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  本文關(guān)鍵詞：乳腺癌新輔助化療療效預(yù)測因子的研究及預(yù)后分析　出處：《山東大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 乳腺癌 新輔助化療 預(yù)后 預(yù)測因子

【摘要】：背景：乳腺癌是女性最常見的惡性腫瘤之一,占女性新發(fā)癌癥總數(shù)的1/4,死亡率占女性癌癥的15%,居女性惡性腫瘤死亡率之首。乳腺癌不僅嚴(yán)重威脅著女性的生命和身心健康,還對經(jīng)濟、社會、家庭造成極大的影響。國家癌癥中心數(shù)據(jù)顯示,2011年我國女性乳腺癌新發(fā)病例約24.8萬例,占女性新發(fā)癌種的37.86%。中國腫瘤登記年報數(shù)據(jù)顯示,2012年我國女性乳腺癌發(fā)病率已高達42.55/10萬。隨著科技不斷進步,乳腺癌治療發(fā)展為手術(shù)、放療、化療、免疫治療和靶向治療相結(jié)合較系統(tǒng)的綜合治療模式,取得了良好的臨床療效,但乳腺癌仍為我國女性重要的死亡原因。作為系統(tǒng)治療的重要組成部分,新輔助化療已在局部晚期病人中得到廣泛應(yīng)用,部分可手術(shù)乳腺癌患者也通過選擇新輔助化療,獲得了降期保乳手術(shù)的機會。新輔助化療還可以選擇出敏感化療方案,消除或減少微轉(zhuǎn)移灶,防止遠處轉(zhuǎn)移等。此外,患者進行新輔助化療還可以為其后續(xù)治療提供寶貴的預(yù)后信息,例如以往研究認為新輔助化療后達到病理完全緩解(pathological complete remission, pCR)的病人較未達pCR病人可獲得更長的無病生存(disease-free survival, DFS)和總生存(overall survival, OS);新輔助化療后Ki67指數(shù)的降低同樣預(yù)示著較好的生存獲益。目前新輔助化療的有效率可達60-90%,病理完全緩解率20%,但仍然難以避免出現(xiàn)部分患者化療期間病情進展的情況,而且大部分病人新輔助化療后達不到pCR。本研究通過收集女性乳腺癌患者初診、新輔助化療前后、生存狀況等的相關(guān)資料,探尋新輔助化療病理完全緩解的預(yù)測指標(biāo),分析新輔助化療者的生存獲益,為篩選出新輔助化療敏感者提供參考,進而為乳腺癌個體化治療提供依據(jù)。目的：1.探索新輔助化療病理完全緩解的預(yù)測因子；2.對乳腺癌病例進行生存分析,明確pCR的預(yù)后預(yù)測價值,比較新輔助化療病人及術(shù)后輔助化療病人的生存差異,明確降期保乳是否影響患者預(yù)后。方法：回顧2004.5-2014.1期間于山東大學(xué)第二醫(yī)院乳腺外科入院治療的女性乳腺癌患者,對其臨床資料進行收集及分析。收集的信息包括：患者年齡、身高、體重、身體質(zhì)量指數(shù)(BMI)、月經(jīng)狀態(tài)、生育情況、哺乳情況,高血壓病史、乳腺癌家族史、乳腺良性疾病史；初診時腫瘤特點、腋窩及鎖骨上淋巴結(jié)狀態(tài)；患者所接受手術(shù)方式；患者活檢及手術(shù)病理類型、組織學(xué)分級、免疫組化、腫瘤切面積、淋巴結(jié)轉(zhuǎn)移情況；術(shù)后化療、放療、內(nèi)分泌治療等情況；通過電話隨訪、科室隨訪庫及既往病歷查閱獲取患者復(fù)發(fā)及生存狀況。入組標(biāo)準(zhǔn)：入組患者均于山東大學(xué)第二醫(yī)院接受手術(shù)并完成其治療方案,患者病理類型均為浸潤性非特殊癌；排除標(biāo)準(zhǔn)：非初發(fā)乳腺癌、初診為IV期的乳腺癌、未于山東大學(xué)第二醫(yī)院完成規(guī)定的治療方案(化療、手術(shù))、浸潤性特殊癌及原位癌。應(yīng)用χ2檢驗分析化療前分類變量與pCR的關(guān)系,采用獨立樣本t檢驗分析化療前連續(xù)性變量與pCR的關(guān)系。單因素分析具有統(tǒng)計學(xué)意義的變量采用二元Logistic回歸進行多因素分析；采用Kaplan-Meier法分析及Log-rank檢驗分析獲得pCR的病例與未獲得pCR病例、不同分期病例新輔助化療與輔助化療的生存差異。以p0.05為差異具有統(tǒng)計學(xué)意義。結(jié)果：1.基本特征描述根據(jù)入組標(biāo)準(zhǔn),從2004.5-2014.1期間于山東大學(xué)第二醫(yī)院乳腺外科入院治療的乳腺癌患者638例,其中140(21.94%)名接受新輔助化療并行根治性手術(shù),498(78.06%)名患者接受手術(shù)及術(shù)后輔助化療。2.pCR影響因素分析2.1單因素分析：與未達到pCR組的患者相比,達到pCR組病例平均哺乳時間短(t=-3.447,p=0.001)；腫瘤小(t=-2.509,p=0.013),且直徑≤3cm的比例更高(χ2=9.840,p=0.002)；體重或BMI值更大(體重：t=2.822,p=0.006；BMI：t=2.772,p=0.007),而體重60kg或BMI25的比例高(體重：χ2=5.563,p=0.018;BMI：χ2=5.280,p=0.022)；新輔助化療周期長(t=3.762,p=0.000)。而未達pCR組和達到pCR組間平均年齡、平均身高、既往積乳史者比例、絕經(jīng)者比例、乳腺良性疾病史者比例、有乳腺癌家族史者比例、高血壓病史者比例、糖尿病史者比例、臨床分期比例差異沒有統(tǒng)計學(xué)意義(p0.05)。與未達到pCR組相比,pCR組病例有較高的ER陰性比例(62.5%vs22.6%,χ2=15.194,p=0.000)；較高的PR陰性比例(70.8%vs41.7%,χ2=6.751,p=0.013);較高的HER-2陽性比例(47.4%vs19.0%,χ=6.762,p=0.009)。而pCR組與未達pCR組的組織學(xué)分級沒有統(tǒng)計學(xué)差異(χ2=1.119,p=0.572)。pCR組的Ki-67指數(shù)較未達pCR組高,但沒有統(tǒng)計學(xué)差異(46.1%vs35.9%,t=1.973,p=0.051);將Ki-67以14%為界值,分為低表達組高表達組進行檢驗,也未表現(xiàn)出Ki-67對pCR的預(yù)測意義(χ2=3.282,p=0.070)。HER2過表達型pCR率高于luminal A型和luminal B型的pCR率,差異具有統(tǒng)計學(xué)意義(χ2=7.697,p=0.006；χ2=13.807,p=0.001)；三陰型pCR率同樣高于luminal A型和luminal B型,但其與luminal A型的pCR率差異沒有統(tǒng)計學(xué)意義(χ2=3.715,p=0.054),與luminal B型的pCR率差異有統(tǒng)計學(xué)意義(χ2=5.125,p=0.024)；三陰型乳腺癌新輔助化療后pCR率低于HER2過表達型,但兩者差異無統(tǒng)計學(xué)意義(χ2=0.395,p=0.440)。