Omission of axillary surgery for ipsilateral breast tumor recurrence with negative nodes after previous breast-conserving surgery: is it oncologically safe?

PURPOSE: Salvage mastectomy is traditionally recommended for patients who developed ipsilateral breast tumor recurrence (IBTR) in light of previous breast irradiation. However, it remains controversial whether surgical axillary staging (SAS) is necessary for IBTR patients with negative nodes. This study aimed to evaluate the oncologic safety of omitting SAS for IBTR. METHODS: We retrospectively identified patients who developed invasive IBTR with negative nodes after undergoing breast-conserving surgery (BCS) from 2010 to 2018. Patterns of care in nodal staging were analyzed based on prior axillary staging status. Clinicopathologic characteristics and adjuvant treatment of the initial tumor, as well as the IBTR, were compared between the SAS and no SAS groups. Kaplan-Meier method and Cox regression model were utilized to compare the locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates after IBTR removal between the two groups. RESULTS: A total of 154 IBTR patients were eligible for final analysis. Compared to the no SAS group, SAS group was less likely to undergo ALND (15.1 vs 73.3%, p < 0.001) at initial BCS, had a longer recurrence interval (2.8 vs 2.1 years, p = 0.03), and were more likely to have discordant molecular subtype (35.8 vs 12.9%, p = 0.001) and different quadrant location (37.7 vs 19.8%, p = 0.02) with primary tumor. However, the extent of axillary staging did not affect systemic or radiation recommendations. In the subgroup of patients without previous ALND, the clinicopathologic characteristics were roughly comparable. No significant differences were observed in LRRFS, DMFS or OS between the two groups. CONCLUSION: For node-negative IBTR patients, we observed selection bias on the basis of prior ALND, shorter recurrence interval, and concordant molecular subtype favoring no SAS but comparable LRRFS, DMFS, and OS. These results support a wider consideration of sparing SAS in the management of IBTR, especially in patients without previous ALND.

Detection of breast cancer stem cell gene mutations in circulating free DNA during the evolution of metastases.

PURPOSE: Limited knowledge exists on the detection of breast cancer stem cell (BCSC)-related mutations in circulating free DNA (cfDNA) from patients with advanced cancers. Identification of new cancer biomarkers may allow for earlier detection of disease progression and treatment strategy modifications. METHODS: We conducted a prospective study to determine the feasibility and prognostic utility of droplet digital polymerase chain reaction (ddPCR)-based BCSC gene mutation analysis of cfDNA in patients with breast cancer. RESULTS: Detection of quantitative BCSC gene mutation in cfDNA by ddPCR mirrors disease progression and thus may represent a valuable and cost-effective measure of tumor burden. We have previously shown that hematological and neurological expressed 1-like (HN1L), ribosomal protein L39 (RPL39), and myeloid leukemia factor 2 (MLF2) are novel targets for BCSC self-renewal, and targeting these genetic alterations could be useful for personalized genomic-based therapy. CONCLUSION: BCSC mutation detection in cfDNA may have important implications for diagnosis, prognosis, and serial monitoring.

Cell-free DNA as a molecular tool for monitoring disease progression and response to therapy in breast cancer patients.

Due to the spatial and temporal genomic heterogeneity of breast cancer, genomic sequencing obtained from a single biopsy may not capture the complete genomic profile of tumors. Thus, we propose that cell-free DNA (cfDNA) in plasma may be an alternate source of genomic information to provide comprehensive data throughout a patient's clinical course. We performed a retrospective chart review of 100 patients with stage 4 or high-risk stage 3 breast cancer. The degree of agreement between genomic alterations found in tumor DNA (tDNA) and cfDNA was determined by Cohen's Kappa. Clinical disease progression was compared to mutant allele frequency using a two-sided Fisher's exact test. The presence of mutations and mutant allele frequency was correlated with progression-free survival (PFS) using a Cox proportional hazards model and a log-rank test. The most commonly found genomic alterations were mutations in TP53 and PIK3CA, and amplification of EGFR and ERBB2. PIK3CA mutation and ERBB2 amplification demonstrated robust agreement between tDNA and cfDNA (Cohen's kappa = 0.64 and 0.77, respectively). TP53 mutation and EGFR amplification demonstrated poor agreement between tDNA and cfDNA (Cohen's kappa = 0.18 and 0.33, respectively). The directional changes of TP53 and PIK3CA mutant allele frequency were closely associated with response to therapy (p = 0.002). The presence of TP53 mutation (p = 0.0004) and PIK3CA mutant allele frequency [p = 0.01, HR 1.074 (95 % CI 1.018-1.134)] was excellent predictors of PFS. Identification of selected cancer-specific genomic alterations from cfDNA may be a noninvasive way to monitor disease progression, predict PFS, and offer targeted therapy.

