乳腺癌新辅助化疗疗效预测因子的研究及预后分析

发布时间：2018-01-08 12:33

本文关键词：乳腺癌新辅助化疗疗效预测因子的研究及预后分析　出处：《山东大学》2015年硕士论文　论文类型：学位论文

【摘要】：背景：乳腺癌是女性最常见的恶性肿瘤之一,占女性新发癌症总数的1/4,死亡率占女性癌症的15%,居女性恶性肿瘤死亡率之首。乳腺癌不仅严重威胁着女性的生命和身心健康,还对经济、社会、家庭造成极大的影响。国家癌症中心数据显示,2011年我国女性乳腺癌新发病例约24.8万例,占女性新发癌种的37.86%。中国肿瘤登记年报数据显示,2012年我国女性乳腺癌发病率已高达42.55/10万。随着科技不断进步,乳腺癌治疗发展为手术、放疗、化疗、免疫治疗和靶向治疗相结合较系统的综合治疗模式,取得了良好的临床疗效,但乳腺癌仍为我国女性重要的死亡原因。作为系统治疗的重要组成部分,新辅助化疗已在局部晚期病人中得到广泛应用,部分可手术乳腺癌患者也通过选择新辅助化疗,获得了降期保乳手术的机会。新辅助化疗还可以选择出敏感化疗方案,消除或减少微转移灶,防止远处转移等。此外,患者进行新辅助化疗还可以为其后续治疗提供宝贵的预后信息,例如以往研究认为新辅助化疗后达到病理完全缓解(pathological complete remission, pCR)的病人较未达pCR病人可获得更长的无病生存(disease-free survival, DFS)和总生存(overall survival, OS);新辅助化疗后Ki67指数的降低同样预示着较好的生存获益。目前新辅助化疗的有效率可达60-90%,病理完全缓解率20%,但仍然难以避免出现部分患者化疗期间病情进展的情况,而且大部分病人新辅助化疗后达不到pCR。本研究通过收集女性乳腺癌患者初诊、新辅助化疗前后、生存状况等的相关资料,探寻新辅助化疗病理完全缓解的预测指标,分析新辅助化疗者的生存获益,为筛选出新辅助化疗敏感者提供参考,进而为乳腺癌个体化治疗提供依据。目的：1.探索新辅助化疗病理完全缓解的预测因子；2.对乳腺癌病例进行生存分析,明确pCR的预后预测价值,比较新辅助化疗病人及术后辅助化疗病人的生存差异,明确降期保乳是否影响患者预后。方法：回顾2004.5-2014.1期间于山东大学第二医院乳腺外科入院治疗的女性乳腺癌患者,对其临床资料进行收集及分析。收集的信息包括：患者年龄、身高、体重、身体质量指数(BMI)、月经状态、生育情况、哺乳情况,高血压病史、乳腺癌家族史、乳腺良性疾病史；初诊时肿瘤特点、腋窝及锁骨上淋巴结状态；患者所接受手术方式；患者活检及手术病理类型、组织学分级、免疫组化、肿瘤切面积、淋巴结转移情况；术后化疗、放疗、内分泌治疗等情况；通过电话随访、科室随访库及既往病历查阅获取患者复发及生存状况。入组标准：入组患者均于山东大学第二医院接受手术并完成其治疗方案,患者病理类型均为浸润性非特殊癌；排除标准：非初发乳腺癌、初诊为IV期的乳腺癌、未于山东大学第二医院完成规定的治疗方案(化疗、手术)、浸润性特殊癌及原位癌。应用χ2检验分析化疗前分类变量与pCR的关系,采用独立样本t检验分析化疗前连续性变量与pCR的关系。单因素分析具有统计学意义的变量采用二元Logistic回归进行多因素分析；采用Kaplan-Meier法分析及Log-rank检验分析获得pCR的病例与未获得pCR病例、不同分期病例新辅助化疗与辅助化疗的生存差异。以p0.05为差异具有统计学意义。结果：1.基本特征描述根据入组标准,从2004.5-2014.1期间于山东大学第二医院乳腺外科入院治疗的乳腺癌患者638例,其中140(21.94%)名接受新辅助化疗并行根治性手术,498(78.06%)名患者接受手术及术后辅助化疗。2.pCR影响因素分析2.1单因素分析：与未达到pCR组的患者相比,达到pCR组病例平均哺乳时间短(t=-3.447,p=0.001)；肿瘤小(t=-2.509,p=0.013),且直径≤3cm的比例更高(χ2=9.840,p=0.002)；体重或BMI值更大(体重：t=2.822,p=0.006；BMI：t=2.772,p=0.007),而体重60kg或BMI25的比例高(体重：χ2=5.563,p=0.018;BMI：χ2=5.280,p=0.022)；新辅助化疗周期长(t=3.762,p=0.000)。