摘要
目的：乳腺癌是一种在临床表现、组织学形态、分子分型上都具有很强异质性的恶性肿瘤。三阴性乳腺癌(Triple Negative Breast Cancer, TNBC)定义为雌激素受体(estrogen receptor, ER)、孕激素受体(progesterone receptor, PR)表达均阴性、且无人表皮样生长因子受体2(human epidermal growth factor receptor2, Her2)过表达的一种亚型乳腺癌。TNBC一般恶性程度高、预后差、且具有异质性,迄今无公认的关键性预后生物标记物。Claudins (CLDNs)是细胞问紧密连接的重要组成部分,根据基础及临床研究结果推论,它们可能在乳腺癌的发生及发展中发挥重要的作用。Luminal型乳腺癌是最常见的另一亚型乳腺癌,约占60-80%,表现为激素受体阳性(HR+),而晚期乳腺癌有70%以上会发生骨转移,且骨转移更容易发生于HR+乳腺癌患者。本研究目的一旨在探讨CLDNs及Ki-67蛋白表达与临床预后的关系。另外探讨HR+乳腺癌单纯骨转移患者的预后因素和最佳治疗策略。
方法：一、收集中国医学科学院肿瘤医院自2004年7月至2006年12月可手术的173例TNBC患者。选择该组病例患者的乳腺肿瘤标本进行CLDN1, CLDN2, CLDN4, CLDN7和Ki-67免疫组化检测。CLDNs阳性表达的界值为膜表达10%,而Ki-67高表达的界值为15%。采用卡方检测和Kaplan-Meier法分析CLDNs和Ki-67蛋白表达在TNBC的临床病理特征和预后、化疗疗效的关系。同时多因素回归分析用于检验CLDNs和Ki-67蛋白表达在TNBC预后方面的作用。
二、收集2005年1月至2010年10月我院诊治的139例HR+乳腺癌单纯骨转移患者的临床病理资料,探讨不同治疗策略和临床因素对预后的影响,同时分析不同治疗策略对骨相关事件的影响。
结果：一、该组TNBC病例的中位年龄为54岁(范围：24-78岁),中位随访期为64.6月。CLDN1, CLDN2, CLDN4和CLDN7的阳性表达率为44.5%、54.9%、76.9%和73.4%；Ki-67蛋白高表达率为61.8%。整组病例分析结果显示,CLDN1阴性表达的患者无疾病复发时间(RFS)和总生存期(OS)显著缩短,P值均为<0.0001；无论是在淋巴结阳性(n=97),还是在淋巴结阴性亚组(n=76)中都得到了类似的结果。但是,CLDN2阴性表达仅增加淋巴结阳性患者的复发风险(P=0.008)。Ki-67高表达的患者较Ki-67低表达患者RFS明显缩短,(P=0.022),OS方面无显著差异；进一步分析提示CLDN1或CLDN2阴性表达且Ki-67阳性表达的患者RFS和OS均明显缩短,P<0.0001。CLDN1或CLDN2蛋白表达与是否含蒽环类或紫杉类辅助化疗方案的疗效无关。同样,CLDNs蛋白表达及Ki-67蛋白表达与新辅助化疗疗效及晚期TNBC一线化疗的疗效无相关性,P>0.05。只有CLDN1阴性表达与淋巴结转移状态相关,P=0.014,然而CLDN1(?)性表达与间质淋巴细胞浸润有关,P=0.017；此外年龄小于等于50岁、肿瘤细胞分级3级较年龄大于50岁、肿瘤细胞分级2级的TNBC患者CLDN4表达率明显增高,P值分别为0.012和0.003。多因素分析结果显示,CLDN1蛋白阳性表达是RFS和OS的独立预后良好因素(HR0.164,95%CI0.0079-0.338, P<0.0001; HRO.289,95%CI0.130-0.643, P=0.002)。但是,CLDN4或CLDN7蛋白表达与其他临床因素及预后均无显著关联。
二、全组激素受体阳性单纯骨转移患者平均年龄为47.9岁。139例患者中,接受一线化疗者99例,一线内分泌治疗者40例。139例患者中位总生存期为61月,一线化疗组与一线内分泌治疗组患者5年生存率无显著差异(HR0.687,95%CI0.307-1.539, P=0.362).单因素分析结果提示无病生存期>3年(HR0.333,95%CI0.138-0.803, P=0.014)、淋巴结转移小于10个组患者(HR0.239,95%CI0.102-0.562, P=0.001)预后较好,在COX多因素回归分析它们仍是独立的预后良好因素。一线化疗组总骨相关事件发生率较一线内分泌治疗组低,分别为45.4%(45/99)与62.5%(25/40),但差异无显著性(P=0.092)。
结论：一、总的来说,大多数TNBC乳腺肿瘤组织Ki-67高表达。CLDN1蛋白表达与腋窝淋巴结转移显著负相关,而CLDN4阳性表达与肿瘤细胞高分级显著相关。尽管CLDN1和CLDN2阴性表达预示着TNBC患者预后变差,但是CLDN1、CLDN2和Ki-67可能并不能用于指导化疗方案的选择。建议开展前瞻性的临床研究,以探讨CLDN1和CLDN2在TNBC中肿瘤发生、发展中的生物学机制。
二、术后无病生存期>3年、淋巴结小于10个是HR+乳腺癌单纯骨转移患者独立的预后良好因素。这类患者一线无论选择内分泌治疗还是化疗,对总生存影响不明显,但一线化疗可能有助于减少骨相关事件,建议采取个体化治疗策略。
Objective Breast cancer (BC) comprises a heterogeneous group oftumors with different clinical characteristics, biologic features and various molecular subtypes.Triple negative breast cancer (TNBC) is defined as the absence of estrogen receptor (ER) and progesterone receptor (PR)expression and human epidermal growth factor receptor2(Her2) overexpression. TNBC is a heterogeneous distinct subtype without definite prognostic markers with aggressive behavior and worse prognosis. Claudins (CLDNs) are major components of the tight junction presumably playing an important role in carcinogenesis and progression of BC. Luminal breast cancer was characterized as hormone receptor positive (HR+) BC, which is the most prevalent another phenotype of BC, accounting for for60%-80%in all subtypes of breast cancer. More than70%metastatic breast cancer will develop bone metastasis. First, the study was aimed to investigate the association between CDLNs, Ki-67protein expression and clinical outcomes of TNBC.The sencond aim was to investigate treatment outcomes of different first-line regimens and prognostic factors forHR+breast cancer patients with bone-only metastasis.
