[Show abstract][Hide abstract] ABSTRACT: IntroductionPhosphatidylinositol 3-kinase (PI3K) pathway deregulation (i.e. PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) has been shown to enhance breast cancer cell survival and confer resistance to chemotherapeutic agents. We studied the prognostic and predictive value of PIK3CA mutations and PTEN low in patients receiving paclitaxel alone or in combination with lapatinib.Methods
Immunohistochemistry and mutation analyses were used to evaluate PTEN and PIK3CA, respectively. Kaplan-Meier analysis with log-rank tests, logistic regression and Cox models were used in analyses of these biomarkers with efficacy endpoints.ResultsIn the overall population, PIK3CA mutations were associated with poorer overall survival (OS) (hazard ratio [HR]¿=¿1.87; 95% confidence interval [CI]: 1.22, 2.88; P¿=¿0.001). PTEN expression was not associated with OS (P¿=¿0.474). In the PIK3CA wild-type subgroup, lapatinib plus paclitaxel reduced risk of progression compared with paclitaxel alone (HR¿=¿0.44; 95% CI: 0.28, 0.69; P¿<¿0.0001); progression-free survival (PFS) was not significantly improved within the PIK3CA mutation subgroup (P¿=¿0.179). In the PTEN low group, OS was improved with addition of lapatinib (P¿=¿0.039). In both PTEN subgroups, addition of lapatinib was associated with improvements in PFS (P¿<¿0.050). PIK3CA and PTEN were not predictive of treatment based on interaction tests (P¿>¿0.05).ConclusionPTEN was neither a significant prognostic nor predictive factor. PIK3CA mutations were an adverse prognostic factor for survival but not predictive for lapatinib benefit.Trial registrationClinicalTrials.gov NCT00281658 (registered 23 January 2006).
Breast cancer research: BCR 07/2014; 16(4):405. · 5.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in monitoring therapy responses and analyze the predictive value of tumor biomarkers in neoadjuvant chemotherapy for breast cancer.
[Show abstract][Hide abstract] ABSTRACT: This multicenter prospective study aimed to assess the utility of dynamic enhanced magnetic resonance imaging (MRI) prior to breast-conserving surgery for breast cancer.
[Show abstract][Hide abstract] ABSTRACT: To explore the clinical characteristics and prognosis of ductal carcinoma in situ (DCIS) and early stage ductal breast cancer with invasive depth ≤ 1 cm.
Follow-up analyses were performed for the clinical data of 57 patients with DCIS, 46 with pT1mic and 74 with pT1a-b breast cancer treated or consulted at our hospital. Single factor analysis was used to examine their prognostic factors.
Among them, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2(HER-2) positive rate and visual tumor size (2.0(0.1-7.0) vs 2.0(0.5-10.0) vs 2.0(0.3-10.0) cm)had no statistical differences between 3 groups (all P > 0.05). After median follow-up periods of 63, 38, 59 months, 12 patients suffered recurrence and metastasis and the rate of each group had no statistical differences. For pT1a-b patients with positive hormone receptor, endocrine therapy markedly reduced the risk of recurrence and metastasis (P = 0.024) . pT1mic, pT1a-b patients on chemotherapy had higher or comparable recurrence rate versus those without. And DCIS patients on chemotherapy had a much higher recurrence rate (P = 0.016) . In pT1a-b group, HER-2 positive patients had higher recurrence and metastasis rates. Yet there was a decreasing tendency after Herceptin treatment.
Chemotherapy without proper indications may not improve the prognosis of DCIS, pT1mic and pT1a-b patients. Endocrine therapy is the crucial prognostic factor of patients with positive hormone receptor. Use of Herceptin for HER-2-positive patients is probably significant.
[Show abstract][Hide abstract] ABSTRACT: To explore the prediction value for dynamic changes of circulating tumor cell (CTC) in therapeutic response and prognosis of Chinese metastatic breast cancer patients.
A total of 300 metastatic breast cancer patients from six breast cancer centers in China were included from March 2010 to January 2011. The CTC levels of metastatic breast cancer patients were detected with a CellSearch system before starting a new systemic therapy (baseline) and after 3-4, 6-8 weeks. The progression-free survival (PFS) of different groups according to dynamic changes of CTC was estimated by the Kaplan-Meier method and compared with Log-Rank test.