而未达pCR组和达到pCR组间平均年龄、平均身高、既往积乳史者比例、绝经者比例、乳腺良性疾病史者比例、有乳腺癌家族史者比例、高血压病史者比例、糖尿病史者比例、临床分期比例差异没有统计学意义(p0.05)。与未达到pCR组相比,pCR组病例有较高的ER阴性比例(62.5%vs22.6%,χ2=15.194,p=0.000)；较高的PR阴性比例(70.8%vs41.7%,χ2=6.751,p=0.013);较高的HER-2阳性比例(47.4%vs19.0%,χ=6.762,p=0.009)。而pCR组与未达pCR组的组织学分级没有统计学差异(χ2=1.119,p=0.572)。pCR组的Ki-67指数较未达pCR组高,但没有统计学差异(46.1%vs35.9%,t=1.973,p=0.051);将Ki-67以14%为界值,分为低表达组高表达组进行检验,也未表现出Ki-67对pCR的预测意义(χ2=3.282,p=0.070)。HER2过表达型pCR率高于luminal A型和luminal B型的pCR率,差异具有统计学意义(χ2=7.697,p=0.006；χ2=13.807,p=0.001)；三阴型pCR率同样高于luminal A型和luminal B型,但其与luminal A型的pCR率差异没有统计学意义(χ2=3.715,p=0.054),与luminal B型的pCR率差异有统计学意义(χ2=5.125,p=0.024)；三阴型乳腺癌新辅助化疗后pCR率低于HER2过表达型,但两者差异无统计学意义(χ2=0.395,p=0.440)。2.2多因素分析：Logistic回归分析发现可做为病理完全缓解(pCR)独立预测指标的因素有：ER(OR=0.047,95%CI:0.008-0.283).体重(OR=1.143,95%CI：1.026-1.273)。3.新辅助化疗患者生存分析新辅助化疗后pCR组和未达到pCR组的无复发生存无明显差异(χ2=0.138,p=0.711)；尽管在随访时间内pCR组没有死亡病例,但总生存分析发现pCR组与未达到pCR组的总生存没有统计学差异(χ2=2.982,p=0.084)。新辅助化疗获得pCR患者与术后辅助化疗患者的生存获益无明显差异(DFS:χ=1.896, p=0.169; OS:χ=0.572, p=0.449),但未获得pCR的新辅助患者生存获益明显差于术后辅助化疗患者(DFS:χ=8.359,p=0.004; OS: χ=12.579,p=0.000)。将Ⅱ、Ⅲ期的新辅助化疗组和辅助化疗组病例进行生存分析,结果发现Ⅱ、Ⅲ期患者接受新辅助化疗和术后辅助化疗后的DFS、OS同样没有统计学差异(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)。接受保乳手术的患者与接受保乳手术后化疗、新辅助化疗后未行保乳的患者的DFS、OS均无统计学差异(新辅助化疗保乳vs保乳后化疗DFS：χ2=0.097,p=0.756；OS:χ2=0.077,p=0.781新辅助化疗保乳vs新辅助化疗后未保乳DFS: χ2=0.571,p=0.450；OS:χ2=0.629,p=0.428)。结论：1、乳腺癌新辅助化疗的患者中,高体重、高BMI、哺乳时间短、查体肿瘤直径小、化疗前ER(-)、PR(-)、HER2阳性表达者具有更高的病理完全缓解率(pCR)；ER状态和体重是pCR的独立预测因子。2、不同临床分期的乳腺癌患者间的pCR率无统计学差异；HER2过表达型和三阴型乳腺癌新辅助化疗pCR率优于luminal型,但HER2过表达型和三阴型乳腺癌间的pCR率无统计学差异。3、新辅助化疗获得pCR具有较好的预后倾向,但与未达pCR者相比差异无统计学意义；Ⅱ、Ⅲ期乳腺癌新辅助化疗与术后辅助化疗的预后无明显差异;新辅助化疗后接受保乳手术的患者并未增加复发、生存风险。
[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.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R737.9

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