Inhibition of autophagy enhances the cytotoxic effect of PA-MSHA in breast cancer.

BACKGROUND: PA-MSHA, a genetically engineered Pseudomonas aeruginosa (PA) strain, is currently under investigation as a new anti-cancer drug. It can induce cell cycle arrest and apoptosis in different human cancer cells, including hormone receptor negative breast cancer cells. However, the underlying mechanism of tumor lethality mediated by PA-MSHA remains to be fully investigated. METHODS: The effect of PA-MSHA on human hormone receptor negative breast cancer cells was analyzed by morphological measurement, western blot, cell proliferation assay and mouse xenograft model. RESULTS: PA-MSHA was found to induce endoplasmic reticulum (ER) stress in breast cancer cell lines through the IRE1 signaling pathway. Inhibiting autophagy potentiated the cytotoxic effect of PA-MSHA while treating breast cancer cell lines. In mouse xenograft model, PA-MSHA produced more pronounced tumor suppression in mice inoculated with IRE1 gene knockdown. MDA-MB-231HM cells. CONCLUSIONS: These findings demonstrated inhibiting autophagy together with PA-MSHA might be a promising therapeutic strategy in treating hormone receptor negative breast cancer cells.

Neoadjuvant Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) and chemotherapy versus placebo plus chemotherapy in patients with HER2-negative breast cancer: a randomized, controlled, double-blind trial.

Background: According to preclinical experiments, Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) exerts antiproliferative effects against breast cancer cells. It has been approved by the State Food and Drug Administration in China for complementary cancer treatment, and its safety has been confirmed in previous clinical trials. The present randomized, controlled, double-blind clinical trial was conducted to investigate the efficacy and safety of neoadjuvant PA-MSHA and placebo with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: Eligible patients aged 18 years or older with previously untreated HER2-negative stage II-III breast cancer were enrolled and randomly assigned at a 1:1 ratio to receive neoadjuvant chemotherapy with PA-MSHA or a placebo. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to assess clinical response every 2 cycles. The primary endpoint was the objective response rate (ORR) based on the clinical response following neoadjuvant chemotherapy. Results: A total of 75 patients were randomly assigned to either the PA-MSHA group (37 patients) or the control group (38 patients). The ORR was found to be significantly higher in the PA-MSHA group compared with the control group [86.5% versus 60.5%; rate difference 26.0; 95% confidence interval (CI): 5.9-43.5%; P=0.011]. The pathological complete response (pCR) and survival outcomes did not differ significantly between the 2 groups. Patients with immune-related adverse events (irAEs) appeared to benefit from the PA-MSHA treatment, with greater disease-free, relapse-free, and overall survival. The application of PA-MSHA to neoadjuvant chemotherapy did not increase the incidence of severe adverse events. Moreover, the addition of PA-MSHA increased serum interferon-γ levels and the percentage of peripheral blood T cells, CD8+/CD4+ T cells, CD8+CD28+ T cells, and natural killer (NK) cells, and decreased serum interleukin 4 levels. Conclusions: The addition of PA-MSHA to neoadjuvant chemotherapy is an effective alternative regimen for HER2-negative breast cancer. Patients with irAEs caused by PA-MSHA may obtain more benefits from this treatment. Trial Registration: Chinese Clinical Trial Registry ChiCTR-TRC-10000794.

Predicting sentinel lymph node metastasis in a Chinese breast cancer population: assessment of an existing nomogram and a new predictive nomogram.