2.2多因素分析：Logistic回歸分析發(fā)現(xiàn)可做為病理完全緩解(pCR)獨立預(yù)測指標(biāo)的因素有：ER(OR=0.047,95%CI:0.008-0.283).體重(OR=1.143,95%CI：1.026-1.273)。3.新輔助化療患者生存分析新輔助化療后pCR組和未達到pCR組的無復(fù)發(fā)生存無明顯差異(χ2=0.138,p=0.711)；盡管在隨訪時間內(nèi)pCR組沒有死亡病例,但總生存分析發(fā)現(xiàn)pCR組與未達到pCR組的總生存沒有統(tǒng)計學(xué)差異(χ2=2.982,p=0.084)。新輔助化療獲得pCR患者與術(shù)后輔助化療患者的生存獲益無明顯差異(DFS:χ=1.896, p=0.169; OS:χ=0.572, p=0.449),但未獲得pCR的新輔助患者生存獲益明顯差于術(shù)后輔助化療患者(DFS:χ=8.359,p=0.004; OS: χ=12.579,p=0.000)。將Ⅱ、Ⅲ期的新輔助化療組和輔助化療組病例進行生存分析,結(jié)果發(fā)現(xiàn)Ⅱ、Ⅲ期患者接受新輔助化療和術(shù)后輔助化療后的DFS、OS同樣沒有統(tǒng)計學(xué)差異(Ⅱ期DFS:χ=0.266,p=0.606; OS:χ=0.098,p=0.754; Ⅲ期DFS:χ=0.100,p=0.752; OS:χ=2.494, p=0.114)。接受保乳手術(shù)的患者與接受保乳手術(shù)后化療、新輔助化療后未行保乳的患者的DFS、OS均無統(tǒng)計學(xué)差異(新輔助化療保乳vs保乳后化療DFS：χ2=0.097,p=0.756；OS:χ2=0.077,p=0.781新輔助化療保乳vs新輔助化療后未保乳DFS: χ2=0.571,p=0.450；OS:χ2=0.629,p=0.428)。結(jié)論：1、乳腺癌新輔助化療的患者中,高體重、高BMI、哺乳時間短、查體腫瘤直徑小、化療前ER(-)、PR(-)、HER2陽性表達者具有更高的病理完全緩解率(pCR)；ER狀態(tài)和體重是pCR的獨立預(yù)測因子。2、不同臨床分期的乳腺癌患者間的pCR率無統(tǒng)計學(xué)差異；HER2過表達型和三陰型乳腺癌新輔助化療pCR率優(yōu)于luminal型,但HER2過表達型和三陰型乳腺癌間的pCR率無統(tǒng)計學(xué)差異。3、新輔助化療獲得pCR具有較好的預(yù)后傾向,但與未達pCR者相比差異無統(tǒng)計學(xué)意義；Ⅱ、Ⅲ期乳腺癌新輔助化療與術(shù)后輔助化療的預(yù)后無明顯差異;新輔助化療后接受保乳手術(shù)的患者并未增加復(fù)發(fā)、生存風(fēng)險。
[Abstract]:Background: breast cancer is one of the most common malignant tumors of women, women accounted for 1/4 of the total number of new cancer, mortality of female cancer mortality ranks 15%, the first female malignancy. Breast cancer is not only a serious threat to women's lives and health, but also to the economic, social, and caused a great impact data from the national family. The cancer center shows that in 2011 China's women approximately 248 thousand new cases of breast cancer cases, accounting for female primary cancer 37.86%. China cancer registry annual data show that in 2012 China's female breast cancer incidence rate has reached 42.55/10 million. With the continuous progress of science and technology, the development of treatment for breast cancer surgery, radiotherapy, chemotherapy, immune treatment and targeted therapy combined with comprehensive treatment mode systematically, and achieved a good clinical efficacy, but breast cancer is still an important reason for our female death. As an important part of the new treatment system, auxiliary Chemotherapy has been widely used in locally advanced patients, some operable breast cancer patients through selection of neoadjuvant chemotherapy, obtained downstaging chance of breast conserving surgery. Neoadjuvant chemotherapy can also select sensitive to chemotherapy, to reduce or eliminate the micrometastasis, prevent distant metastasis. In addition, patients treated with neoadjuvant the treatment of chemotherapy can also provide valuable prognostic information, such as previous studies that after neoadjuvant chemotherapy achieved pathological complete