生物学因子与乳腺癌新辅助化疗疗效的相关性研究
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摘要
目的：
随着对乳腺癌认识的发展,乳腺癌为全身疾病的观点已被广泛接受。新辅助化疗作为乳腺癌全身治疗的重要方面,具有缩小肿瘤,提高保乳率；控制全身微小转移灶,抑制术中肿瘤细胞转移活性；提供肿瘤化疗敏感性信息,为化疗方案选择提供依据等多种优点。多项临床研究显示,行新辅助化疗后达到病理完全缓解的患者有较长的总生存期(OS)及无病生存期(DFS),为重要的生存预后指标。
目前乳腺癌新辅助化疗的病理完全缓解率约3%-30%,大部分患者未能达到病理完全缓解,甚至部分患者因对化疗药物耐药而出现疾病进展,因此寻找能有效预测新辅助化疗疗效的指标,筛选出敏感患者进行个体化治疗,在提高新辅助化疗效率的同时,还可使不敏感患者避免不必要的化疗毒不良反应,对指导乳腺癌的临床治疗意义重大。
我们通过研究乳腺癌生物学因子ER、PR、HER2、Ki67、p53、Bcl-2及Topo-Ⅱα表达情况与新辅助化疗后病理完全缓解之间的关系,探索上述指标对乳腺癌新辅助化疗病理完全缓解的预测价值,为筛选新辅助化疗敏感患者提供参考依据。
对象与方法：
采用1：1匹配的病例对照研究方法,收集山东大学第二医院乳腺外科自2008年12月至2010年12月收治的行TE方案新辅助化疗并达到病理完全缓解的浸润性导管癌患者15例,作为研究组。所有患者均为女性,年龄34-62岁,中位年龄为48岁,其中绝经前患者7例,绝经后患者8例。其中ⅡA期6例、ⅡB期4例、ⅢA期5例,化疗前系统检查均未发现远处转移。所有患者均进行TE(多西他赛75mg/m2,表阿霉素60mg/m2)方案新辅助化疗治疗,治疗疗程为3-6周期,平均疗程为5.3±1.18周期。
从我科乳腺癌新辅助患者数据库筛选出行TE方案新辅助化疗,并未达到病理完全缓解的患者,与研究组15例患者按照年龄(±5岁)、绝经与否、肿瘤类型、肿瘤分期(大小±1cm)、化疗疗程情况按1：1进行配对,作为对照组。所有患者行新辅助化疗前均未接受化疗、放射治疗及内分泌治疗。
对研究组及对照组患者新辅助化疗前麦默通切检标本,采用免疫组化(即用型二步法)检测其ER、PR、HER2、Ki67、p53、Bcl-2及Topo-Ⅱα的表达情况,分析上述指标与乳腺癌新辅助化疗病理完全缓解之间的关系。所有数据分析应用SPSS16.0统计学软件完成。
结果：
研究组中,ER阳性比例为33.3%(5例),阴性比例为66.7%(10例),对照组中,ER阳性比例为80%(12例),阴性比例为20%(3例)。Ki67阳性细胞比例为0-20%的患者在研究组与对照组中分别为1例(6.7%)及5例(33.3%)、21%40%分别为6例(40%)及4例(26.7%)、41%-60%分别为2例(13.3%)及4例(26.7%)、61%-80%分别为6例(40%)及2例(13.3%)。单因素分析发现化疗前切检标本的ER阴性及Ki67高指数与新辅助化疗后病理完全缓解有关(p<0.05)。多因素分析发现仅ER表达状态为乳腺癌新辅助化疗病理完全缓解独立的预测指标(p=0.05,OR=0.125,95%CI：0.016-0.999)。乳腺癌新辅助化疗前切检组织中PR、HER2、p53、Bcl-2及Topo-Ⅱα的表达情况在研究组与对照组间的差异无统计学意义(p>0.05)。
结论：
新辅助化疗前切检标本ER阴性表达及Ki67高指数的患者有较高的病理完全缓解率,而PR、HER2、p53、Bcl-2及Topo-Ⅱα表达情况与病理完全缓解无显著性相关。仅ER阴性表达状态可作为乳腺癌新辅助化疗病理完全缓解独立的预测指标,该研究结果可为我们筛选新辅助化疗敏感患者提供参考依据,指导乳腺癌临床治疗。
Purpose
With the development of the knowledge about breast cancer, the view that breast cancer is an systemic disease has been widely accepted. Neoadjuvant chemotherapy has been a very important part of breast cancer systemic treatment. Neoadjuvant chemotherapy can downsize the tumors and increase the rate of breast-conserving surgery; control the micro-metastasis focus; provide information on tumor response to the chemotherapeutic agent. Many clinical researches show that the pathological complete responses after neoadjuvant chemotherapy helps in achieving longer overall survival and disease-free survival.