We assessed the MSKCC nomogram performance in predicting SLN metastases in a Chinese breast cancer population. A new model (the SCH nomogram) was developed with clinically relevant variables and possible advantages. Data were collected from 1,545 patients who had a successful SLN biopsy between March 2005 and November 2011. We validated the MSKCC nomogram in the modeling and validation group. Clinical and pathologic features of SLN biopsy in modeling group of 1,000 patients were assessed with multivariable logistic regression to predict the presence of SLN metastasis in breast cancer. The SCH nomogram was created from the logistic regression model and subsequently applied to 545 consecutive SLN biopsies. By multivariate analysis, age, tumor size, tumor location, tumor type, and lymphovascular invasion were identified as independent predictors of SLN metastasis. The SCH nomogram was then developed using the five variables. The new model was accurate and discriminating (with an AUC of 0.7649 in the modeling group) compared to the MSKCC nomogram (with an AUC of 0.7105 in the modeling group). The area under the ROC curve for the SCH nomogram in the validation population is 0.7587. The actual probability trends for the various deciles were comparable to the predicted probabilities. The false-negative rates of the SCH nomogram were 1.67, 3.54, and 8.20 % for the predicted probability cut-off points of 5, 10, and 15 %, respectively. Compared with the MSKCC nomogram, the SCH nomogram has a better AUC with fewer variables and has lower false-negative rates for the low-probability subgroups. The SCH nomogram could serve as a more acceptable clinical tool in preoperative discussions with patients, especially very-low-risk patients. When applied to these patients, the SCH nomogram could be used to safely avoid a SLN procedure. The nomogram should be validated in various patient populations to demonstrate its reproducibility.

Outcome of pure mucinous breast carcinoma compared to infiltrating ductal carcinoma: a population-based study from China.

PURPOSE: Pure mucinous breast carcinoma (PMBC) is a rare pathologic finding. Few studies have addressed the biologic features of PMBC and prognostic factors among patients with this disease. We performed a study to compare PMBC and invasive ductal carcinoma (IDC) by means of a large database to reliably assess the biologic phenotype and clinical behavior of PMBC. METHODS: A total of 2,511 patients who met the inclusion criteria were identified from 1999 to 2010; 2,202 patients had pure IDC and 309 had PMBC. Clinical and biologic features, overall survival, and recurrence/metastasis-free survival (RFS) were compared for both groups. RESULTS: PMBC had favorable characteristics including smaller size, lower rates of lymph node positivity, lower stage, higher expression of hormone receptors, and less HER2 overexpression. Patients with PMBC had better 10-year RFS (71 %) than patients with IDC (64 %). Multivariate analysis revealed that node status and tumor, node, metastasis system (TNM) stage were statistically significant prognostic factors for survival. RFS curves stratified for node status revealed a highly significant difference between node negative and node positive patients. Additionally, patients with PMBC underwent breast-conserving surgery (BCS) more frequently than patients with IDC, and the 5-year overall survival rate of the BCS group was not significantly different from the total mastectomy group. CONCLUSIONS: PMBC in Chinese women showed less aggressive behavior and had a better prognosis than IDC, and this favorable outcome was maintained after 10 years. Node status and TNM stage appeared to be the most significant predictors of worse prognosis. BCS should be preferred over mastectomy in the treatment of early-stage PMBC.

Spatiotemporal Patterns of Loco-Regional Recurrence After Breast-Conserving Surgery.

BACKGROUND: Loco-regional recurrences (LRR) following breast-conserving surgery (BCS) remain a heterogeneous class of disease that has significant variation in its biological behavior and prognosis. METHODS: To delineate the spatiotemporal patterns of LRR after BCS, we analyzed the data of 4325 patients treated with BCS from 2006 to 2016. Clinico-pathological and treatment specific factors were analyzed using the Cox proportional hazards model to identify factors predictive for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype. RESULTS: With a median follow-up of 66 months, 120 (2.8%) LRRs were recorded as the first site of failure. Age, pathologic stage, and molecular subtype were identified as predictors of LRR. The major recurrence type was ipsilateral breast tumor recurrence, which mainly (83.6%) occurred ≤5y post surgery. In the overall population, ARR curves showed that relapse peaked in the first 2.5 years. Patients with regional nodal recurrence, shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2-positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery. CONCLUSIONS: LRR risk following BCS is generally low in Chinese ethnicity. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.

