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author:("Xie, guantao")
1.  Early prediction of pathological outcomes to neoadjuvant chemotherapy in breast cancer patients using automated breast ultrasound 
Objective
Early assessment of response to neoadjuvant chemotherapy (NAC) for breast cancer allows therapy to be individualized. The optimal assessment method has not been established. We investigated the accuracy of automated breast ultrasound (ABUS) to predict pathological outcomes after NAC.
Methods
A total of 290 breast cancer patients were eligible for this study. Tumor response after 2 cycles of chemotherapy was assessed using the product change of two largest perpendicular diameters (PC) or the longest diameter change (LDC). PC and LDC were analyzed on the axial and the coronal planes respectively. Receiver operating characteristic (ROC) curves were used to evaluate overall performance of the prediction methods. Youden's indexes were calculated to select the optimal cut-off value for each method. Sensitivity, specificity, positive and negative predictive values (PPV and NPV) and the area under the ROC curve (AUC) were calculated accordingly.
Results
ypT0/is was achieved in 42 patients (14.5%) while ypT0 was achieved in 30 patients (10.3%) after NAC. All four prediction methods (PC on axial planes, LDC on axial planes, PC on coronal planes and LDC on coronal planes) displayed high AUCs (all>0.82), with the highest of 0.89 [95% confidence interval (95% CI), 0.83-0.95] when mid-treatment ABUS was used to predict final pathological complete remission (pCR). High sensitivities (85.7%-88.1%) were observed across all four prediction methods while high specificities (81.5%-85.1%) were observed in two methods used PC. The optimal cut-off values defined by our data replicate the WHO and the RECIST criteria. Lower AUCs were observed when mid-treatment ABUS was used to predict poor pathological outcomes.
Conclusions
ABUS is a useful tool in early evaluation of pCR after NAC while less reliable when predicting poor pathological outcomes.
doi:10.21147/j.issn.1000-9604.2016.05.02
PMCID: PMC5101221  PMID: 27877006
Automated breast ultrasound; breast neoplasms; drug monitoring; neoadjuvant therapy; pathological complete remission; ultrasonography
2.  A single-center, randomized, parallel controlled study comparing the efficacy and safety aspects of three anthracycline-based regimens as neoadjuvant chemotherapy in primary breast cancer 
This study aimed to compare the efficacy and safety aspects of three anthracycline-based regimens as neoadjuvant chemotherapy in primary breast cancer. Five-hundred and one patients with clinical stage I–III invasive breast cancer were randomly assigned to receive four cycles of neoadjuvant chemotherapy with either CEFci arm (5-Fu 200 mg/m2 daily by 24-h continuous infusion and epirubicin 100 mg/m2 and cyclophosphamide 600 mg/m2 intravenous bolus on day 1), CEF arm (cyclophosphamide 600 mg/m2, epirubicin 100 mg/m2, and 5-Fu 600 mg/m2 i.v. on day 1), or EC arm (epirubicin 100 mg/m2 and cyclophosphamide 600 mg/m2 i.v. on day 1). The pathologic responses to chemotherapy were assessed according to the Miller and Payne grading system (MP). A total of 485 patients were included in the intent-to-treat population. Breast pathologic complete response (pCR) rate was 18.9 % (31/164) in CEFci arm, 15.0 % (24/160) in CEF arm, and 12.4 % (20/161) in EC arm (P = 0.266). MP grading system 4/5 response rate was significantly higher in CEFci arm than that in CEF arm and EC arm (44.5, 31.3 and 27.3 %, respectively, P = 0.003). There was no significant difference on grade III/IV neutropenia among three arms (P = 0.538), but thrombocytopenia, decreased hemoglobin, and elevated aminotransferase appeared to be observed more in CEFci arm (P = 0.040, 0.059, and 0.073, respectively). CEFci did not reach a higher pCR rate compared with CEF or EC in patients with primary breast cancer. The potential advantage of CEFci in improving pathologic response still requires further research. The accompanied hematologic and biochemical toxicities, and the catheter-related complications should also be noted.
doi:10.1007/s10549-016-3843-7
PMCID: PMC4903108  PMID: 27250001
Breast cancer; 5-Fluorouracil; Neoadjuvant chemotherapy; Pathologic complete response
3.  Calcium and Magnesium Ions Are Membrane-Active against Stationary-Phase Staphylococcus aureus with High Specificity 
Scientific Reports  2016;6:20628.