Methods1. Altogether, a consecutive cohort of173TNBC cases in Cancer Hospital and Institute, Chinese Academy of Medical Sciences were retrospectively collected from Julylst,2004to Dec30,2006. Primary breast tumor specimens from the cohort of TNBC patients were analyzed for CLDN1, CLDN2, CLDN4, CLDN7and Ki-67expression by immunohistochemistry (IHC). The cut-off values for CLDNs and Ki-67positive expression are10%(membrane) and15%, respectively. Their relationships to clinicopathological parameters, clinical outcomes and chemotherapy efficacy were evaluated by Chi-square test and Kaplan-Meier method. And Multivariate Cox regression analysis was performed to determine the significance of CLDNs and Ki-67expression in survival of the cohort.
2.139HR+BrCa patients with bone-only metastasisbetween Jan1,2005and Oct31,2010were retrospectively reviewed. Clinical pathologic characteristics were analyzed, different treatment regimens and clinical factors on survivals were also estimated. Moreover, the effects of different treatment regimens on skeletal-related events (SREs) were explored.
Resultsl. Median age of the entire TNBC group was54years (range:24-78years). Median follow up was64.6months.CLDNl-, CLDN2-, CLDN4-, CLDN7-membrane positiveand Ki-67high expression were detected in44.5%,54.9%,76.9%,73.4%and61.8%of tumor samples, respectively. CLDN1-negative expression was correlated with worse recurrence free survival (RFS) and overall survival (OS)(P＜0.0001and P＜0.05, respectively), no matter in lymph node positive (LN+) or lymph node negative (LN-) patients. Only CLDN2-negative expression cases in LN+subgroup demonstrated significantly higher risk of recurrence (P=0.008). Cases with Ki-67high expression had shown worse RFS compared tocases with Ki-67low expression, Pvalue had significance (P=0.022), but no significant difference had been detected in OS between Ki-67positive and Ki-67negative cases. Patients with CDLN1-or CLDN2-negative and Ki-67high expressionshowed significantly worse RFSor OS time than those with either CLDN1-or CLDN2-positive or Ki-67low expression (P＜0.0001).Regarding to chemotherapy regimens, protein expression of CLDN1or CLDN2had no correlation with prognosis of cases with or without anthracycline-based or taxane-based (neo) adjuvant chemotherapy regimens. Theresults showed that CLDNs protein expression or Ki-67expression had no significant correlation with the efficacy of chemotherapy whether in neo-adjuvant or first line metastatic setting. Only CLDN1-negative expression was related to lymph node metastasis (P=0.014), but CLDN1-positve expression was associated with interstitial lymphocytes infiltration, P=0.017. CLDN4expression was significantly higher in TNBC patients≤50years old with tumor grade3compared to TNBC patients>50years old with tumor grade2(P=0.012and P=0.003, respectively).Multivariate analysis revealed that CLDN1positive expression was an independent prognostic factor for decreased risk of recurrence and death (HR0.164,95%CI0.0079-0.338, P<0.0001; HR0.289,95%CI0.130-0.643, P=0.002). However, CLDN4or CLDN7expression wasnot associated with other clinical characteristics or survival parameters.
2. Mean age of the cohort with HR+bone-only metastasis was47.9years. In this cohort,99patients received first-line chemotherapy regimens, and40patients received first-line endocrine drugs. Medianoverall survival time of all patients was61months.No significant difference was noted in5-year overall survival rate between first-line chemotherapy group (49.4%) and first-line endocrine group (44.3%)(HR0.687,95%CI0.307-1.539, P=0.362). Furthermore, interval of disease-free survival>3years and number of positive lymph nodes<10were favorable prognostic factors by univariate analyses (HR0.333,95%CI0.138-0.803, P=0.014; HR0.239,95%CI0.102-0.562, P=0.001); and they were also independent favorable prognostic factors on multivariate Cox-regression analyses. The proportion of patients with SREs was decreased by first-line chemotherapy group compared with first-line endocrine drugs group,45/99(45.4%) VS25/40(62.5%) respectively, nonetheless, the difference was not significant (P=0.092).
Conclusion
1. Overall, most of cases had high expression level of Ki-67. CLDN1expression was negatively correlated with lymphnode metastasis. However, CLDN4-positive expression was associated with higher tumor grade. CLDN1-and CLDN2-negative expression or Ki-67high expression is poor prognostic marker for clinical outcomes of TNBC, but not predictive markers for adjuvant chemotherapy. Prospective studies to explore the underlying mechanism of CLDN1and CLDN2in TNBC are warranted.
2. Interval of disease-free survival>3years and number of positive lymphnodes10were independent favorable prognostic factors. The overall survivalof HR+BrCa patients with bone-only metastasis was not significantly different between first-line chemotherapy group and endocrine therapy group. First-line chemotherapy may help prevent incidence of SREs. Both endocrine therapy and chemotherapy are effective for HR+BrCa patients with bone-only metastasis and should be prescribed individually.
引文
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