PA-MSHA inhibits proliferation and induces apoptosis through the up-regulation and activation of caspases in the human breast cancer cell lines.

To investigate the effects of PA-MSHA (Pseudomonas aeruginosa-mannose sensitive hemagglutinin) on inhibiting proliferation of breast cancer cell lines and to explore its mechanisms of action in human breast cancer cells. MCF-10A, MCF-7, MDA-MB-468, and MDA-MB-231HM cells were treated with PA-MSHA or PA (Heat-killed P. aeruginosa) at different concentrations and different times. Changes of cell super-microstructure were observed by transmission electron microscopy. Cell cycle distribution and apoptosis induced by PA-MSHA were measured by flow cytometry (FCM) with PI staining, ANNEXIN V-FITC staining and Hoechst33258 staining under fluorescence microscopy. Western blot was used to evaluate the expression level of apoptosis-related molecules. A time-dependent and concentration-dependent cytotoxic effect of PA-MSHA was observed in MDA-MB-468 and MDA-MB-231HM cells but not in MCF-10A or MCF-7 cells. The advent of PA-MSHA changed cell morphology, that is to say, increases in autophagosomes, and vacuoles in the cytoplasm could also be observed. FCM with PI staining, ANNEXIN V-FITC and Hoechst33258 staining showed that the different concentrations of PA-MSHA could all induce the apoptosis and G(0)-G(1) cell cycle arrest of breast cancer cells. Cleaved caspase 3, 8, 9, and Fas protein expression levels were strongly associated with an increase in apoptosis of the breast cancer cells. There was a direct relationship with increased concentrations of PA-MSHA but not of PA. Completely different from PA, PA-MSHA may impart antiproliferative effects against breast cancer cells by inducing apoptosis mediated by at least a death receptor-related cell apoptosis signal pathway, and affecting the cell cycle regulation machinery.

Basal cytokeratin expression in relation to immunohistochemical and clinical characterization in breast cancer patients with triple negative phenotype.

AIMS AND BACKGROUND: To evaluate the immunohistochemical characterization of CK5/6 and CK17 and whether the expression level of the two markers was correlated with clinical outcome or pathological feature in triple negative (ER-, PR-, HER-2-) patients with breast cancer. METHODS AND STUDY DESIGN: We carried out an immunohistochemical assay for CK5/6 and CK17 markers on formalin-fixed invasive carcinoma samples from 112 patients who were diagnosed between 2000 and 2002. All of them had an immunohistochemical triple negative status and follow-up information available. RESULTS: Of the 112 patients characterized by triple negative immunohistochemical status, 82 (73.2%) were disease free with no relapse or metastasis. In total, CK5/6 and CK17 were both determined positive in 33.9% (38/112) of the 112 tumor samples, and 46.4% (52/112) were regarded as positive for CK5/6 or CK17. The Kaplan-Meier curve showed that positive staining for CK5/6, CK17, or CK which means CK5/6 positive or CK17 positive, was associated with worse disease-free survival (P = 0.020, P = 0.032, P = 0.003), and positive staining for CK5/6 or CK was associated with worse overall survival (P = 0.027, P = 0.015). When we considered 91 patients whose pathological type was invasive ductal carcinoma, we found that there was also an association between CK5/6 or CK17 immunostaining and high grade (P = 0.030). In addition, these two markers were also associated with axillary lymph node status (P = 0.044). The Cox regression multiple-factor analysis showed that pathological stage, grade and expression of CK were the factors affecting both disease-free and overall survival, whereas age and menopausal status were independent factors affecting disease-free and overall survival, respectively. CONCLUSIONS; Positive staining for CK5/6 or CK17 was associated with a worse prognosis, high tumor grade and positive axillary lymph nodes.

Triple-negative breast cancer types exhibit a distinct poor clinical characteristic in lymph node-negative Chinese patients.

