Clinical pathological characteristics and prognostic analysis of diabetic women with luminal subtype breast cancer

This study selected luminal-type breast cancer patients as the study subjects. The patients were divided into groups according to the presence of diabetes and the types of medication used, and the patients' clinicopathological characteristics and prognostic indicators were explored. A total of 5,785 patients with luminal-type breast cancer admitted to Tianjin Medical University Cancer Institute and Hospital between January 2002 and December 2006 were selected as the study subjects. The subjects included 680 breast cancer patients with diabetes and 5,105 breast cancer patients without diabetes. The patients were divided into Luminal A, Luminal B (high ki67), and Luminal B (her-2/neu+) subtypes. Each subtype was further divided into a metformin group, a non-metformin group, and a nondiabetic group. The research indicators included breast cancer mortality, age, body mass index (BMI), amenorrhea, the presence of cardiovascular and cerebrovascular disease, pathological stage, pathological type, lymph node involvement, vessel carcinoma embolus, and the chemotherapy and endocrine regimen. A Kaplan–Meier analysis was conducted to analyze the differences in breast cancer mortality rates among the groups. The Cox proportional hazard model was adopted to detect independent factors related to prognosis. Kaplan–Meier univariate analysis showed that for the Luminal A, Luminal B (high ki67), and Luminal B (her-2/neu+) subtypes, the cancer-specific mortality rates differed significantly among the metformin, non-metformin, and nondiabetic groups. The 5-year survival rates were 94 %, 82 %, and 91 % (P?=?0.002); 93.5 %, 81 %, and 89 % (P?<?0.001); and 84 %, 77 %, and 83 % (P?=?0.035) for the subtypes within each group, respectively. Cox regression multivariate analysis showed that compared with the metformin group, all three subtypes of the, the non-metformin group showed poorer prognosis (hazard ratio [HR], 3.579; 95 % confidence interval [CI], 1.506–8.506 [P?=?0.004]; HR, 3.232; 95 % CI, 1.839–5.678 [P?<?0.001]; HR, 2.034; 95 % CI,1.019–4.059 [P?=?0.044] for Luminal A, Luminal B (high ki67), and Luminal B (her-2/neu+, respectively). Compared with the metformin group, the diabetic group showed poorer prognosis only for the Luminal B (high ki67) subtype (HR, 1.762; 95 % CI, 1.033–3.005 [P?=?0.038]). In addition, for the Luminal A, Luminal B (high ki67), and Luminal B (her-2/neu+) subgroups, there was a higher proportion of elderly patients (P?<?0.001) and postmenopausal patients (P?<?0.001) in the metformin and non-metformin groups than in the nondiabetic group. Moreover, the probability of having cardiovascular and cerebrovascular disease was also higher (P?<?0.001) in the metformin and non-metformin groups. For the Luminal B (high ki67) and Luminal B (her-2/neu +) subgroups, there was a higher proportion of obese patients in the metformin and non-metformin groups (P?<?0.001). In terms of clinical characteristics, for the Luminal B (high ki67) subtype, the proportion of patients with invasive ductal carcinoma was lower in the non-metformin group than in the other two groups (P?=?0.001). In both the metformin and non-metformin groups, the proportion of T3/4 patients was higher (P?<?0.001), the proportion of patients with lymph node metastasis was higher (P?=?0.001), and the proportion of patients with vessel carcinoma embolus was higher (P?=?0.001) compared with the nondiabetic group. In conclusion, compared with the metformin group, the non-metformin group had a poorer prognosis for all subtypes of luminal breast cancer. In the diabetic group, only patients with the Luminal B (high ki67) subtype exhibited a poorer prognosis. Therefore, different diabetes medication may have a different impact on the prognosis of different subtypes of luminal breast cancer.     

Predictive and prognostic significance of cytoplasmic expression of ELAV-like protein HuR in invasive breast cancer treated with neoadjuvant chemotherapy