Staphylococcus aureus (S. aureus) is notorious for its ability to acquire antibiotic-resistance, and antibiotic-resistant S. aureus has become a wide-spread cause of high mortality rate. Novel antimicrobials capable of eradicating S. aureus cells including antibiotic-resistant ones are thus highly desired. Membrane-active bactericides and species-specific antimicrobials are two promising sources of novel anti-infective agents for fighting against bacterial antibiotic-resistance. We herein show that Ca2+ and Mg2+, two alkaline-earth-metal ions physiologically essential for diverse living organisms, both disrupt model S. aureus membranes and kill stationary-phase S. aureus cells, indicative of membrane-activity. In contrast to S. aureus, Escherichia coli and Bacillus subtilis exhibit unaffected survival after similar treatment with these two cations, indicative of species-specific activity against S. aureus. Moreover, neither Ca2+ nor Mg2+ lyses mouse red blood cells, indicative of hemo-compatibility. This works suggests that Ca2+ and Mg2+ may have implications in targeted eradication of S. aureus pathogen including the antibiotic-resistant ones.
doi:10.1038/srep20628
PMCID: PMC4749956  PMID: 26865182
4.  A genome-wide association study identifies WT1 variant with better response to 5-fluorouracil, pirarubicin and cyclophosphamide neoadjuvant chemotherapy in breast cancer patients 
Oncotarget  2015;7(4):5042-5052.
Breast cancer is believed to result from the interplay of genetic and non-genetic risk factors, and individual genetic variation may influence the efficacy of chemotherapy. Here we conducted a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with response to anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer patients. In the discovery stage, we divided 92 patients who received anthracycline-based neoadjuvant chemotherapy into 2 groups according to pathologic response and performed a genome-wide study using Affymetrix SNP6.0 genechip. Of 389,795 SNPs associated with pathologic complete response (pCR), we identified 2 SNPs, rs6044100 and rs1799937, that were significantly associated with pCR after neoadjuvant chemotherapy. In the validation stage, genotype analysis of samples from an independent cohort of 401 patients who received anthracycline-based neoadjuvant regimens and 467 patients who received taxane-based regimens was performed using sequencing analysis. We found that only SNP rs1799937, located in the WT1 gene, was associated with pCR after anthracycline-based neoadjuvant therapy (AA vs GG; odds ratio [OR], 2.81; 95% confidence interval [CI], 1.13–6.98; P < 0.05) but not after taxane-based neoadjuvant therapy (AA vs GG; OR, 0.85; 95% CI, 0.36–2.04; P = 0.72). These results suggest that WT1 may be a potential target of anthracycline-based neoadjuvant therapy for breast cancer.
doi:10.18632/oncotarget.5837
PMCID: PMC4826264  PMID: 26573232
WT1; rs1799937; breast cancer; anthracycline; neoadjuvant chemotherapy
5.  Association between HER2 status and response to neoadjuvant anthracycline followed by paclitaxel plus carboplatin chemotherapy without trastuzumab in breast cancer 
Background
We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen in the absence of trastuzumab.
Methods
Women (n=372) with operable primary breast cancer initially received two cycles of neoadjuvant anthracyclines, the clinical tumor response was assessed, then patients were received four cycles of paclitaxel plus carboplatin regimen. All the patients did not received trastuzumab treatment in the neoadjuvant setting. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core-biopsy breast cancer tissue obtained before the neoadjuvant chemotherapy.
Results
Eighteen percent (67/372) of patients achieved a pathologic complete response (pCR) in their breast. HER2-positive tumors had a significant higher pCR rate than HER2-negative tumors (33.0% versus 13.5%, P<0.001) in this cohort of 372 patients, and positive HER2 status remained an independent favorable predictor of pCR in a multivariate analysis [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.18 to 4.36, P=0.015]. Furthermore, patients who responded to initial anthracycline regimens were more likely to respond to paclitaxel plus carboplatin than patients who did not (pCR, 27.2% versus 14.6%, P=0.005). Patients with HER2-positive tumors exhibited a significant higher pCR rate than did patients with HER2-negative tumors in both anthracycline response group (40.5% versus 20.0%, P=0.025) and anthracycline non-response group (28.3% versus 11.3%, P=0.002).
