Correction to: Identification of the functional role of peroxiredoxin 6 in the progression of breast cancer.

After the publication of this work [1] an error in Fig. 1c was brought to our attention: the Western blots for PRDX6 and ß-actin were similar to those shown in lanes 5-6 of Fig. 4g. To verify these findings, we have repeated this experiment and the results are shown in a new Fig. 1c below. The repeated experimental results are consistent with the previously reported findings in the original study [1] and the functional role for PRDX6 in malignant progression of human cancer including breast cancer has been widely documented and recognized in numerous other studies [2]. We apologize for the error. However, this correction does not affect the conclusions of the article.

Weekly paclitaxel/carboplatin/trastuzumab therapy improves pathologic complete remission in aggressive HER2-positive breast cancers, especially in luminal-B subtype, compared with a once-every-3-weeks schedule.

BACKGROUND: The efficacy and tolerability of two different schedules of paclitaxel, carboplatin, and trastuzumab (PCarH) for HER2-positive, locally aggressive (stage IIB-IIIC) breast cancers were evaluated in this phase II trial. METHODS: Patients were randomly assigned to receive either weekly (12 doses over 16 weeks) or once-every-3-weeks (4 doses over 12 weeks) treatment. The primary endpoint was pathologic complete remission (pCR) in the breast and axilla. To detect an assumed 35% pCR absolute difference between the two schedules, a minimum of 26 assessable patients in each group was required (two-sided α = 0.05, ß = 0.2). RESULTS: A total of 56 patients were enrolled (weekly group, n = 29; every-3-weeks group, n = 27). In the intent-to-treat analysis, pCR in the breast/axilla were found in 31 patients (55%; 95% confidence interval [CI]: 41%-69%). Compared with the every-3-weeks schedule, the weekly administration achieved higher pCR (41% vs. 69%; p = .03). After adjustment for clinical and pathological factors, the weekly administration was more effective than the every-3-weeks schedule, with hazard ratio of 0.3 (95% CI: 0.1-0.9; p = .03). Interestingly, weekly administration resulted in high pCR rates in both luminal-B (HER2-positive) and ERBB2+ tumors (67% vs. 71%; p = .78), whereas luminal-B (HER2-positive) tumors benefited less from the every-3-weeks schedule compared with the ERBB2+ tumors (21% vs. 62%, p = .03). These results remain after multivariate adjustment, showing weekly administration was more effective in the luminal-B (HER2-positive) subgroup (p = .02) but not in the ERBB2+ subgroup (p = .50). CONCLUSION: A more frequent administration might improve the possibility of eradicating invasive cancer in the breast and axilla, especially in the luminal-B (HER2-positive) subtype. Further studies to validate our findings are warranted.

Adherence to endocrine therapy in patients with hormone receptor-positive early-stage breast cancer: a retrospective study.

BACKGROUND: The persistence and adherence to endocrine therapy (ET) in hormone receptor-positive (HR +) breast cancer patients remain far less than optimal. AIM: This retrospective study aimed to evaluate adherence to ET and to identify influencing factors in early-stage HR + breast cancer patients. METHOD: A stratified random sampling method was used to select patients admitted for breast cancer surgery at a university hospital in Shanghai, China. Patients who received ET medications in the hospital information system (HIS) were included. The primary outcomes were early discontinuation of and adherence to ET. Potential factors influencing the discontinuation and adherence were assessed using univariate and multivariate logistic regression analyses. RESULTS: In total, 706 patients were included, and 161 (22.8%) discontinued ET in less than five years from the first prescription. The discontinuation rates from the one-year to the five-year treatment were 5.38, 16.70, 32.27, 51.52, and 50.00%, respectively (P < 0.001). The rates of adherence (defined as medication possession ratio ≥ 80%) from the first to the fifth year were 85.18, 82.25, 82.18, 72.92, and 73.68%, respectively (P = 0.18). Age, insurance, and surgery type impacted ET discontinuation and adherence. However, the type of medication only impacted the adherence to ET. CONCLUSION: Persistence and adherence to ET in patients with breast cancer remain far from optimal and decrease over time. More attention should be paid to patients aged ≥ 70 years and those without insurance who tend to have early discontinuation of ET.

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.

Tumor characteristics and the clinical outcome of invasive lobular carcinoma compared to infiltrating ductal carcinoma in a Chinese population.