Cytoplasmic HuR is associated with reduced survival in invasive breast cancer. We designed this study to determine the predictive and prognostic value of HuR expression in women with breast cancer who underwent neoadjuvant chemotherapy followed by surgical resection. We immunohistochemically analyzed cytoplasmic HuR expression in tumor biopsy cores obtained from 139 patients with invasive breast cancers who received paclitaxel and anthracycline-based neoadjuvant chemotherapy. We evaluated the relationship of HuR expression level with pathologic complete response (pCR), local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), recurrence-free survival (RFS), and overall survival (OS). Cytoplasmic HuR expression was present in 60 cases (43.2 %). The expression of cytoplasmic HuR was significantly associated with high nuclear grade (P < 0.0001) and ER (P = 0.001) and PR (P = 0.005) status. Multivariate regression analysis further revealed that high nuclear grade (P = 0.023), negative ER status (P = 0.043), and human epidermal growth factor receptor 2 (HER2) overexpression (P < 0.0001), but not cytoplasmic HuR expression, were significant independent predictors of pCR. Interestingly, multivariate Cox analysis revealed that cytoplasmic HuR expression was a strong independent predictor of reduced LRFS (P = 0.014), DRFS (P = 0.001), RFS (P < 0.0001), and OS (P = 0.019) irrespective of pCR. Furthermore, the patient group with tumors showing both expression of cytoplasmic HuR and non-pCR had a worse prognosis in LRFS (P = 0.048), DRFS (P < 0.0001), RFS (P < 0.0001), and OS (P = 0.001) than did other patient groups; patients with tumors showing negative cytoplasmic expression of HuR and pCR had the best prognosis in all RFS and OS. Cytoplasmic expression of HuR is an independent prognostic marker in breast cancer patients undergoing chemotherapy. Combination analyses of HuR expression and pCR, compared with pCR alone, can better predict clinical outcome in patients with primary breast cancer.     

Impacts of HER2-overexpression and molecular targeting therapy on the efficacy of stereotactic radiosurgery for brain metastases from breast cancer

Advances in chemotherapy for breast cancer (BC) have prolonged overall survival, especially for patients with human epidermal growth factor receptor-2 (HER2) positive cancer. We evaluated the effectiveness and limitations of stereotactic radiosurgery (SRS) for brain metastases (BM) from BC in conjunction with molecular targeting chemotherapy. Outcomes were retrospectively reviewed in 80 consecutive patients who underwent gamma knife SRS for BM from BC between January 2009 and February 2012. The overall survival (OS), neurological death-free survival (NS) and local tumor control endpoints were calculated, and prognostic factors were investigated using proportional hazards models. In 40 patients with HER2-overexpression, treatment results were compared between two sub-groups: lapatinib-based therapy (24 patients) versus non-lapatinib-based therapy (16 patients). The rates of 1- and 2-year OS after SRS were 50 and 26 %, respectively. The median survival time (MST) was 11.4 months. HER2-overexpression (P < 0.001), recursive partitioning analysis class (P = 0.018) and total planning target volume on initial SRS (P = 0.004) were associated with OS. The MSTs in HER2-positive and –negative patients were 16.6 and 7.1 months, respectively (P = 0.001). The rates of 1- and 2-year NS were 90 and 78 %, respectively. The rates of 1- and 2-year local tumor control were 84 and 70 %, respectively. Factors associated with local tumor control included lesion volume (P < 0.001) and peripheral dose (P = 0.003). In sub-analysis of patients with HER2-overexpression, lapatinib-based chemotherapy was also associated with better local tumor control (P = 0.002). The 1-year local tumor control rate of the lapatinib group was significantly better than that of the non-lapatinib group (86 vs. 69 %, P < 0.001). SRS is a safe and effective management option for selected patients with BM from BC. Patients with HER2-overexpressing tumors were found to be a distinct subgroup for which a longer survival time can be expected. Synergistic anti-tumor effects of lapatinib on BM in conjunction with SRS were suggested.     

Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers

The purpose of this article is to evaluate the prognostic value of androgen receptor (AR) expression in patients with estrogen receptor (ER)-positive breast cancer, treated with endocrine therapy, with or without the addition of chemotherapy. A consecutive series of 953 patients with ER-positive breast cancer, treated between 1998 and 2003, was selected. Repeated immunohistochemistry confirmed the expression of ER in the tumor of 938 patients. AR expression was measured by immunohistochemistry. The Kaplan–Meier method, logrank test and multivariate Cox models were used to explore the impact of AR expression on time to relapse (TTR) and disease specific survival (DSS) in all patients and in subgroups treated with chemo-endocrine therapy or endocrine therapy alone. AR immunoreactivity was assessable in 859 tumors and positive in 609 (70.9%). AR expression was a significant marker of good prognosis for TTR (P = 0.001) and DSS (P < 0.001). This effect was particularly evident in the group of patients receiving chemo-endocrine therapy (TTR (P = 0.015) and DSS (P < 0.001)). Cox models confirmed AR as an independent variable for both TTR (P = 0.003, HR 0.444, 95%CI 0.258–0.765) and DSS (P < 0.001, HR 0.135, 95%CI 0.054–0.337). Thus, we focused on ER-positive luminal B breast cancer that may be selected for chemotherapy because of their more aggressive immunophenotype. In this subset AR expression identified a group of patients with better prognosis for TTR (P = 0.017, HR 0.521, 95%CI 0.306–0.888) and DSS (P = 0.001, HR 0.276, 95% CI 0.130–0.588). AR expression is an independent prognostic factor of better outcome in patients with ER-positive breast cancers.     

