為37.50%(12/32)、47.37%(9/19)、30.00%(9/30); PR 表達狀態(tài)的改變在 ET、TEC、CEF 三種方案所占比例分別為 21.88% (7/32)、15.79% (3/19)、16.67%(5/30); PR表達水平的改變在TEC方案較為明顯,而表達狀態(tài)的改變在ET方案較為明顯。4. ER、PR表達水平及表達狀態(tài)的改變在ET、TEC、CEF三種化療方案間無明顯差別(P=0.498, 0.835)。5.新輔助化療前后NLR的變化只在TEC方案有統(tǒng)計學意義(P=0.003),在ET、CEF方案無統(tǒng)計學意義(P0.05),但是這個結(jié)果不能排除人粒細胞集落刺激因子(G-CSF)的影響。新輔助化療前后PLR的變化在ET、TEC、CEF方案均具有統(tǒng)計學意義(P0.05)。6.新輔助化療后大多數(shù)患者PLR升高。7.新輔助化療前后NLR、PLR的變化均與化療方案相關(P=0.011,0.002)。8.新輔助化療引起的ER/PR的變化與NLR/PLR的變化不相關(P0.05)。9.新輔助化療前ER、PR的表達狀態(tài)與新輔助化療療效不相關(P=0.555,0.748)。10.新輔助化療前NLR1.67或者PLR151.27的患者其新輔助化療療效較好[(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)]。結(jié)論:本文從新輔助化療前乳腺癌組織ER/PR的表達狀態(tài)、表達水平及與新輔助化療前中性粒細胞/淋巴細胞比值(Neutrophil/lymphocyte ration,NLR)、血小板/淋巴細胞比值(Platelet/lymphocyte ecoration,PLR)之間的相互關系切入,分析了新輔助化療前后的ER、PR的表達變化與NLR/PLR的相關性及其與臨床療效的關系,研究發(fā)現(xiàn):1.新輔助化療前的ER、PR的表達狀態(tài)與NLR、PLR水平無相關性,但ER、PR的表達水平與NLR、PLR有一定關聯(lián)性,目前很少有類似的研究報道。2.新輔助化療后乳腺癌患者的NLR、PLR會發(fā)生明顯的改變,其中PLR會升高,這種變化與新輔助化療方案具有明顯的相關性,而且不同的方案效應不同;新輔助化療會改變部分患者ER、PR的表達狀態(tài)或表達水平,此變化與NLR、PLR的改變及化療方案不相關。目前還沒有類似的研究報道。3.對新輔助化療前ER、PR、NLR、PLR與新輔助化療療效相關性的分析證明,ER、PR的表達狀態(tài)與NAC療效沒有明顯的相關性,但是新輔助化療前NLRlloW、PLRlloW的患者其新輔助化療療效較好,提示NLR、PLR有望成為乳腺癌新輔助化療療效評價的有效預測因子。
[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.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R737.9

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