BACKGROUND: We sought to compare the baseline demographics, standard pathologic factors and long-term clinical outcomes between ILC and infiltrating ductal carcinoma (IDC) using a large database. METHODS: Clinicopathologic features, overall survival (OS), and recurrence/metastasis-free survival (RFS) were compared between 2,202 patients with IDC and 215 patients with ILC. RESULTS: ILC was significantly more likely to be associated with a favorable phenotype, but the incidence of contralateral breast cancer was higher for ILC patients than for IDC patients (8.4% vs. 3.9%; P=0.001). The frequencies of recurrence/metastasis (P = 0.980) and death (P = 0.064) were similar among patients with IDC and patients with ILC after adjustment for tumor size and nodal status. The median follow-up was 42.8 months. CONCLUSIONS: Chinese women with ILCs do not have better clinical outcomes than their counterparts with IDC. Management decisions should be based on individual patient and tumor biologic characteristics, and not on lobular histology.

Molecular subtype approximated by quantitative estrogen receptor, progesterone receptor and Her2 can predict the prognosis of breast cancer.

AIMS AND BACKGROUND: To investigate the clinicopathological characteristics and prognosis of breast cancer subtypes classified by quantitative estrogen receptor (ER), progesterone receptor (PR), and Her2. METHODS AND STUDY DESIGN: 923 patients with primary breast cancer having a median age of 53 years who were treated at the Cancer Hospital of Fudan University in Shanghai between January 2002 and June 2004 were retrospectively analyzed. Four molecular subtypes were constructed from the immunohistochemical results of quantitative hormone receptor (HR) and Her2 status. HR+ was defined as ER+ and PR+, HR+/- as ER/PR+ at lower levels or lacking either ER or PR, and HR- as both ER- and PR-. The four subtypes were HR+/Her2-, HR+/-/Her2-, HR-/Her2- (triple-negative), and Her2+. Clinical and pathological parameters, disease-free survival (DFS), and overall survival (OS) measurements were compared between patients with different molecular subtypes. RESULTS: The proportions of HR+/Her2-, HR+/-/Her2-, triple-negative, and Her2+ breast cancer were 36.6% (338/923), 22.9% (211/923), 20.6% (190/923), and 19.9% (194/923). The median follow-up was 49.0 months (4-77 months). In 145 cases disease recurrence or death occurred. In multivariate analysis with the HR+/Her2- subtype taken as the reference category, triple-negative and Her2+ subtypes were associated with increased recurrence and death with a hazard ratio (HR) of 2.05 (95% CI 1.31-3.20; P = 0.002) and 1.89 (95% CI 1.20-2.97, P = 0.006) for DFS and 2.84 (95% CI 1.45-5.55; P = 0.002) and 2.95 (95% CI 1.51-5.77, P = 0.002) for OS, respectively; the HR+/-/Her2- subtype was marginally associated with poor prognosis with HR 1.51 (95% CI 0.94-2.43; P = 0.088) and 1.90 (95% CI 0.92-3.94; P = 0.084) for DFS and OS, respectively. CONCLUSIONS: Breast cancer subtypes based on quantitative ER, PR, and Her2 may be predictive of prognosis. Patients whose tumors were not HR+/Her2- had a worse outcome in our study.

Clinicopathological features of the triple-negative tumors in Chinese breast cancer patients.

In order to analyze the clinicopathological features of Chinese triple negative tumors, we performed a retrospective study of 1993 female unilateral breast cancer patients undergoing surgery in Cancer Hospital of Fudan University, Shanghai, China. Survival curves were performed with Kaplan-Meier method and annual recurrence hazard was estimated by hazard function. We observed that the rate of larger tumors in triple negative patients was higher than that in HR+/ERBB2- women, but lower than that in ERBB2+ subgroup (P = 0.0001). In addition, 21.83% of triple negative patients had four or more axillary lymph nodes involved as compared to 27.40% of ERBB2+ women and 22.75% of HR+/ERBB2- subgroup (P = 0.0056). In the survival analysis, we found a statistical significance for recurrence-free survival (RFS) among the three subgroups (P = 0.0037), with the rate of 72.89% for ERBB2+ patients, 78.40% for HR+/ERBB2- ones and 75.76% for triple negative ones at the 11th year respectively. When it came to hazard peaks, discrepancies existed in different subgroups. Similar to HR+/ERBB2- patients, triple negative subgroup showed an early major recurrence surge peaking at approximately year 2.5 as opposed to ERBB2+ counterparts with a tapering sharp at the 1st year. Furthermore, the first peak of triple negative tumors was higher than that of HR+/ERBB2- patients, but lower than that of ERBB2+ ones. Therefore, our findings suggested biological characteristics and prognostic outlook of Chinese triple negative breast cancers might be more favorable and somewhat different from those in Western populations.