Association between single nucleotide polymorphisms of the transforming growth factor-beta1 gene and overall survival in unresectable locally advanced non-small-cell lung cancer patients treated with radio(chemo)therapy in a Chinese population

Transmembrane protease, serine 4 (TMPRSS4), is a novel type II transmembrane serine protease that is highly expressed on the cell surface in pancreatic, thyroid, lung, and other cancer tissues, although its oncogenic significance and molecular mechanisms are unknown. In a series of 109 primary breast cancer patients, we performed a comprehensive analysis of TMPRSS4 expression using immunohistochemistry. The relationship between TMPRSS4 expression and the clinicopathological characteristics or prognosis was evaluated. Results showed that breast cancer tissues exhibited higher levels of TMPRSS4 expression compared with benign tissues (65.1 versus 17.5 %, P < 0.001). High expression of TMPRSS4 was significantly correlated with lymph node metastasis (P < 0.001), high pathological grade (P = 0.001), and tumor size >2 cm (P = 0.006), but not correlated with other clinicopathological parameters, including the patient’s age (P = 0.289), menopausal status (P = 0.300), histological subtype (P = 0.418), and status of estrogen receptor (ER) (P = 0.913), progesterone receptor (PR) (P = 0.247), and HER-2 (P = 0.882). Patients with high expression of TMPRSS4 had shorter OS and DFS than those with low expression (P = 0.0009 and P = 0.0044, respectively). TMPRSS4 expression and lymph node metastasis were independent prognostic factors for both OS and DFS by multivariate analysis. Based on our results, we propose TMPRSS4 as a putative biological marker for breast cancer and as an indicator of poor prognosis.     

Worse prognosis of metaplastic breast cancer patients than other patients with triple-negative breast cancer

The present study was designed to assess the clinical characteristics and outcomes of metaplastic breast cancer (MBC) compared to general invasive ductal carcinoma (IDC) and the triple-negative subtype (TN-IDC). The study population included 35 MBC and 2,839 IDC patients, including 473 TN-IDC diagnoses, from the National Cancer Center, Korea between 2001 and 2008. The clinicopathological characteristics and clinical outcomes were retrospectively reviewed. Mean age of patients was 47.4 years for the MBC group and 48.3 years for the IDC group. The MBC patients presented with a larger tumor size (≥T2, 74.3% vs. 38.8%, P < 0.001), more distant metastasis at the first diagnosis (8.6% vs. 2.0%, P = 0.04), higher histologic grade (grade 3, 65.7% vs. 41.4%, P < 0.001), fewer estrogen receptor (ER), and progesterone receptor (PgR) positivity (ER+, 5.7% vs. 65.4%, P < 0.001; PgR+, 8.6% vs. 55.8%, P < 0.001), higher Ki-67 expression (35.5 ± 26.2% vs. 20.6 ± 19.8%, P = 0.024), and more TN subtypes (80.0% vs. 16.7%, P < 0.001) compared to the IDC group. Fifteen (46.8%) MBC patients and 260 (9.3%) IDC patients experienced disease recurrence with a median follow-up of 47.2 months (range 4.9–100.6 months). MBC was a poor prognostic factor for disease recurrence and overall survival in univariate and multivariate analysis (HR 3.89 in recurrence, 95% CI: 1.36–11.14, P = 0.01; HR 5.29 in death, 95% CI: 2.15–13.01, P < 0.001). MBC patients also experienced more disease recurrence (HR 3.99, 95% CI: 1.31–12.19, P = 0.01) and poorer overall survival (HR 3.14, 95% CI: 1.19–8.29, P = 0.02) compared to the 473 TN-IDC patients, as reflected by aggressive pathological features. Patients with MBC appeared to have inherently aggressive tumor biology with poorer clinical outcomes than those with general IDC or TN-IDC.     