But only 3%～30% of patients that accept breast cancer neoadjuvant chemotherapy can get pathological complete responses. Most patients can't get pathological complete responses. Beside, some patients have disease progression because of resistance to the chemotherapeutic agent. So finding the indicators that can predict the neoadjuvant chemotherapy's effect is very important to individual therapy.
We had studied the relationship between the expression of the biological markers including ER, PR, HER2, Ki67, p53, Bcl-2 and Topo-Ⅱαand the pathological complete responses after neoadjuvant chemotherapy. The goal of this study was to explore the predictive value of those biological markers for the pathological complete responses of neoadjuvant chemotherapy in breast cancer.
Participants and methods:
This was a 1:1 match case-control study. From December 2008 to December 2010,15 female patients with breast cancer in the Second Hospital Of Shandong University Breast Surgery Department getting pathological complete responses after taking TE neoadjuvant chemotherapy were enrolled in the study group. Age from 34-62 years old (medianage 48),7 patients were premenopause and 8 patients were postmenopausal. All of the tumor were Invasive ductal carcinomas, stageⅡA 6 cases, stageⅡB 4 cases, stageⅢA 5 cases. All of the patients did not discover distant metastases. They were gave TE (Docetaxel 75mg/m2 +Epirubicin 60mg/m2) neoadjuvant chemotherapy for 3～6 cycles(mean 5.3±1.18).
The 15 cases in the study group were 1:1 paired with patients form the data base of TE neoadjuvant chemotherapy patients that did not get the pathological complete responses in our department, according to age(±5 years), pausimenia or not, pathologic category, tumor size(±1cm) and Chemotherapy cycles. The screened 15 patients were enrolled as the control group. All of the patients did not get any chemotherapy, radiotherapy or endocrine therapy before enrolled in this study.
We examine the expression of the ER, PR, HER2, Ki67, p53, Bcl-2 and Topo-Ⅱαusing the immunohistochemistry (twostepmethod) and learn the relationship between those biological markers and pathological complete responses. All statistical analysises were performed by SPSS16.0.
Results:
In the study group, the rate of ER positive was 33.3%(5 cases), and the rate of ER negative was 66.7%(10 cases).In the control group, the rate of ER positive was 80%(12 cases), and the rate of ER negative was 20%(3 cases).The Ki67 scores from 0 to 20% of the study group and the control group were 6.7%(1 cases) and 33.3%(5 cases); 21%～40% were 40%(6 cases) and 26.7%(4 cases); 41%～60% were 13.3%(2 cases) and 26.7%(4 cases); 61%～80% were 40%(6 cases) and 13.3%(2 cases). Using the matching counting material McNemarχ2 Test, we could get that ER state had relationship with pathological complete responses of the neoadjuvant chemotherapy (p=0.039). By the Wilcoxon Ranks Test, we could get that Ki67 also had relationship with pathological complete responses(Z=-2.07, p=0.039). In a multivariate model, ER negative was the only predictive of the pathological complete responses (p=0.05, OR=0.125,95%CI:0.016～0.999).The statuses of PR, HER2, p53, Bcl-2 and Topo-Ⅱαdid not show significant difference between the study group and the control group(p>0.05).
Conclusion:
ER state and Ki67 score had relationship with pathological complete responses of the neoadjuvant chemotherapy. The statuses of PR, HER2, p53, Bcl-2 and Topo-Ⅱαdid not show significant difference between the study group and the control group. ER negative was the only predictive of the pathological complete responses of the neoadjuvant chemotherapy which could guide the clinical treatment of breast cancer.