Breast cancer in a transitional society over 18 years: trends and present status in Shanghai, China.

As a metropolis with rapid social and economic development over the past three decades, Shanghai has a breast cancer incidence that surpasses all other cancer registries in China. In order to estimate the regular changing patterns of female breast cancer in urban Shanghai, population-based incidence data from 1975 to 2004 were studied. In addition, a one-hospital-based in-patient database of 7,443 female breast cancer patients treated surgically between January-1990 and July-2007 were reviewed, retrospectively. We observed that breast cancer incidence increased dramatically over the past 30 years and documented a peak incidence represented by the middle-age group (45-59 years), which emerged in the last 20 years. The incidence peak moved from the 40-44 year group in the previous two decades to the 50-54 year group in the most recent decade. Median age at diagnosis was earlier in Shanghai than in the western countries, although it increased from 47.5-year in 1990 to 50-year in 2007. Considerably higher exposure to reproductive risk factors and relatively fewer hormone-dependent cases were observed. The proportion of asymptomatic cases detected by screening gradually increased, as well as that of early-stage cases (from 78.6% in 1990 to 93.3% in 2007) and carcinoma in situ (14.7% in 2007). Analysis of surgical treatment patterns suggested a trend of less-invasive options. Both age of peak incidence and median age at diagnosis increase with time, which suggests that increased incidence trending along with increasing age, will be observed in the future. Consequently, specific screening protocol should be refined to consider birth cohorts.

The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives.

PALB2 has been recently identified as breast cancer susceptibility gene in western populations. To investigate the contribution of PALB2 mutations to Chinese non-BRCA1/BRCA2 hereditary breast cancer, we screened all coding exons and intron-exon boundaries of PALB2 in 360 Chinese women with early-onset breast cancer or affected relatives from five breast disease clinical centers in China by utilizing PCR-DHPLC and DNA sequencing analysis. Some genetic variants identified in the cases were then studied in 864 normal controls with no personal or family history of breast cancer. Two protein-truncating PALB2 mutations, 751C>T and 1050_1051delAAinsTCT, were identified in three separate families, and 751C>T was a recurrent mutation. Neither of them, however, were present in the controls (P=0.025). All the truncating mutations occurred in exon 4 of PALB2, and there were still three unclassified variants were detected in the same fragment. We found that exon 4 accounted for 44.1% (15/34) of the person-times carrying with any variant in our study. PALB2 mutations were responsible for approximately 1% of Chinese women with early-onset breast cancer and affected relatives. Our results suggested that a detection of exon 4 before the assay of the whole PALB2 gene might be a cost-effective approach to the screening of Chinese population.

Mutation analysis of BRIP1/BACH1 in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives.

The proper interaction between BRIP1/BACH1 and BRCA1 protein has been found to be crucial for BRCA1-mediated DNA double-strand break repair and BRIP1/BACH1 mutations were estimated to confer a relative risk for breast cancer of 2.0 in western populations. In Chinese population, BRCA1 mutations could explain a relatively large proportion of inherited breast cancer cases in comparison with BRCA2 mutations, which probably deduced a hypothesis that those genes involved in BRCA1-mediated DNA repair pathway might play a more significant role in the etiology of Chinese breast cancer. To investigate the contribution of BRIP1/BACH1 mutations to the predisposition of Chinese non-BRCA1/BRCA2 hereditary breast cancer, we screened all the coding exons and adjacent intronic splice junction regions of BRIP1/BACH1 in 357 Chinese women with early-onset breast cancer or affected relatives from five different breast disease clinical centers in China, using PCR-DHPLC and DNA sequencing analysis. Some genetic variants identified in the cases were then studied in 864 normal controls with no personal or family history of breast cancer. We found no protein-truncated mutations in our population, while a novel recurrent non-synonymous variant, Q944E, was detected in two independent families in contrast with none in the controls, interestingly, this alteration occurs in the BRCA1 binding domain of the BACH1 protein. Then a further study performed on the two mutation positive families revealed the partial co-segregation of this mutation allele with cancer. The novel alteration Q944E identified in our study possibly represents a rare disease-related allele, nevertheless functional analysis is still warranted to resolve the ability of this altered BACH1 protein to bind BRCA1. Altogether, the results of our study indicated that germline mutations in BRIP1/BACH were extremely rare in Chinese population and there was no evidence for the recommendation of BRIP1/BACH1 for genetic testing in Chinese.