Ep-CAM RNA expression predicts metastasis-free survival in three cohorts of untreated node-negative breast cancer

Epithelial cell adhesion molecule (Ep-CAM) recently received increased attention as a prognostic factor in breast cancer. We aimed to validate the influence of Ep-CAM RNA expression in untreated node-negative breast cancer. Ep-CAM RNA expression was evaluated utilizing microarray-based gene-expression profiling in 194 consecutive node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting. The prognostic significance of Ep-CAM RNA expression for disease-free survival (DFS), metastasis-free survival (MFS), and breast cancer-specific overall survival (OS) was evaluated in univariate and multivariate analysis adjusted for age, grading, pTstage, ER as well as PR receptor and HER-2 status. Additionally, Ep-CAM RNA expression was compared with immunohistochemistry (IHC) for Ep-CAM in 194 patients. The prognostic impact of Ep-CAM gene expression was validated in further 588 node-negative breast cancer patients. Levels of Ep-CAM RNA expression showed a significant correlation with IHC (P = 0.001) and predicted in univariate analysis DFS (P = 0.001, HR = 2.4), MFS (P = 0.003, HR = 2.5), and OS (P = 0.002, HR = 3.1) accurately. The prognostic influence of Ep-CAM RNA was significant also in multivariate analysis for DFS (P = 0.017, HR = 2.0), MFS (P = 0.049, HR = 1.9), and OS (P = 0.042, HR = 2.3), respectively. The association with MFS was confirmed in an independent validation cohort in univariate (P = 0.006, HR = 1.9) and multivariate (P = 0.035, HR = 1.7) analysis. Ep-CAM RNA correlated with the proliferation metagene (P < 0.001, R=0.425) Nevertheless, in multivariate analysis, Ep-CAM was associated with MFS independent from the proliferation metagene (P = 0.030, HR = 1.8). In conclusion, Ep-CAM RNA expression is associated with poor MFS in three cohorts of untreated node-negative breast cancer.     

Luminal B型乳腺癌合并糖尿病患者临床病理特征及预后分析

  目的  探讨luminal B型乳腺癌合并糖尿病患者临床病理特征及预后特点。  方法  选取天津医科大学肿瘤医院2002年1月至2006年12月收治的luminal B型乳腺癌4 401例,其中合并糖尿病乳腺癌479例及未合并糖尿病乳腺癌3 392例。按照高敏感性luminal B和Her-2阳性luminal B两种亚型分组进行对比研究。各亚型进一步分组为二甲双胍治疗组、非二甲双胍治疗组和非糖尿病组。研究指标包括乳腺癌死亡率、临床病理分期、淋巴结状况、化疗方案及内分泌治疗方案。Kaplan-Meier方法分析各分组之间死亡率是否存在差异。Cox比例风险模型用于检测与预后相关的独立因素。  结果  Kaplan-Meier单因素分析法显示高敏感性luminal B、Her-2阳性luminal B型中二甲双胍治疗组、非二甲双胍治疗组和非糖尿病组癌症死亡率均存在显著性差异,5年生存率依次为93.5%、81.0%、89.0%（P < 0.001）和84.0%、77.0%、83.0%（P=0.035）。Cox回归模型多因素分析显示两类分型中相对于二甲双胍治疗组,非二甲双胍治疗组预后较差（P < 0.001,P=0.044）。但仅高敏感性luminal B分型相对于二甲双胍治疗组,非糖尿病组预后较差（P=0.038）。临床特征方面,二甲双胍治疗组和非二甲双胍治疗组T3~4期患者比例高（P < 0.001）,更易发生淋巴结转移（P=0.001）。  结论  luminal B型乳腺癌分型中以二甲双胍治疗组作为参考,非二甲双胍治疗组均预示较差的预后,其中仅高敏感性luminal B分型中非糖尿病组预示了较差的预后。糖尿病用药对不同的luminal B分型乳腺癌患者预后影响可能不同。      

Correlation of FANCM expression with clinical factors in luminal B breast cancer

Background

The genotype of Fanconi Anemia complementation group M (FANCM) was previously found to be associated with breast cancer risk in several populations. Here, we studied the expression of FANCM and its correlation with clinical characteristics in Chinese patients with breast cancer.

Methods

We performed an immunohistochemical study of FANCM protein in clinical breast cancer tissues from 310 patients along with 44 adjacent tissues.

Results

FANCM protein level is lower in triple-negative breast cancer tissues than in other subtypes (P = 0.008). In addition, high FANCM expression correlated with pathology type IDC (P = 0.040), estrogen receptor positive (P < 0.001), progesterone receptor positive (P = 0.001), and low Ki-67 status (P = 0.003). Multivariate analysis revealed that FANCM status was an independent prognostic factor for overall survival (P = 0.017) in luminal B breast cancer.

Conclusions

FANCM levels are significantly associated with different subtypes of human breast cancer. Specifically, FANCM could play a role in the progression of luminal B breast cancer.