Comparative studies on the clinical features and outcomes of triple-negative subgroups to human epidermal growth factor receptor-2 (HER-2) overexpression, and luminal A and B subgroups in lymph node-negative breast cancer patients, are important to correctly evaluate clinical prognosis. A total of 1132 Chinese breast cancer patients were enrolled in a retrospective analysis. We characterized and identified prognostic information in the triple-negative subgroup [estrogen receptor (ER)-, progesterone receptor (PR)- and HER-2-negative] and compared that to HER-2 overexpression, and the luminal A and B subgroups. By using immunohistochemical staining, the triple-negative subgroup showed 17% (193/1132) in the whole group. However, HER-2 overexpression, and the luminal A and B subgroups were 11.2, 47.9 and 23.9%, respectively. Tumors in the triple-negative subgroup showed a higher histological grade (P=0.025) and lower invasive ductal carcinoma (P=0.007), compared to the three subgroups. More patients in the luminal A subgroup had received adjuvant chemotherapy (P=0.007). The difference of disease-free survival rates among the four subgroups was significant (P=0.0001). The P-value for overall survival was 0.0598. No significant difference among the four subgroups in lymph node-positive and non-chemotherapy breast cancers was found. From our data the poor clinical outcomes were independent of age, histological grade, tumor size, lymph nodal status, chemotherapy and clinical stages. Our data suggest that the triple-negative subgroup exhibits a distinct poor clinical outcome, especially in lymph node-negative Chinese breast cancer patients.

[Expression of CK5/6 and CK17 and its correlation with prognosis of triple-negative breast cancer patients].

OBJECTIVE: To investigate the correlation of CK5/6 and CK17 expression with clinical outcome in patients with triple-negative [ER(-), PR(-), Her-2(-)] breast cancer. METHODS: 112 patients with breast cancer treated by surgery between 2000 and 2002 were included in this study. All cases were immunohistochemically proven to be triple-negative. Samples of formalin-fixed and paraffin-embedded surgical specimens were obtained for immunohistological examination for CK5/6 and CK17 expression. The correlation of the gene expression with clinicopathological features and outcome of the patients was analyzed. RESULTS: Of the 112 triple-negative patients, five-year disease-free survival rate was 73.2% (82/112). The positive rate of both CK5/6 and CK17 was 21.4% (24/112), either CK5/6 or CK17 positive was 46.4% (52/112). It was shown by Kaplan-Meier curve that positive CK5/6, CK17 or CKs (CK5/6 or CK17 positive) was correlated with poor five-year disease-free survival (P = 0.020, P = 0.032, P = 0.003); and positive staining of CK5/6 or CKs was correlated with poor five-year overall survival (P = 0.027, P = 0.015). Of the 91 patients with invasive ductal carcinoma, a correlation of CK5/6 or CK17 positive staining with high grade differentiation was observed (P = 0.030), and with axillary lymph node metastasis was also noticed (P = 0.044). Multivariate analysis by Cox regression showed that differentiation grade, pathological stage and expression of CK5/6 were factors affecting both the disease-free-survival and overall-survival, while menopausal status was an independent factor affecting the disease-free-survival. CONCLUSION: Positive expression of CK5/6 or CK17 in patients with triple-negative breast cancer is correlated with poor prognosis, high grade differentiation and axillary lymph node metastasis.

Elevated miR-301a expression indicates a poor prognosis for breast cancer patients.

Although microRNA-301a (miR-301a) has been reported to function as an oncogene in many human cancers, there are limited data regarding miR-301a and breast tumours. In this study, we first detected the expression of miR-301a using an in situ hybridization (ISH) -based classification system in 380 samples of BC tissue, including both non-TNBC (triple-negative breast cancer) and TNBC specimens. Our results suggest that analysing miR-301a expression in breast tissue biopsy specimens at the time of diagnosis could have the potential to identify patients who might be candidates for active surveillance. We validated our results that higher expression of miR-301a is associated with a decreased OS in independent public breast cancer databases, such as TCGA and METABRIC, using the online webtool Kaplan-Meier Plotter, which provided additional powerful evidence to confirm the prognostic value of miR-301a. MiR-301a may serve as a potential therapeutic target for patients with breast cancer. According to our results, miR-301a should be considered, and novel therapeutic options are needed to target this aggressive miR-301a-positive type of breast cancer to reduce recurrence and the mortality rate.

PA-MSHA in combination with EGFR tyrosine kinase inhibitor: A new strategy to overcome the drug resistance of non-small cell lung cancer cells.