Models for predicting BRCA1 and BRCA2 mutations in Han Chinese familial breast and/or ovarian cancer patients.

PURPOSE: Our aim was to find an appropriate method to estimate the likelihood that a family history of cancer was a result of a mutation in the BRCA1 or BRCA2 genes. We also compared the performance of the established method with three different methods (Couch, Sh-E and BRCApro) to identify an alternative strategy for genetic council targeted to the specified population. PATIENTS AND METHODS: The family history as well as individual information of two hundred unrelated probands who had completed BRCA1 and BRCA2 mutation screening was analyzed to assess the likelihood of a pathogenic mutation. A model was developed by empirical method. The performance of this model was validated in a separate patient cohort compared with BRCApro. RESULTS: Several factors were associated with mutations in univariate analysis and a logistic model was devised to estimate the probability for a proband of harboring a mutation in BRCA1 and/or BRCA2. Using a greater than 10% probability threshold, the highest accuracy was achieved by the established model when compared to other three models, presenting the highest sensitivity, PPV, NPV and area under ROC curve. The empirical model showed a better ROC curve compared to BRCApro in the verification cohort. CONCLUSION: A probability model targeted to Han Chinese population should be a useful tool in the genetic counseling for the specified ethnic. Its ability to predict BRCA2 mutation carriers needs to be improved.

Fiberoptic ductoscopy-guided intraductal biopsy improve the diagnosis of nipple discharge.

Fiberoptic ductoscopy (FDS)-guided intraductal biopsy is a minimally invasive technique developed to obtain pathologic diagnoses for patients with spontaneous nipple discharge. We performed biopsies of 53 intraductal lesions from March 2006 to April 2007 followed by surgical microdochectomy. FDS-guided intraductal biopsy was shown to be a minimally invasive, safe, and convenient technique with a high ability (90.6%) to get adequate samples. Twenty-seven solitary papillomas, 12 multiple intraductal papilloma, five ductal hyperplasia, three ductal carcinoma in situ, and one invasive ductal carcinoma were diagnosed. Compared with conventional microdochectomy, FDS-guided intraductal biopsy can significantly increase the detection rate of solitary papilloma (40.7% versus 92.6%, p < 0.05). It should be a routine procedure after intraductal lesion found by screening FDS. Since it would underestimate all multiple intraductal papilloma and some (50%) cancer, microdochectomy is inevitable if biopsies show atypical ductal hyperplasia.

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.

[Effect of postoperative pregnancy upon prognosis of young breast cancer patients].

OBJECTIVE: To examine the effect of postoperative pregnancy upon the prognosis of young Chinese breast cancer patients. METHODS: Four hundred and thirty-two female unilateral breast cancer patients aged 35 or younger were retrospectively reviewed. Kaplan-Meier analysis and Log Rank test were used for univariate analysis of factors predictive of disease-free survival (DFS) and overall survival (OS). Multivariate analysis was carried out using the Cox proportional hazards model. RESULTS: Eighteen patients were identified to have postoperative pregnancy, including 5 full-term pregnancy and 13 abortions with the earliest pregnancy taking place at Month 17 post-operation. After a median follow-up of 62 months (6 - 237 months), the DFS and OS rates were 72.5% (313/432) and 88.7% (383/432) respectively. On multivariate analysis, postoperative pregnancy, clinical stage and number of pathologically involved axillary lymph node were significantly associated with DFS. And the axillary lymph node status was also predictive of OS. No death occurred in patient with postoperative pregnancy. There was no significant association between postoperative pregnancy and OS. CONCLUSION: Postoperative pregnancy has no adverse effect upon the prognosis of young breast cancer patients.

[Study on predictors of long term results for neo-adjuvant chemotherapy in locally advanced breast cancer].