     

Significance of vascular endothelial growth factor,interleukin-18 and nitric oxide in patients with breast cancer: correlation with carbohydrate antigen 15.3

The aim of this study was to determine serum concentrations of angiogenic factors including vascular endothelial growth factor (VEGF), interleukin 18 (IL-18) and nitric oxide (NO) in patients with breast cancer and to evaluate whether these factors will be correlated with CA 15.3, as a routine tumor marker for breast cancer or not. This study was conducted on 44 patients with breast cancer and 15 healthy individuals as a control group. The results demonstrated significant increase in serum IL-18, NO and CA 15.3 levels in sera of breast cancer patients when compared to those of the control group (P < 0.001, P = 0.016 and P < 0.001, respectively). However, the mean serum level of VEGF in patients as showed insignificant increase compared to that of the controls was not significant (P = 0.311). Sensitivity of CA 15.3, VEGF, IL-18 and NO to detect patients with disease was 52.2, 21.3, 77.2 and 70.4 %, respectively. In addition, positive status of serum CA 15.3 and/or IL-18 was found in 39 out of 44 (88.6 %) patients, and the positive status of serum CA 15.3 and/or NO was only found in 35 out of 44 (79.5 %). In conclusion, the simultaneous determination of IL-18 or NO in combination with the CA 15.3 may increase the sensitivity to diagnose breast cancer and may aid in disease prognosis.

     

Survival benefit from ovarian metastatectomy in colorectal cancer patients with ovarian metastasis: a retrospective analysis

Purpose

A recent study demonstrated that colorectal cancer (CRC) with ovarian metastases was less responsive to chemotherapy compared with extraovarian metastases. Hence, the ovary may actually represent a “sanctuary” for metastatic cells from CRC. The aim of the study was to investigate the impact of ovarian metastatectomy on survival of CRC patients with ovarian metastasis.

Methods

Between 1996 and 2008, 83 CRC patients underwent an oophorectomy. For the historical control, 47 CRC patients with ovarian metastasis without resection were included in the analysis.

Results

The median age was younger (48 years) in the oophorectomy group compared with the historical control (54 years; P = 0.012). The proportion of synchronous metastasis was higher in the oophorectomy group than in the control group (57 vs. 30%; P = 0.003). After a median follow-up duration of 60.8 months (range of 7.4–169.7 months), the median OS was significantly longer in the oophorectomy group (28.1 vs. 21.2 months, oophorectomy vs. non-oophorectomy; P = 0.038). For ovary-specific survival (date of ovarian metastasis diagnosis to death), CRC patients with an oophorectomy showed a significantly more favorable survival rate than the control group (20.8 vs. 10.9 months; P < 0.001). In univariate analyses, oophorectomy (P = 0.038), unilaterality of ovarian metastasis (P = 0.032), metastasis confined to ovaries (P < 0.001), normal CEA level (P < 0.001), good performance status (P = 0.001), palliative chemotherapy (P = 0.001), and primary disease resection (P = 0.005) were identified as significantly good prognostic factors for overall survival. The oophorectomy, chemotherapy, metastasis confined to ovaries, normal CEA level, and good performance status retained statistical significance at the multivariate level (P = 0.003, P = 0.004, P = 0.005, P = 0.015, and P = 0.029, respectively).

Conclusions

Based on this retrospective analysis, the ovarian metastatectomy significantly prolonged survival in CRC patients with ovarian metastases. The potential role of an ovarian metastatectomy in the management of CRC should be prospectively studied.     

Through the lens of culture: quality of life among Latina breast cancer survivors

Latinas have lower quality of life than Caucasian cancer survivors but we know little about factors associated with quality of life in this growing population. Bilingual staff conducted interviews with a national cross-sectional sample of 264 Latina breast cancer survivors. Quality of life was measured using the Functional Assessment of Cancer Therapy-Breast (FACT-B). Regression models evaluated associations between culture, social and medical context and overall quality of life and its subdomains. Latina survivors were 1–5 years post-diagnosis and reported a lower mean quality of life score compared to other published reports of non-Latina survivors (M = 105; SD = 19.4 on the FACT-B). Culturally based feelings of breast cancer-related stigma and shame were consistently related to lower overall quality of life and lower well-being in each quality of life domain. Social and medical contextual factors were independently related to quality of life; together cultural, social and medical context factors uniquely accounted for 62 % of the explained model variance of overall quality of life (Adjusted R ² = 0.53, P < 0.001). Similar relationships were seen for quality of life subdomains in which cultural, social, and medical contextual variables independently contributed to the overall variance of each final model: physical well-being (Adjusted R ² = 0.23, P < .001), social well-being (Adjusted R ² = 0.51, P < 0.001), emotional well-being (Adjusted R ² = 0.28, P < 0.001), functional well-being (Adjusted R ² = 0.41, P < 0.001), and additional breast concerns (Adjusted R ² = 0.40, P < 0.001). Efforts to improve Latinas’ survivorship experiences should consider cultural, social, and medical contextual factors to close existing quality of life gaps between Latinas and other survivors.     