The inhibition of epidermal growth factor receptor (EGFR) signaling by Gefitinib provides a promising treatment strategy for non-small cell lung cancer (NSCLC); however, drug resistance to Gefitinib and other tyrosine kinase inhibitors presents a major issue. Using NSCLC cell lines with differential EGFR status, we examined the potency of PA-MSHA (Pseudomonas aeruginosa-mannose-sensitive hemagglutinin) in combination with Gefitinib on proliferation, apoptosis, cell cycle arrest, EGFR signaling and tumor growth. PC-9, A549, and NCI-H1975 cells were treated with PA-MSHA, Gefetinib, or PA-MSHA plus Gefetinib at different concentrations and times. The effects of the drugs on proliferation, cell cycle distribution and apoptosis were evaluated. The activation of EGFR and apoptotic signaling-related molecules was evaluated by Western blotting in the presence or absence of EGFR siRNA. Tumor growth and pathway signaling activation was assessed by xenografts in nude mice. A time-dependent and concentration-dependent cytotoxic effect of PA-MSHA was observed in all NSCLC cells tested. The combination of PA-MSHA plus Gefitinib enhanced the growth inhibition, sub-G1 content and apoptosis over that observed with either agent alone. Furthermore, the combination of PA-MSHA plus Gefitinib resulted in caspase-3/caspase-9 cleavage and increased inhibition of EGFR-dependent activation of AKT and ERK phosphorylation. Combination treatment was more effective in reducing tumor size and EGFR activation than either agent alone. These data suggest that PA-MSHA and Gefitinib function additively to suppress the proliferative effects of NSCLC cells of differential EGFR status. The combination of PA-MSHA and Gefitinib provides a potential new strategy to conquer drug resistance for anti-EGFR-targeted therapy of NSCLC.

Changing attitudes toward needle biopsies of breast cancer in Shanghai: experience and current status over the past 8 years.

Diagnostic patterns in breast cancer have greatly changed over the past few decades, and core needle biopsy (CNB) has become a reliable procedure for detecting breast cancer without invasive surgery. To estimate the changing diagnostic patterns of breast cancer in urban Shanghai, 11,947 women with breast lesions detected by preoperative needle biopsy between January 1995 and December 2012 were selected from the Shanghai Cancer Data base, which integrates information from approximately 50% of breast cancer patients in Shanghai. The CNB procedure uses an automated prone unit, biopsy gun, and 14-gauge needles under freehand or ultrasound guidance and was performed by experienced radiologists and surgeons specializing in needle biopsies. Diagnosis and classification for each patient were independently evaluated by pathologists. Over the indicated 8-year period, biopsy type consisted of 11,947 ultrasound-guided core needle biopsies (UCNBs), 2,015 ultrasound-guided vacuum-assisted biopsies (UVABs), and 654 stereotactic X-ray-guided vacuum-assisted biopsies (XVABs). For all the 11,947 women included in this study, image-guided needle biopsy was the initial diagnostic procedure. Approximately 81.0% of biopsied samples were histopathologically determined to be malignant lesions, 5.5% were determined to be high-risk lesions, and 13.5% were determined to be benign lesions. The number of patients choosing UCNB increased at the greatest rate, and UCNB has become a standard procedure for histodiagnosis because it is inexpensive, convenient, and accurate. The overall false-negative rate of CNB was 1.7%, and the specific false-negative rates for UCNB, UVAB, and XVAB, were 1.7%, 0%, and 0%, respectively. This study suggests that the use of preoperative needle biopsy as the initial breast cancer diagnostic procedure is acceptable in urban Shanghai. Preoperative needle biopsy is now a standard procedure in the Shanghai Cancer Center because it may reduce the number of surgeries needed to treat breast cancer.

Prognostic value of myeloid differentiation primary response 88 and Toll-like receptor 4 in breast cancer patients.