Conclusions
Under the circumstance of no trastuzumab treatment, women with HER2-positive cancers derive a large benefit from paclitaxel-carboplatin-based neoadjuvant chemotherapy.
doi:10.3978/j.issn.1000-9604.2015.12.03
PMCID: PMC4697102  PMID: 26752929
HER2; breast cancer; neoadjuvant chemotherapy; paclitaxel; carboplatin
6.  Breast-conserving therapy and modified radical mastectomy for primary breast carcinoma: a matched comparative study 
Background
To compare two types of therapy for primary breast carcinoma, breast-conserving therapy (BCT) and modified radical mastectomy (MRM), in a matched cohort study.
Methods
A series of 1,746 patients with primary breast cancer treated with BCT or MRM in a single Chinese institute between January 2000 and February 2009 were analyzed retrospectively to compare their outcomes with respect to the incidence of local recurrence (LR), distant metastasis, and survival. The patients were matched with regard to age at diagnosis, spreading to axillary lymph nodes, hormone receptor status, the use of neoadjuvant chemotherapy and maximal tumor diameter. The match ratio was 1:1, and each arm included 873 patients.
Results
The median follow-up period was 71 months. The 6-year disease-free survival (DFS) and 6-year distant disease-free survival (DDFS) rates differed significantly between two groups. The 6-year local recurrence-free survival (LRFS) rates were 98.2% [95% confidence interval (CI): 0.973-0.989] in the BCT group and 98.7% (95% CI: 0.980-0.994) in the MRM group (P=0.182), respectively. DFS rates in BCT and MRM groups were 91.3% (95% CI: 0.894-0.932) and 86.3% (95% CI: 0.840-0.886) (P<0.001), respectively, whereas the DDFS rates in BCT and MRM groups were 93.6% (95% CI: 0.922-0.950) and 87.7% (95% CI: 0.854-0.900) (P<0.001), respectively.
Conclusions
BCT in eligible patients is as effective as MRM with respect to local tumor control, DFS and DDFS, and may result in a better outcome than MRM in Chinese primary breast cancer patients.
doi:10.3978/j.issn.1000-9604.2015.11.02
PMCID: PMC4697104  PMID: 26752928
Breast carcinoma; breast-conserving therapy (BCT); mastectomy; recurrence; survival
7.  Mutations in RECQL Gene Are Associated with Predisposition to Breast Cancer 
PLoS Genetics  2015;11(5):e1005228.
The genetic cause for approximately 80% of familial breast cancer patients is unknown. Here, by sequencing the entire exomes of nine early-onset familial breast cancer patients without BRCA1/2 mutations (diagnosed with breast cancer at or before the age of 35) we found that two index cases carried a potentially deleterious mutation in the RECQL gene (RecQ helicase-like; chr12p12). Recent studies suggested that RECQL is involved in DNA double-strand break repair and it plays an important role in the maintenance of genomic stability. Therefore, we further screened the RECQL gene in an additional 439 unrelated familial breast cancer patients. In total, we found three nonsense mutations leading to a truncated protein of RECQL (p.L128X, p.W172X, and p.Q266X), one mutation affecting mRNA splicing (c.395-2A>G), and five missense mutations disrupting the helicase activity of RECQL (p.A195S, p.R215Q, p.R455C, p.M458K, and p.T562I), as evaluated through an in vitro helicase assay. Taken together, 9 out of 448 BRCA-negative familial breast cancer patients carried a pathogenic mutation of the RECQL gene compared with one of the 1,588 controls (P = 9.14×10-6). Our findings suggest that RECQL is a potential breast cancer susceptibility gene and that mutations in this gene contribute to familial breast cancer development.
Author Summary
In this study, we aimed to find novel breast cancer susceptibility genes by whole-exome sequencing in nine early-onset familial breast cancer patients without BRCA1/2 mutations. We found that two index cases carried a potentially deleterious mutation in the RECQL gene (RecQ helicase-like). We further screened the RECQL gene in an additional 439 unrelated familial breast cancer patients. In total, we found nine index cases carried a pathogenic mutation in the RECQL gene among the 448 BRCA-negative familial breast cancer patients. The RECQL is one of five RecQ helicase proteins (named RECQL, BLM, WRN, RECQL4 and RECQL5). RECQL is considered to be genome caretaker, and mutations in three of five RecQ genes, BLM, WRN and RECQ4 are associated with cancer predisposition and/or premature aging. Here, we are the first to report that mutations in the RECQL gene are associated with predisposition to breast cancer and this finding may have potential clinical implications and raise research questions about RECQL.
doi:10.1371/journal.pgen.1005228
PMCID: PMC4422667  PMID: 25945795
8.  Association between CHEK2 H371Y mutation and response to neoadjuvant chemotherapy in women with breast cancer 
BMC Cancer  2015;15:194.