Expression of HAb18G is associated with tumor progression and prognosis of breast carcinoma

HAb18G is a recently identified hepatoma-associated antigen and its association with tumor growth, invasion, and angiogenesis has been studied in a variety of tumors. However, its role in the tumor progression of breast cancer has not been explored. HAb18G expression was examined by immunohistochemistry in pathological sections of 1,637 breast tissue samples and by in situ hybridization in 41 cases of invasive breast carcinomas (BC). While not detected in any cases of tumor-like conditions or benign tumors of breast, and only rarely in normal tissue (4.4%), HAb18G expression was gradually up-regulated from atypical ductal hyperplasia (27.3%), to ductal carcinoma-in situ (59.8%), and to BC (61.4%) (P < 0.01). Its expression in BC was correlated positively with C-erbB-2 expression and histologic grade (P < 0.001), and negatively with the expression of estrogen and progesterone receptors (P < 0.001). Significant differences of expression were also identified among the subgroups of BC examined: in decreasing order from invasive micropapillary carcinoma, ductal carcinoma, lobular carcinoma, papillary carcinoma, medullary carcinoma, to mucinous adenocarcinoma (P = 0.001), corresponding to their known clinical aggressiveness. In an expanded group of 186 BC patients with proper follow up, our previous findings were confirmed: HAb18G expression was significantly associated with local recurrence, distant metastasis and tumor mortality (P < 0.01). We also demonstrated that up-regulated tumor expression of HAb18G was a significant predictor of reduced disease progression-free survival rate and a shorter overall survival, independent of systemic therapies. In conclusion, this study suggests that HAb18G expression is associated with BC progression and prognosis. Further evaluation of this new marker in breast cancer is indicated.     

Differential expression of immune-related markers in breast cancer by molecular phenotypes

The purpose of this study is to investigate the relationship between expression of immune-related molecules such as STAT1, CD20, IL-8, IFN-γ, tumor genetic phenotype, and the clinical course of invasive breast cancer. We constructed tissue microarrays from the breast cancers of 727 patients and classified the cases as either luminal A, luminal B, HER-2, or triple negative breast cancer (TNBC) based on standard pathological and clinical classifications using genetic phenotype. Surrogate immunohistochemical stains (STAT1, CD20, IL-8, IFN-γ) and HER-2 FISH were performed on each microarray. Of the 727 patients cases, 303 (41.7 %) were luminal A, 169 (23.2 %) were luminal B, 71 (9.8 %) were HER2+, and 184 (25.3 %) were TNBC. The expression of STAT1 in tumor cells was higher in luminal-type cancers than in HER2+ and TNBC (P < 0.001), and the TNBC-type tumors showed the highest levels of stromal STAT1 expression (P < 0.001), stromal IL-8 expression (P = 0.005), and CD20 index (P < 0.001). Luminal A type tumors showed the lowest expression of these markers. The stromal IL-8 positivity was associated with shorter DFS and OS in ER positive group, HER-2 negative group, and luminal A group (P < 0.05). To conclude, the immune-related molecules, STAT1, IFN-γ, IL-8, and CD20 are differentially expressed and define particular molecular subtypes which correlate with genetically defined types of tumors. High expression of STAT1 in tumor cells is observed in luminal-type tumors, whereas stromal expression of STAT1, stromal IL-8, and IL-8 in tumor cells is the highest in TNBC-type tumors.     

Changes in adherence to statins and subsequent lipid profiles during and following breast cancer treatment

Breast cancer tends to arise in older women who are also burdened with comorbidities such as cardiovascular disease (CVD). Increasing numbers of breast cancer survivors and an aging population warrant a better understanding of CVD management and adherence to preventive therapies. We estimated adherence to statins and therapeutic goal lipid values during the year before breast cancer diagnosis or baseline, treatment period, and in subsequent years of clinical management among breast cancer survivors. We sampled women from an existing cohort of 4,221 women diagnosed with incident early stage (I, II) invasive breast cancer from 1990 to 2008 and enrolled in a large integrated group practice health plan. Among prevalent statin users (N = 1,393), medication adherence and persistence were measured by medication possession ratio (MPR), % adherent (MPR < 0.80), and discontinuation rates. Laboratory data on LDL and HDL were obtained for the coinciding periods. Mean MPR for statin use (0.78 vs. 0.68; P < 0.001) and proportion adherent (67.0 vs. 51.9 %; P < 0.001) declined from baseline to the treatment period. Mean LDL (143 mg/dL baseline vs. 150 mg/dL treatment period; P < 0.001) and proportion not at LDL goal (60.1 vs. 70.8 %; P < 0.001) coincided with decreases in adherence. During treatment, non-adherent statin users had the highest mean LDL (160.4 mg/dL) and proportion not at goal LDL (91.8 %) overall. Adherence did not return to baseline in subsequent years following treatment although LDL levels did. HDL did not differ by periods of interest or adherence levels. Adherence to statins in this population was poor, particularly in the treatment period, and lagged in returning to baseline. Understanding the influence of life events such as cancer diagnosis and treatment on management of comorbidities and adherence to preventive therapies are important to the growing population of breast cancer survivors.     