remission (pathological complete, remission, pCR) disease-free survival in patients who are not pCR patients can get a longer (disease-free survival, DFS) and overall survival (overall, survival, OS); reduce after chemotherapy, the Ki67 index also indicates better survival benefit. The neoadjuvant chemotherapy efficiency up to 60-90%, pathological complete remission rate was 20%, but it is still difficult to avoid some patients The progress of disease during chemotherapy, neoadjuvant chemotherapy and most patients up to pCR. on the newly diagnosed women with breast cancer, neoadjuvant chemotherapy, living conditions and other relevant information, to explore the predictors of neoadjuvant chemotherapy and pathological complete remission, neoadjuvant chemotherapy of the survival benefit, provide a reference for screening the neoadjuvant chemotherapy sensitivity, and then provide the basis for individualized treatment of breast cancer. Objective: To explore the 1. predictive factors of neoadjuvant chemotherapy and pathological complete remission; survival analysis of 2. cases of breast cancer, clear pCR prognostic value, survival difference between patients undergoing neoadjuvant chemotherapy and postoperative adjuvant chemotherapy patients, a clear drop whether affect the prognosis of patients with breast conserving period. Methods: female patients with breast cancer in the second hospital of Shandong University of breast surgery hospitalized during the period of 2004.5-2014.1, the pro Clinical data were collected and analyzed. The information collected included: age, height, weight, body mass index (BMI), menstruation, fertility, lactation, hypertension, family history of breast cancer, benign breast disease; tumor characteristics at diagnosis, status of axillary and supraclavicular lymph nodes of patients; surgery; patients with biopsy and surgical pathological type, histological grade, immunohistochemistry, tumor size, lymph node metastasis; postoperative chemotherapy, radiotherapy, endocrine therapy and so on; through telephone follow-up, with the medical records department of accessing the database and previous access to obtain recurrence and survival status of patients. Inclusioncriteria: group the patients in the second hospital of Shandong University underwent surgery and complete their treatment, patients with pathological types were nonspecific invasive breast carcinoma; exclusion criteria: non primary breast cancer, diagnosed as stage IV breast cancer, not in Shandong The second hospital completed the prescribed treatment regimen (chemotherapy, surgery), invasive cancer and carcinoma in situ. The special application of 2 test analysis of the relationship between categorical variables before chemotherapy and pCR, independent samples t test was used to analysis of the relationship between continuous variables and pCR before chemotherapy. The single factor analysis with variable statistical significance by two yuan Logistic