The median follow-up time was 36.86 weeks. The median PFS of patients with ≥ 5 CTCs/7.5 ml at baseline but with < 5 CTCs/7.5 ml after treatment of 3-4 weeks was significantly prolonged than that those with persistent ≥ 5 CTCs/7.5 ml at the same timepoint (30.4 vs 14.1 weeks, P = 0.010). Furthermore, the median PFS of former had no significant statistic difference with those with < 5 CTCs/7.5 ml at baseline (30.4 vs 42.0 weeks, P = 0.780). The analysis result of PFS for three groups according to CTC of 6-8 weeks treatment was consistent with that according to CTC of 3-4 weeks. The median PFS of patients with ≥ 5 CTCs/7.5 ml at baseline but with < 5 CTCs/7.5 ml after treatment of 6-8 weeks was significantly prolonged than that those with persistent ≥ 5 CTCs/7.5 ml at the same time point (33.4 vs 8.9 weeks, P = 0.000). The median PFS of former had no significant statistic difference with those with < 5 CTCs/7.5 ml at baseline(33.4 vs 42.0 weeks, P = 0.950).
The dynamic changes of CTC levels during therapy may predict an improvement of progression disease risk and has significance in therapeutic efficacy monitoring.
[Show abstract][Hide abstract] ABSTRACT: Objective To construct eukaryotic expression vector of myc-tagged human HER2 and investigate its role in breast cancer cell proliferation and drug resistance. Methods Human HER2 gene was amplified by PCR and cloned into the pXJ-40-myc vector. The recombinant myc-HER2 was identified by enzyme digestion and sequencing, transfected into breast cancer cell line ZR75-1, and then was detected by Western blotting. Next, CCK8 assay was performed to investigate myc-Her2 transfected cell proliferation. Trastuzumab, anti-Her2 antibody, was added to determine the sensitivity of cells transfected with myc-Her2. Results Enzyme digestion and sequencing confirmed the myc-HER2 vector was constructed successfully. Western blotting showed the expression of myc-HER2 in the ZR75-1 cells. The result of cell growth curve showed that cells transfected with myc-her2 grew significantly faster than the control cells. Moreover, trastuzumab obviously suppressed the growth of ZR75-1 cells transfected with myc-HER2. Conclusion The myc-HER2 vector was successfully constructed which lays an experimental foundation for the study of HER2 drug resistance to trastuzumab.
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 06/2013; 29(6):606-8.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this prospective, nonrandomized, controlled study was to compare the regimen of continuously administering trastuzumab and capecitabine (HX) with the regimen of lapatinib plus capecitabine (LX) for metastatic breast cancer (MBC) patients who are resistant to trastuzumab and have previously received taxane treatment. The patients in the HX group received trastuzumab (6 mg/kg every 21 days following a loading dose of 8 mg/kg on cycle 1) and capecitabine (2,000 mg/m(2)/day, days 1 to 14 every 21 days). The patients in the LX group received lapatinib (1,250 mg/day) and capecitabine (2,000 mg/m(2)/day, days 1 to 14 every 21 days). The median progression-free survival (PFS) of the patients in the HX and LX groups was 4.5 vs. 6.0 months, respectively (p = 0.006). The proportion of patients having a PFS ≥6 months in the HX and LX groups was 30 vs. 55 %, respectively (p = 0.005). The incidence rate of new brain metastases during treatment was 12 and 3 % in the HX and LX groups, respectively, which was not significantly different (p = 0.16). In conclusion, application of the lapatinib plus capecitabine regimen in MBC patients with a trastuzumab-resistant tumor can more effectively control the disease compared with continuous administration of trastuzumab plus capecitabine.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: This study was initiated to investigate the prognostic significance of circulating tumor cell (CTC) enumeration and the predictive value of CTC HER2 expression for efficient anti-HER2 therapy in HER2-positive metastatic breast cancer (MBC) patients. METHODS: Sixty HER2-positive MBC patients were enrolled in the present study. Before the initiation of systemic treatment, CTCs from 7.5 ml of blood were analyzed using the CellSearch system. The progression-free survival (PFS) of the patients was estimated using Kaplan-Meier survival curves. RESULTS: CTCs were detected in 45% (27/60) of the patients, who had shorter median PFS than those without CTCs (2.5 vs. 7.5 months, P = 0.0125). Furthermore, referring to the standard HER2 testing that uses immunohistochemistry (IHC), we proposed a CTC HER2-positive criterion, defined as >30% of CTCs over-expressing HER2. Among patients undergoing anti-HER2 therapy, those with HER2-positive CTCs had longer PFS (8.8 vs. 2.5 months, P = 0.002). Among patients with HER2-positive CTCs, the median PFS for those receiving anti-HER2 therapy was significantly longer than those who were not (8.8 vs. 1.5 months, P = 0.001). Notably, up to 52% (14/27) of the HER2-positive patients were CTC HER2-negative, and anti-HER2 therapy did not significantly improve the median PFS in these patients (2.5 vs. 0.9 months, P = 0.499). CONCLUSIONS: Our findings underscore the necessity of a comprehensive CTC analysis, which may provide valuable prognostic and predictive information for optimizing individually tailored therapies in HER2-positive MBC patients. To test this idea, additional large cohort, multi-center and prospective clinical trials are needed.