PURPOSE: Breast cancer remains a major cause of death in women worldwide, and tumor metastasis is the leading cause of death in breast cancer patients after conventional treatment. Chronic inflammation is often related to the occurrence and growth of various malignancies. This study evaluated the prognosis of breast cancer patients based on contributors to the innate immune response: myeloid differentiation primary response 88 (MyD88) and Toll-like receptor 4 (TLR4). METHODS: We analyzed data from 205 breast invasive ductal carcinoma (IDC) patients who were treated at the Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, from 2002 to 2006. Overall survival (OS) and disease-free survival (DFS) were compared. RESULTS: In total, 152 patients (74.15%) were disease-free without relapse or metastasis, whereas 53 (25.85%) patients developed recurrence or metastasis. A significant positive correlation was observed between MyD88 and TLR4 expression (p<0.001). Patients with high expression were more likely to experience death and recurrence/metastasis events (p<0.05). Patients with low MyD88 or TLR4 expression levels had better DFS and OS than patients with high expression levels (log-rank test: p<0.001). Patients with low MyD88 and TLR4 expression levels had better DFS and OS than patients with high expression levels of either (log-rank test: p<0.001). In a multivariate analysis, high MyD88 expression was an independent predictive factor for decreased DFS (adjusted HR, 3.324; 95% CI, 1.663-6.641; p = 0.001) and OS (adjusted HR, 4.500; 95% CI, 1.546-13.098; p = 0.006). CONCLUSIONS: TLR4-MyD88 signaling pathway activation or MyD88 activation alone may be a risk factor for poor prognosis in breast cancer. Therefore, TLR4-MyD88 signaling pathway activation in tumor biology provides a novel potential target for breast cancer therapy.

Impact of type 2 diabetes mellitus on the prognosis of early stage triple-negative breast cancer in People's Republic of China.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is one of the most common chronic metabolic diseases. Increased cause-specific mortality and decreased disease-free survival (DFS) have been reported among cancer patients with T2DM compared with patients without T2DM, even after adjustments of other comorbidities. However, less is known about the impact of T2DM and other comorbidities on DFS in Chinese patients with early stage triple-negative breast cancer (TNBC). PATIENTS AND METHODS: We assessed patients who were newly diagnosed with early stage primary TNBC at the Department of Breast Surgery, Fudan University, from 2003 to 2011. Of the 1,100 TNBC patients, 865 female patients had invasive and early stage TNBC. The association of the variables in the T2DM and non-T2DM groups was compared using the Pearson's chi-square and independent t-tests. DFS was estimated using the Kaplan-Meier method. The effects of T2DM and other possible risk factors on DFS were assessed by Cox proportional hazards regression using univariate or multivariate analysis. RESULTS: A total of 865 early stage primary TNBC cases were studied, including 104 (12.02%) subjects with T2DM. Metastatic or recurrent disease was detected in 24 (23.08%) patients in the T2DM group and 35 (4.60%) patients in the non-T2DM group. Patients with T2DM exhibited a significantly lower DFS than patients without T2DM (log-rank P<0.001). Similar results were observed when patients with positive lymph nodes were compared with patients with negative lymph nodes (log-rank P=0.003). T2DM was independently associated with a lower DFS after adjustments of other variables (adjusted hazard ratio, 7.719; 95% confidence interval, 4.304-13.843; P<0.001) and adjustments of lymph node positivity (adjusted hazard ratio, 2.407; 95% confidence interval, 1.391-4.166; P=0.002). The DFS rates at 2 years for the T2DM group and the non-T2DM group were 78% and 97%, respectively. The prognostic influence of T2DM was consistent across the subgroups, including subgroups by age (>50 or ≤50), menopausal status (post- or premenopausal), tumor size (>5 cm or ≤5 cm), lymph node involvement (positive or negative), and adjuvant chemotherapy (received or not) using the Kaplan-Meier method (log-rank P<0.05). CONCLUSION: In the People's Republic of China, T2DM is an independent prognostic risk factor that indicates an increased likelihood of recurrence and metastasis in patients with early stage TNBC. The presence of T2DM should be taken into account when evaluating the risk for an early stage TNBC patient. More effective therapeutic regimens are needed for early stage TNBC patients with T2DM.

Patients with nipple-areola Paget's disease and underlying invasive breast carcinoma have very poor survival: a matched cohort study.