multivariate regression analysis; using the method of Kaplan-Meier analysis and Log-rank analysis to obtain pCR cases and pCR cases did not get, the survival difference between different stages of cases of neoadjuvant chemotherapy and adjuvant chemotherapy. The P0.05 was statistically significant difference. Results: 1. basic characteristics description according to the inclusion criteria, from 2004.5-2014.1 in Shandong University second the hospital breast surgery hospital treatment of patients with breast cancer in 638 cases, of which 140 (21.94%) patients received neoadjuvant chemotherapy and radical surgery, 498 (78.06%) patients undergoing surgery .2.pCR analysis of influence factors of chemotherapy and postoperative adjuvant 2.1 single factor: compared with the untreated group of patients reached pCR, up to pCR groups average duration of breastfeeding (t=-3.447, p=0.001); small tumors (t=-2.509, p=0.013), and a higher proportion of less than 3cm in diameter (x 2=9.840, p= 0.002); weight or BMI larger (weight: t=2.822, p=0.006; BMI:t=2.772, p=0.007, 60kg or BMI25) and a high proportion of weight (weight: X 2=5.563, p=0.018; BMI: X 2=5.280, p=0.022); neoadjuvant chemotherapy cycle length (t=3.762, p=0.000). But not as pCR group and pCR group of average age, average height the past history, milk product proportion, menopause ratio, the proportion of benign breast disease history, family history of breast cancer, the proportion of hypertension, the proportion of diabetes, clinical stage ratio difference was not statistically significant (P0.05). Compared with the pCR group did not reach, pCR cases have more The high percentage of ER negative (62.5%vs22.6%, X 2=15.194, p=0.000); the higher the proportion of negative PR (70.8%vs41.7%, X 2=6.751, p=0.013); the positive rate of HER-2 higher (47.4%vs19.0%, X =6.762, p=0.009). The pCR group and the pCR group did not reach the histological grading was not statistically significant (2=1.119, p=0.572).PCR the Ki-67 index is less than pCR group, but the difference was not statistically significant (46.1%vs35.9%, t=1.973, p=0.051); Ki-67 in 14% as the boundary value, divided into low expression group of high expression group were tested, also showed no prognostic significance of Ki-67 of pCR (2=3.282, p=0.070).HER2 overexpression rate of pCR A is higher than that of luminal type and luminal type B pCR rate, the difference was statistically significant (x 2=7.697, p=0.006 x 2=13.807, p=0.001; pCR; three) negative rate is higher than that of luminal A and luminal B, but the luminal A pCR rate difference was not statistically significant (2=3.715, p=0.054), and Lumi Nal B pCR rate was statistically significant (2=5.125, p=0.024); three yin neoadjuvant chemotherapy of breast cancer after pCR was lower than that of HER2 over expression, but the difference was not statistically significant (2=0.395, p=0.440) multivariate analysis of.2.2 regression analysis showed that: Logistic can be used