OBJECTIVE: To identify predictive markers of the long-term outcome for neo-adjuvant chemotherapy (NC) in locally advanced breast cancer (LABC) treated with intravenous vinorelbine (V) and epirubicin (E) combination regimen. METHODS: One hundred and nineteen patients with LABC were treated from September 2001 to May 2006. All patients were diagnosed as invasive breast cancer by 14G core needle biopsy and treated with three cycles of VE regimen before the operation. The patients were subjected to surgery and subsequently were given other three cycles of VE or cyclophosphamide+epirubicin+fluorouracil (CEF) regimen according to the clinical responses. Local-regional radiotherapy was applied to all patients after the chemotherapy and followed by hormone-therapy according to hormone receptor status. The impact of clinical, pathological, and immunohistochemical features on disease free survival (DFS) and overall survival (OS) was evaluated. RESULTS: All patients were evaluable for responses: clinical complete response was documented in 27 patients (22.7%), 78 patients (65.5%) obtained partial clinical response. The pathological complete response was found in 22 cases (18.5%). Of the patients, 115 cases (96.6%) were followed-up for a median time of 63.4 months (range, 9-76 months), the 5-year DFS rate and OS rate was 58.7% and 71.3%, respectively. On multivariate analysis, high pre-Ki-67 (P=0.012) and post-Ki-67 expression (P=0.045), no pathological complete response after NC (P=0.034) were associated with the higher risk of disease relapse; high pre-Ki-67 (P=0.017) and post-Ki-67 expression (P=0.001), negative pre-ER (P=0.002) and no pathological complete response after NC (P=0.034) were associated with a shorter survival. CONCLUSION: Pathological response in primary tumor, pre-Ki-67 and post-Ki-67 expression, pre-ER expression are important predictors of long-term outcome for LABC patients with three cycles of VE regimen before operation.

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.

Neoadjuvant chemotherapy with vinorelbine-containing regimens in elderly patients with locally advanced breast cancer.

BACKGROUND: The purpose of this study was to evaluate retrospectively the efficacy and safety of neoadjuvant chemotherapy with vinorelbine-containing regimens in elderly patient with locally advanced breast cancer (LABC). PATIENTS AND METHODS: From 2002 to 2006, 14 female elderly patients with LABC underwent neoadjuvant chemotherapy with vinorelbine-containing regimens. Vinorelbine alone or in combination with pirarubicin/epirubicin was administered every 3 weeks (25 mg/m2, i.v., day 1 and day 8). All 14 patients received 2-6 cycles of chemotherapy. RESULTS: The median age was 68.5 years (range 65 to 78 years). Six patients had stage IIIA breast tumor, 7 stage IIIB and 1 stage IIIC. There was 1 complete response and 10 partial responses, with an overall response rate of 78.57%, and stable disease in 3 patients (21.43%); there were no patients with progressive disease before surgery. After a median follow-up of 35 months, the estimated 3-year disease-free and overall survival rates were 57% and 69%, respectively. CONCLUSION: The results of the current study showed that vinorelbine-containing neoadjuvant chemotherapy was effective and well-tolerated in elderly patients with LABC.

[BRCA1/2 gene mutation in Chinese familial breast cancer patients: a multi-center report of 115 cases].

OBJECTIVE: To study the BRCA1/2 gene mutation frequency and characteristics in Chinese familial breast cancer patients. METHODS: Denaturing high-performance liquid chromatography (DHPLC) and following DNA sequencing in BRCA1/2 gene whole coding region and exon-intron splicing sites were performed in the specimens obtained during operation from 115 probands of familial breast cancer from 4 breast cancer centers in China. RESULTS: Fourteen cases of gene mutation (11 in BRCA1 and 3 in BRCA2) were found in the 115 breast cancer specimens with an overall mutation rate of 12.2%. After stratification with number of breast cancer patients in family, the frequency of mutation did not change significantly. The average age of disease onset of the families carrying BRCA1/2 mutations was significantly younger than that of the families without mutations (P < 0.01), and the higher the number of young patients in family, the higher the mutation rate. CONCLUSION: In Chinese familial breast cancer patients, age of disease-onset is an effective predictive factor of BRCA1/2 mutation, however, the predictive effect of the number of affective relatives in family is not good.