Background
Our previous study suggested that the recurrent CHEK2 H371Y mutation is a novel pathogenic mutation that confers an increased risk of breast cancer. The purpose of this study was to investigate whether breast cancer patients with CHEK2 H371Y mutation were more likely to respond to neoadjuvant chemotherapy.
Methods
We screened a cohort of 2334 Chinese women with operable primary breast cancer who received a neoadjuvant chemotherapy regimen for CHEK2 H371Y germline mutations. Pathologic complete response (pCR) was defined as the absence of tumor cells in the breast after the completion of neoadjuvant chemotherapy.
Results
Thirty-nine patients (1.7%) with CHEK2 H371Y germline mutation were identified in this cohort of 2334 patients. CHEK2 H371Y mutation carriers had a significantly higher pCR rate than non-carriers (33.3% versus 19.5%, P = 0.031) in the entire study population, and CHEK2 H371Y mutation-positive status remained an independent favorable predictor of pCR in a multivariate analysis (odds ratio [OR] = 3.01; 95% confidence interval [CI]: 1.34- 6.78, P = 0.008). CHEK2 H371Y carriers had a slightly worse distant recurrence-free survival than non-carriers (adjusted hazard ratio [HR] =1.24, 95% CI: 0.59-2.63).
Conclusions
CHEK2 H371Y mutation carriers are more likely to respond to neoadjuvant chemotherapy than are non-carriers.
doi:10.1186/s12885-015-1203-3
PMCID: PMC4378224  PMID: 25884806
9.  miR-127 Regulates Cell Proliferation and Senescence by Targeting BCL6 
PLoS ONE  2013;8(11):e80266.
Cellular senescence occurs as a response to extracellular and intracellular stresses and contributes to aging and age-related pathologies. Emerging evidence suggests that cellular senescence also acts as a potent tumor suppression mechanism that prevents the oncogenic transformation of primary human cells. Recent reports have indicated that miRNAsact as key modulators of cellular senescence by targeting critical regulators of the senescence pathways. We previously reported that miR-127 is up-regulated in senescent fibroblasts. In this report, we identified miR-127 as a novel regulator of cellular senescence that directly targets BCL6. We further showed that miR-127 is down-regulated in breast cancer tissuesand that this down-regulation is associated with up-regulation of BCL6. Over-expression of miR-127 or depletion of BCL6 inhibits breast cancer cell proliferation. Our data suggest that miR-127 may function as a tumor suppressor that modulates the oncogene BCL6.
doi:10.1371/journal.pone.0080266
PMCID: PMC3840165  PMID: 24282530
10.  Value of pre-treatment biomarkers in prediction of response to neoadjuvant endocrine therapy for hormone receptor-positive postmenopausal breast cancer 
Objective
To determine the predictive ability of biomarkers for responses to neoadjuvant endocrine therapy (NET) in postmenopausal breast cancer.
Methods
Consecutive 160 postmenopausal women with T1-3N0-1M0 hormone receptor (HR)-positive invasive breast cancer were treated with anastrozole for 16 weeks before surgery. New slides of tumor specimens taken before and after treatment were conducted centrally for biomarker analysis and classified using the Applied Imaging Ariol MB-8 system. The pathological response was evaluated using the Miller & Payne classification. The cell cycle response was classified according to the change in the Ki67 index after treatment. Multivariable logistic regression analysis was used to calculate the combined index of the biomarkers. Receiver operating characteristic (ROC) curves were used to determine whether parameters may predict response.
Results
The correlation between the pathological and cell cycle responses was low (Spearman correlation coefficient =0.241, P<0.001; Kappa value =0.119, P=0.032). The cell cycle response was significantly associated with pre-treatment estrogen receptor (ER) status (P=0.001), progesterone receptor (PgR) status (P<0.001), human epidermal growth factor receptor 2 (Her-2) status (P=0.050) and the Ki67 index (P<0.001), but the pathological response was not correlated with these factors. Pre-treatment ER levels [area under the curve (AUC) =0.634, 95% confidence interval (95% CI), 0.534-0.735, P=0.008] and combined index of pre-treatment ER and PgR levels (AUC =0.684, 95% CI, 0.591-0.776, P<0.001) could not predict the cell cycle response, but combined index including per-treatment ER/PR/Her-2/Ki67 expression levels could (AUC =0.830, 95% CI, 0.759-0.902, P<0.001).