随着对乳腺癌认识的发展,乳腺癌为全身疾病的观点已被广泛接受。新辅助化疗作为乳腺癌全身治疗的重要方面,具有缩小肿瘤,提高保乳率；控制全身微小转移灶,抑制术中肿瘤细胞转移活性；提供肿瘤化疗敏感性信息,为化疗方案选择提供依据等多种优点。多项临床研究显示,行新辅助化疗后达到病理完全缓解的患者有较长的总生存期(OS)及无病生存期(DFS),为重要的生存预后指标。
目前乳腺癌新辅助化疗的病理完全缓解率约3%-30%,大部分患者未能达到病理完全缓解,甚至部分患者因对化疗药物耐药而出现疾病进展,因此寻找能有效预测新辅助化疗疗效的指标,筛选出敏感患者进行个体化治疗,在提高新辅助化疗效率的同时,还可使不敏感患者避免不必要的化疗毒不良反应,对指导乳腺癌的临床治疗意义重大。
我们通过研究乳腺癌生物学因子ER、PR、HER2、Ki67、p53、Bcl-2及Topo-Ⅱα表达情况与新辅助化疗后病理完全缓解之间的关系,探索上述指标对乳腺癌新辅助化疗病理完全缓解的预测价值,为筛选新辅助化疗敏感患者提供参考依据。
对象与方法：
采用1：1匹配的病例对照研究方法,收集山东大学第二医院乳腺外科自2008年12月至2010年12月收治的行TE方案新辅助化疗并达到病理完全缓解的浸润性导管癌患者15例,作为研究组。所有患者均为女性,年龄34-62岁,中位年龄为48岁,其中绝经前患者7例,绝经后患者8例。其中ⅡA期6例、ⅡB期4例、ⅢA期5例,化疗前系统检查均未发现远处转移。所有患者均进行TE(多西他赛75mg/m2,表阿霉素60mg/m2)方案新辅助化疗治疗,治疗疗程为3-6周期,平均疗程为5.3±1.18周期。
从我科乳腺癌新辅助患者数据库筛选出行TE方案新辅助化疗,并未达到病理完全缓解的患者,与研究组15例患者按照年龄(±5岁)、绝经与否、肿瘤类型、肿瘤分期(大小±1cm)、化疗疗程情况按1：1进行配对,作为对照组。所有患者行新辅助化疗前均未接受化疗、放射治疗及内分泌治疗。
对研究组及对照组患者新辅助化疗前麦默通切检标本,采用免疫组化(即用型二步法)检测其ER、PR、HER2、Ki67、p53、Bcl-2及Topo-Ⅱα的表达情况,分析上述指标与乳腺癌新辅助化疗病理完全缓解之间的关系。所有数据分析应用SPSS16.0统计学软件完成。
结果：
研究组中,ER阳性比例为33.3%(5例),阴性比例为66.7%(10例),对照组中,ER阳性比例为80%(12例),阴性比例为20%(3例)。Ki67阳性细胞比例为0-20%的患者在研究组与对照组中分别为1例(6.7%)及5例(33.3%)、21%40%分别为6例(40%)及4例(26.7%)、41%-60%分别为2例(13.3%)及4例(26.7%)、61%-80%分别为6例(40%)及2例(13.3%)。单因素分析发现化疗前切检标本的ER阴性及Ki67高指数与新辅助化疗后病理完全缓解有关(p<0.05)。多因素分析发现仅ER表达状态为乳腺癌新辅助化疗病理完全缓解独立的预测指标(p=0.05,OR=0.125,95%CI：0.016-0.999)。乳腺癌新辅助化疗前切检组织中PR、HER2、p53、Bcl-2及Topo-Ⅱα的表达情况在研究组与对照组间的差异无统计学意义(p>0.05)。
结论：
新辅助化疗前切检标本ER阴性表达及Ki67高指数的患者有较高的病理完全缓解率,而PR、HER2、p53、Bcl-2及Topo-Ⅱα表达情况与病理完全缓解无显著性相关。仅ER阴性表达状态可作为乳腺癌新辅助化疗病理完全缓解独立的预测指标,该研究结果可为我们筛选新辅助化疗敏感患者提供参考依据,指导乳腺癌临床治疗。
Purpose
With the development of the knowledge about breast cancer, the view that breast cancer is an systemic disease has been widely accepted. Neoadjuvant chemotherapy has been a very important part of breast cancer systemic treatment. Neoadjuvant chemotherapy can downsize the tumors and increase the rate of breast-conserving surgery; control the micro-metastasis focus; provide information on tumor response to the chemotherapeutic agent. Many clinical researches show that the pathological complete responses after neoadjuvant chemotherapy helps in achieving longer overall survival and disease-free survival.
