Study On The Prognostic Heterogeneity Of Breast Cancer

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).Conclusion1. 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.