The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer

Glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP) are commonly used as markers of endoplasmic reticulum (ER) stress. As an ER chaperone, GRP78 functions as a potent anti-apoptotic factor and confers drug resistance, whereas CHOP is a key initiating factor of ER stress-related cell death. We aimed at investigating the predictive values of GRP78 and CHOP in breast cancer patients who underwent adjuvant chemotherapy. An immunohistochemistry screen for GRP78 and CHOP was performed using a tissue microarray containing 250 tumors from female patients diagnosed with invasive ductal breast carcinoma at the Fudan University Shanghai Cancer Center. The staining results were scored semi-quantitatively, and a prediction model was constructed to verify the hypothesis. In this retrospective cohort study, CHOP correlated with prolonged disease-free survival (HR = 0.385, 95 % CI 0.215–0.688; P = 0.001), whereas GRP78 showed an opposite association (HR = 4.573; 95 % CI 2.291–9.128; P < 0.001). Moreover, in a GRP78-positive subset, CHOP overexpression correlated with a lower risk of recurrence. In the receiver operating characteristic analysis, the prediction capability of the predictive model combining the above two markers surpassed that of the traditional model (P = 0.0085 for the area under the curve comparison). Within the anthracycline-treatment subgroup, the combined GRP78 and CHOP exhibited similar predictive significance. Cumulatively, our findings suggest a tight association between ER stress markers and clinical outcomes for patients with breast cancer.     

Analysis of clinically relevant values of Ki-67 labeling index in Japanese breast cancer patients

Background

It has become important to standardize the methods of Ki-67 evaluation in breast cancer patients, especially those used in the interpretation and scoring of immunoreactivity. Therefore, in this study, we examined the Ki-67 immunoreactivity of breast cancer surgical specimens processed and stained in the same manner in one single Japanese institution by counting nuclear immunoreactivity in the same fashion.

Methods

We examined 408 Japanese breast cancers with invasive ductal carcinoma and studied the correlation between Ki-67 labeling index and ER/HER2 status and histological grade of breast cancer. We also analyzed overall survival (OS) and disease-free survival (DFS) of these patients according to individual Ki-67 labeling index.

Results

There were statistically significant differences of Ki-67 labeling index between ER positive/HER2 negative and ER positive/HER2 positive, ER negative/HER2 positive or ER negative/HER2 negative, and ER positive/HER2 positive and ER negative/HER2 negative groups (all P < 0.001). There were also statistically significant differences of Ki-67 labeling index among each histological grade (P < 0.001, respectively). As for multivariate analyses, Ki-67 labeling index was strongly associated with OS (HR 39.12, P = 0.031) and DFS (HR 10.85, P = 0.011) in ER positive and HER2 negative breast cancer patients. In addition, a statistically significant difference was noted between classical luminal A group and “20 % luminal A” in DFS (P = 0.039) but not between classical luminal A group and “25 % luminal A” (P = 0.105).

Conclusions

A significant positive correlation was detected between Ki-67 labeling index and ER/HER2 status and histological grades of the cases examined in our study. The suggested optimal cutoff point of Ki-67 labeling index is between 20 and 25 % in ER positive and HER2 negative breast cancer patients.     