But only 3%～30% of patients that accept breast cancer neoadjuvant chemotherapy can get pathological complete responses. Most patients can't get pathological complete responses. Beside, some patients have disease progression because of resistance to the chemotherapeutic agent. So finding the indicators that can predict the neoadjuvant chemotherapy's effect is very important to individual therapy.
We had studied the relationship between the expression of the biological markers including ER, PR, HER2, Ki67, p53, Bcl-2 and Topo-Ⅱαand the pathological complete responses after neoadjuvant chemotherapy. The goal of this study was to explore the predictive value of those biological markers for the pathological complete responses of neoadjuvant chemotherapy in breast cancer.
Participants and methods:
This was a 1:1 match case-control study. From December 2008 to December 2010,15 female patients with breast cancer in the Second Hospital Of Shandong University Breast Surgery Department getting pathological complete responses after taking TE neoadjuvant chemotherapy were enrolled in the study group. Age from 34-62 years old (medianage 48),7 patients were premenopause and 8 patients were postmenopausal. All of the tumor were Invasive ductal carcinomas, stageⅡA 6 cases, stageⅡB 4 cases, stageⅢA 5 cases. All of the patients did not discover distant metastases. They were gave TE (Docetaxel 75mg/m2 +Epirubicin 60mg/m2) neoadjuvant chemotherapy for 3～6 cycles(mean 5.3±1.18).
The 15 cases in the study group were 1:1 paired with patients form the data base of TE neoadjuvant chemotherapy patients that did not get the pathological complete responses in our department, according to age(±5 years), pausimenia or not, pathologic category, tumor size(±1cm) and Chemotherapy cycles. The screened 15 patients were enrolled as the control group. All of the patients did not get any chemotherapy, radiotherapy or endocrine therapy before enrolled in this study.
We examine the expression of the ER, PR, HER2, Ki67, p53, Bcl-2 and Topo-Ⅱαusing the immunohistochemistry (twostepmethod) and learn the relationship between those biological markers and pathological complete responses. All statistical analysises were performed by SPSS16.0.
Results:
In the study group, the rate of ER positive was 33.3%(5 cases), and the rate of ER negative was 66.7%(10 cases).In the control group, the rate of ER positive was 80%(12 cases), and the rate of ER negative was 20%(3 cases).The Ki67 scores from 0 to 20% of the study group and the control group were 6.7%(1 cases) and 33.3%(5 cases); 21%～40% were 40%(6 cases) and 26.7%(4 cases); 41%～60% were 13.3%(2 cases) and 26.7%(4 cases); 61%～80% were 40%(6 cases) and 13.3%(2 cases). Using the matching counting material McNemarχ2 Test, we could get that ER state had relationship with pathological complete responses of the neoadjuvant chemotherapy (p=0.039). By the Wilcoxon Ranks Test, we could get that Ki67 also had relationship with pathological complete responses(Z=-2.07, p=0.039). In a multivariate model, ER negative was the only predictive of the pathological complete responses (p=0.05, OR=0.125,95%CI:0.016～0.999).The statuses of PR, HER2, p53, Bcl-2 and Topo-Ⅱαdid not show significant difference between the study group and the control group(p>0.05).
Conclusion:
ER state and Ki67 score had relationship with pathological complete responses of the neoadjuvant chemotherapy. The statuses of PR, HER2, p53, Bcl-2 and Topo-Ⅱαdid not show significant difference between the study group and the control group. ER negative was the only predictive of the pathological complete responses of the neoadjuvant chemotherapy which could guide the clinical treatment of breast cancer.
引文
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