Quantitative contrast-enhanced ultrasound evaluation of pathological complete response in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy.

PURPOSE: To clarify whether the quantitative parameters of contrast-enhanced ultrasound (CEUS) can be used to predict pathological complete response (pCR) in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy (NAC). MATERIAL AND METHODS: Fifty-one patients with histologically proved locally advanced breast cancer scheduled for NAC were enrolled. The quantitative data for CEUS and the tumor diameter were collected at baseline and before surgery, and compared with the pathological response. Multiple logistic regression analysis was performed to examine quantitative parameters at CEUS and the tumor diameter to predict the pCR, and receiver operating characteristic (ROC) curve analysis was used as a summary statistic. RESULTS: Multiple logistic regression analysis revealed that PEAK (the maximum intensity of the time-intensity curve during bolus transit), PEAK%, TTP% (time to peak), and diameter% were significant independent predictors of pCR, and the area under the ROC curve was 0.932(Az1), and the sensitivity and specificity to predict pCR were 93.7% and 80.0%. The area under the ROC curve for the quantitative parameters was 0.927(Az2), and the sensitivity and specificity to predict pCR were 81.2% and 94.3%. For diameter%, the area under the ROC curve was 0.786 (Az3), and the sensitivity and specificity to predict pCR were 93.8% and 54.3%. The values of Az1 and Az2 were significantly higher than that of Az3 (P = 0.027 and P = 0.034, respectively). However, there was no significant difference between the values of Az1 and Az2 (P = 0.825). CONCLUSION: Quantitative analysis of tumor blood perfusion with CEUS is superior to diameter% to predict pCR, and can be used as a functional technique to evaluate tumor response to NAC.

Identification of the functional role of peroxiredoxin 6 in the progression of breast cancer.

INTRODUCTION: The molecular mechanisms involved in breast cancer metastasis still remain unclear to date. In our previous study, differential expression of peroxiredoxin 6 was found between the highly metastatic MDA-MB-435HM cells and their parental counterparts, MDA-MB-435 cells. In this study, we investigated the effects of peroxiredoxin 6 on the proliferation and metastatic potential of human breast cancer cells and their potential mechanism. METHODS: Expression of peroxiredoxin 6 in the highly metastatic MDA-MB-231HM cells was investigated by RT-PCR, real-time PCR and western blot. A recombinant expression plasmid of the human peroxiredoxin 6 gene was constructed and transfected into MDA-MB-231 and MDA-MB-435 cells. The effects of peroxiredoxin 6 on the proliferation and invasion of MDA-MB-231 and MDA-MB-435 cells were investigated by the Cell Counting Kit-8 method, colony-formation assay, adhesion assay, flow cytometry and invasion assay in vitro. miRNA was used to downregulate the expression of peroxiredoxin 6. Genes related to the invasion and metastasis of cancer were determined by RT-PCR, real-time PCR and western blot. The tumorigenicity and spontaneously metastatic capability regulated by peroxiredoxin 6 were determined using an orthotopic xenograft tumor model in athymic mice. RESULTS: Overexpression of peroxiredoxin 6 in MDA-MB-231HM cells compared with their parental counterparts was confirmed. Upregulation of peroxiredoxin 6 enhanced the in vitro proliferation and invasion of breast cancer cells. The enhancement was associated with decreasing levels of tissue inhibitor of matrix metalloproteinase (TIMP)-2 and increasing levels of the urokinase-type plasminogen activator receptor (uPAR), Ets-1 (E26 transformation-specific-1), matrix metalloproteinase (MMP)-9 and RhoC (ras homolog gene family, member C) expression. The results were further demonstrated by RNA interference experiments in vitro. In an in vivo study, we also demonstrated that peroxiredoxin 6-transfected breast cancer cells grew much faster and had more pulmonary metastases than control cells. By contrast, peroxiredoxin 6 knockdown breast cancer cells grew more slowly and had fewer pulmonary metastases. Effects similar to those of peroxiredoxin 6 on the uPAR, Ets-1, MMP-9, RhoC and TIMP-2 expression observed in in vitro studies were found in the in vivo study. CONCLUSION: Overexpression of peroxiredoxin 6 leads to a more invasive phenotype and metastatic potential in human breast cancer, at least in part, through regulation of the levels of uPAR, Ets-1, MMP-9, RhoC and TIMP-2 expression.