Demographic and clinico-pathological characteristics in patients with triple-negative and non-triple-negative breast cancer

We investigate retrospectively the demographic and clinico-pathological characteristics of patients with triple-negative breast cancer (TNBC) compared to those with non-TNBC. Patients with breast cancer diagnosed from 1981 to 2008 in our clinic were retrospectively analyzed. Patient demographics including survival data and tumor characteristics were obtained from charts. A total of 795 patients were assessed in the study, including 140 patients (17.6%) with TNBC and 655 patients (82.4%) with non-TNBC. Patients with non-TNBC were further classified into 3 groups according to hormone receptor (HR) and HER-2 status. Median age was 49 (range 38–60 years) and similar between patients with TNBC and non-TNBC. Patients with TNBC had an increased likelihood of a higher histological grade III compared with HR(+) HER-2(?) subgroup (P > 0.001) and lower stage compared with HR(+)/HER2(+) and HR(?)/HER2(+) subgroups (P < 0.001 and P = 0.002, respectively). In patients with TNBC, the disease-free survival (DFS) rate was 66% at 5 years. In subgroup analysis of non-TNBCs, 5-year-DFS rates of the patients in HR(+)/HER2(?), HR(+)/HER2(+) and HR(?)/HER2(+) subgroups were 59, 66, and 57%, respectively. There was no significant difference between the TNBC and non-TNBC subgroups (P = 0.238). In multivariate analysis, nodal involvement (RR = 2.8, 95% CI: 0.99–8.3, P = 0.052) and the presence of lymphovascular invasion (RR = 3.2, 95% CI: 1.1–9.2, P = 0.029) were significantly associated with increased recurrence risk in patients with TNBC. Although there are differences in patient and tumor features, patients with TNBC had similar clinical course with those with non-TNBC.     

AEG-1 is associated with tumor progression in nonmuscle-invasive bladder cancer

This study was designed to explore the influence of intra-operative perforation on prognosis of low rectal cancer after APR and to investigate the risk factors of perforation. Perforation is not scarce during the procedure of abdominoperineal resection (APR). There is no consensus on perforation rate and related risk factor for APR. Data of 925 patients who received APR for low rectal cancer between January 2000 and August 2008 were reviewed. The intra-operative perforation rate was 7.4 % (68/925). The recurrence rate was 28.6 % in patients with intra-operative perforation compared with 6.8 % in patients with no perforation (P < 0.001); 5-year survival rate in patients with perforation was 41.4 and 66.3 % in patients with no perforation. Univariate analysis showed that intra-operative perforation affected recurrence rate and survival significantly (P < 0.001, P < 0.001); multivariate analysis revealed that intra-operative perforation was an independent prognostic factors for recurrence (RR: 3.087, P < 0.001), while not for survival (RR: 1.331, P = 0.051). Patients aged more than 70 years, T3 tumor and treated by general surgeon had higher perforation rate (P = 0.001, P = 0.004, P = 0.008). Intra-operative perforation affected the prognosis of low rectal cancer after APR significantly. Elderly patient aged more than 70 years, T3 tumor and general surgeon who performed operation were three risk factors of increased perforation rate.     

Expression of organic anion-transporting polypeptide 1A2 and organic cation transporter 6 as a predictor of pathologic response to neoadjuvant chemotherapy in triple negative breast cancer

Organic anion-transporting polypeptide 1A2 (OATP1A2) and organic cation transporter 6 (OCT6) are involved in the uptake of taxanes and anthracyclines, respectively. The aim of this study was to evaluate expression levels of OATP1A2 and OCT6 as a predictor of response to neoadjuvant chemotherapy (NAC) in breast cancer. A total of 124 patients who received anthracycline/taxane-based NAC were included. Expression levels of OATP1A2 and OCT6 were immunohistochemically assessed in core needle biopsies obtained prior to NAC. A pathologic good response (pGR) and a pathologic complete response (pCR) were achieved in 24 and 10 % of patients, respectively. In univariate analysis of the entire cohort, negative hormone receptor (HR) status (pGR and pCR, P < 0.001), high Ki-67 level (pGR, P = 0.03; pCR, P = 0.02), triple negative (TN) subtype (pGR, P = 0.001; pCR, P < 0.001), and high OCT6 (pGR, P = 0.003) were associated with the response. In combined analysis, high OATP1A2/high OCT6 level was also a significant factor for pGR (P = 0.001) and pCR (P = 0.001). Two separate multivariate analyses showed that HR status, TN subtype and combined high OATP1A2/high OCT6 level were significant independent predictors. When TN and non-TN tumors were assessed separately in univariate analysis, high Ki-67 level (P = 0.04) were associated with pGR and combined high OATP1A2/high OCT6 level was associated with both pGR (P = 0.005) and pCR (P = 0.03) in the TN group. Multivariate analysis identified the combined high OATP1A2/high OCT6 level as the sole independent predictor of pGR. In the non-TN group, negative HR status (P = 0.03) and positive HER2 status (P = 0.005) were associated with pGR, but HER2 status was the sole independent predictor of pGR. These results suggest that response-associated predictors may differ between the TN and non-TN tumors. Combined high OATP1A2/high OCT6 may be a potential predictor of response to anthracycline/taxane-based chemotherapy in breast cancer, especially in TN tumors.