as a pathological complete remission (pCR) independent predictors of indicators are: ER (OR=0.047,95%CI:0.008-0.283). Body weight (OR=1.143,95%CI:1.026-1.273) survival analysis of neo adjuvant chemotherapy in patients with.3. after neoadjuvant chemotherapy pCR group and pCR group did not reach the recurrence free survival had no significant difference (2=0.138, p=0.711); although the follow-up time in pCR group were no deaths, but overall survival analysis no statistically significant differences between the pCR group and the overall survival did not reach pCR group (x 2=2.982, p=0.084). Neoadjuvant chemotherapy was pCR patients with postoperative adjuvant chemotherapy in patients with no significant difference between the survival benefit (DFS: x =1.896, p=0. 169; OS: x =0.572, p=0.449), a new auxiliary survival benefit in patients with pCR but did not get significantly worse on postoperative adjuvant chemotherapy (DFS: x =8.359, p=0.004 x =12.579; OS:, p=0.000). 2, the survival analysis phase III neoadjuvant chemotherapy group and chemotherapy group were found 2 after DFS, adjuvant chemotherapy for stage III patients received neoadjuvant chemotherapy and postoperative OS, also no statistically significant difference (II DFS: x =0.266, OS: x =0.098, p=0.606; p=0.754; phase III DFS: x =0.100, p=0.752 x =2.494; OS:, p=0.114). Breast conserving surgery in patients with breast conserving surgery chemotherapy, neoadjuvant chemotherapy after breast conserving patients DFS, OS were not statistically significant (neoadjuvant chemotherapy of breast conserving vs after chemotherapy: DFS x 2=0.097 x 2=0.077, p=0.756; OS:, p=0.781 neoadjuvant chemotherapy breast conserving vs neoadjuvant chemotherapy after breast conserving DFS: x 2= 0.571, p=0.450; OS: x 2=0.629, p=0.428). Conclusion: 1, neoadjuvant chemotherapy for breast cancer patients, high weight, high BMI, duration of breastfeeding, check the small diameter of the tumor before chemotherapy, ER (-), PR (-), the positive expression of HER2 had higher pathological complete remission rate (pCR); ER and.2 are independent of weight status predictors of pCR, different clinical stages of breast cancer among patients with pCR was no significant difference; over expression of HER2 and three negative breast cancer neoadjuvant chemotherapy of pCR was better than luminal, but the over expression of HER2 and three negative breast cancer among pCR was no significant difference in.3, pCR received neoadjuvant chemotherapy has a good prognosis tendency, but with less than pCR were no statistically significant differences between them; II, no significant differences in prognosis and adjuvant chemotherapy neoadjuvant chemotherapy for stage III breast cancer and postoperative; breast conserving surgery patients did not increase the recurrence after neoadjuvant chemotherapy, survival risk.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R737.9

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