Paget's disease (PD) of the breast is a rare disease. The survival rate of PD was reported to depend on the characteristics of the underlying carcinoma. This study aimed to investigate the characteristics and survival rate of PD patients with underlying invasive breast carcinoma (IBC). Fifty-two patients were diagnosed with PD and an associated IBC from 2001 to 2005 in Fudan University Shanghai Cancer Center. Twenty-four (46.2%) had no clinical manifestation of PD and were diagnosed unexpectedly by a histologic examination. The 52 patients were all recruited in this study as the PD group. They tended to have greater chances of lymph node involvement (53.8% vs. 35.7%), lower hormone receptor expression (34.6% vs. 69.7%), higher human epidermal growth factor receptor 2 (HER2) expression (76.9% vs. 21.3%), and worse survival (5-year relapse-free survival (RFS) 52.2% vs. 86.7%, P<0.01; breast cancer-specific overall survival (OS) 62.1% vs. 91.8%, P<0.01) when compared with patients diagnosed with IBC. A matched study was then performed to investigate whether the poor survival of patients in the PD group was due to the unfavorable prognosis of the underlying IBC. One hundred and fifty-six (3∶1 ratio of controls to PD patients) patients diagnosed with IBC only were recruited into the matched group. The match was conducted according to four variables: dimension of IBC, lymph node status, hormone receptor status and HER2 status. The 5-year RFS (52.2% vs. 81.4%, P<0.01) and OS (62.1% vs. 85.9%, P<0.01) were both lower for patients in the PD group than those in the matched group. Patients with PD and underlying IBC had poor survival. Their survival was worse than that of patients with IBC of similar stage and characteristics. For patients with no clinical PD manifestation who were histologically diagnosed as PD, survival might be worse compared to patients with clinically diagnosed PD.

Malignant calcification is an important unfavorable prognostic factor in primary invasive breast cancer.

AIMS: To explore the clinical characteristics and prognostic value of malignant calcification in operable breast cancer. METHODS: A total of 721 patients with invasive ductal carcinoma were divided into two groups based on whether malignant calcifications were observed on mammograms. The association of calcification with pathological features and survival were evaluated. The relative importance of each of the potential prognostic variables was tested using a Cox regression analysis. RESULTS: Compared with tumors without calcification, those with calcification had a larger tumor size, more lymph node involvement, lower estrogen and progesterone receptor expression and higher human epithelial growth factor receptor 2 expression. The 8-year relapse-free survival was lower for patients with calcifications than for those without (77.5 vs 89.2%, P < 0.01). The 8-year overall survival for patients with calcifications was 82.2% compared with 91.9% for those without (P < 0.01). In multivariate analysis, node status, existence of calcification and tumor size were demonstrated to have a prognostic value for relapse-free survival. The node status, existence of calcifications and estrogen receptor status were also prognostic factors for overall survival. CONCLUSION: Mammographic calcification is a poor prognostic factor for patients with invasive ductal carcinoma. Its prognostic value is second only to axillary node status and greater than the other factors evaluated. Thus, breast cancers with calcifications should be regarded as high risk when determining adjuvant treatment.

Expression of dickkopf-1 and beta-catenin related to the prognosis of breast cancer patients with triple negative phenotype.

BACKGROUND AND AIM: We investigated the prognostic importance of dickkopf-1(DKK1) and beta-catenin expression in triple negative breast cancers. METHODS: The expression of DKK1 and beta-catenin was evaluated in breast cell lines using RT-PCR and western blot. Immunohistochemistry was used to characterize the expression pattern of DKK1 and beta-catenin in 85 triple negative breast cancers and prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression modeling. RESULTS: The expression of DKK1 was confirmed in hormone-resistant breast cell lines MDA-MB-231, MDA-MB-231-HM and MDA-MB-435. Expression of DKK1 in triple negative breast cancers correlated with cytoplasmic/nuclear beta-catenin (p = 0.000). Elevated expression of DKK1 and cytoplasmic/nuclear beta-catenin in triple negative cancers indicate poor outcome of patients. DKK1 was also a prognostic factor for patients with earlier stage or no lymph node metastasis. CONCLUSION: DKK1 together with beta-catenin might be important prognostic factors in triple negative breast carcinoma. DKK1 might be a valuable biomarker in predicting the prognosis of patients with earlier stage or no lymph node metastasis. It is possible that through further understanding of the role of Wnt/beta-catenin pathway activation, beta-catenin would be a potential therapeutic target for the triple negative breast cancer.