Conclusions
The combined use of pre-treatment ER/PgR/Her-2/Ki67 expression levels, instead of HR expression levels, may predict the cell cycle response to NET.
doi:10.3978/j.issn.1000-9604.2013.08.01
PMCID: PMC3752359  PMID: 23997526
Breast cancer; neoadjuvant endocrine therapy (NET); responsiveness; predictive value
11.  Protein phosphatase PP6 is required for homology-directed repair of DNA double-strand breaks 
Cell Cycle  2011;10(9):1411-1419.
DNA double-strand breaks (DSBs) are among the most lethal lesions associated with genome stability, which, when destabilized, predisposes organs to cancers. DSBs are primarily fixed either with little fidelity by non-homologous end joining (NHEJ) repair or with high fidelity by homology-directed repair (HDR). The phosphorylated form of H2AX on serine 139 (γ-H2AX) is a marker of DSBs. In this study, we explored if the protein phosphatase PP6 is involved in DSB repair by depletion of its expression in human cancer cell lines, and determined PP6 expression in human breast cancer tissues by immunohistochemistry staining. We found that bacterially produced PP6c (the catalytic subunit of PP6)-containing heterotrimeric combinations exhibit phosphatase activity against γ-H2AX in the in vitro phosphatase assays. Depletion of PP6c or PP6R2 led to persistent high levels of γ-H2AX after DNA damage and a defective HDR. Chromatin immunoprecipitation assays demonstrated that PP6c was recruited to the region adjacent to the DSB sites. Expression of PP6c, PP6R2 and PP6R3 in human breast tumors was significantly lower than those in benign breast diseases. Taken together, our results suggest that γ-H2AX is a physiological substrate of PP6 and PP6 is required for HDR and its expression may harbor a protective role during the development of breast cancer.
doi:10.4161/cc.10.9.15479
PMCID: PMC3117043  PMID: 21451261
protein phosphatase; PP6; γ-H2AX; DNA double-strand break; homology-directed repair
12.  Expression of ER-α36, a Novel Variant of Estrogen Receptor α, and Resistance to Tamoxifen Treatment in Breast Cancer 
Journal of Clinical Oncology  2009;27(21):3423-3429.
Purpose
Recently, a 36-kDa variant of estrogen receptor α (ER-α66), ER-α36, has been identified and cloned. ER-α36 predominantly localizes on the plasma membrane and in the cytoplasm and mediates a membrane-initiated “nongenomic” signaling pathway. Here, we investigate the association between ER-α36 expression and tamoxifen resistance in patients with breast cancer.
Patients and Methods
ER-α36 protein expression in tumors from 896 women (two independent cohorts, 1 and 2) with operable primary breast cancer was assessed using an immunohistochemistry assay.
Results
In the first cohort of 710 consecutive patients, overexpression of ER-α36 was associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) in patients with ER-α66–positive tumors who received tamoxifen treatment (chemotherapy plus tamoxifen or tamoxifen alone, n = 307). In contrast, ER-α36 was not associated with survival in patients with ER-α66–positive tumors who did not receive tamoxifen (chemotherapy alone, n = 129) and in patients with ER-α66–negative tumors whether they received tamoxifen (n = 73) or not (n = 149). In the second cohort of 186 patients who only received tamoxifen as adjuvant therapy, overexpression of ER-α36 was significantly associated with poorer DFS and DSS in 156 ER-α66–positive patients from this cohort, and ER-α36 remained an independent unfavorable factor for both DFS and DSS in these 156 patients by a multivariate analysis (DFS: hazard ratio [HR] = 5.47; 95% CI, 1.81 to 16.51; P =. 003; DSS: HR = 13.97; 95% CI, 1.58 to 123.53; P = .018).
Conclusion
Women with ER-α66–positive tumors that also express high levels of ER-α36 are less likely to benefit from tamoxifen treatment.
doi:10.1200/JCO.2008.17.2254
PMCID: PMC2717750  PMID: 19487384

Results 1-12 (12)