BMC Cancer 04/2013; 13(1):202. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSELapatinib is an oral small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study is designed to test whether the addition of lapatinib to paclitaxel improves overall survival (OS) compared with placebo plus paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).Patients And methodsThis phase III, randomized, double-blind study assessed the efficacy and safety of lapatinib plus paclitaxel compared with placebo plus paclitaxel in patients with newly diagnosed HER2-positive MBC. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), clinical benefit rate, and safety.ResultsThe addition of lapatinib to paclitaxel significantly improved OS versus paclitaxel (treatment hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .0124); median OS was 27.8 versus 20.5 months, respectively. Median PFS was prolonged by 3.2 months, from 6.5 months with placebo plus paclitaxel to 9.7 months with lapatinib plus paclitaxel (HR, 0.52; 95% CI, 0.42 to 0.64; stratified log-rank P < .001). ORR was significantly higher with lapatinib plus paclitaxel compared with placebo plus paclitaxel (69% v 50%, respectively; P < .001). The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm. Only 4% of patients in this group reported febrile neutropenia. Cardiac events were low grade, asymptomatic, and mostly reversible. The incidence of hepatic events was similar in both arms. There were no fatal adverse events in the lapatinib plus paclitaxel arm. CONCLUSION
This trial demonstrated that lapatinib combined with paclitaxel offers a significant and clinically meaningful survival advantage over paclitaxel alone in patients with HER2-positive MBC.
Journal of Clinical Oncology 03/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BRCA1 mutations account for a significant proportion of familial breast and ovarian cancers. In addition, reduced BRCA1 protein is associated with sporadic cancer cases in these tissues. At the cellular level, BRCA1 plays a critical role in multiple cellular functions such as DNA repair and cell cycle checkpoint control. Its protein level is regulated in a cell cycle-dependent manner. However, regulation of BRCA1 protein stability is not fully understood. Our earlier study showed that the amino-terminus of BRCA1 harbors a degron sequence that is sufficient and necessary for conferring BRCA1 degradation. In the current study, we used mass spectrometry to identify Skp1 that regulates BRCA1 protein stability. Small interfering RNA screening that targets all human F-box proteins uncovered FBXO44 as an important protein that influences BRCA1 protein level. The Skp1-Cul1-F-box-protein44 (SCFFBXO44) complex ubiquitinates full length BRCA1 in vitro. Furthermore, the N-terminus of BRCA1 mediates the interaction between BRCA1 and FBXO44. Overexpression of SCFFBXO44 reduces BRCA1 protein level. Taken together, our work strongly suggests that SCFFBXO44 is an E3 ubiquitin ligase responsible for BRCA1 degradation. In addition, FBXO44 expression pattern in breast carcinomas suggests that SCFFBXO44-mediated BRCA1 degradation might contribute to sporadic breast tumor development.
Journal of Biological Chemistry 10/2012; · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We performed an analysis of the efficacy of capecitabine monotherapy as maintenance treatment for metastatic breast cancer (MBC) after response to capecitabine-based chemotherapy [capecitabine plus docetaxel (XT) or vinorelbine (XN)] as a first-line or a second-line treatment. Sixty-four Chinese patients with histologically confirmed MBC received capecitabine maintenance therapy after disease stabilization or maximal response to capecitabine-based combination chemotherapy. Single-agent capecitabine was administered at a dose of 1000 mg/m(2) twice daily for 14 days, followed by a 7-day rest period, every 3 weeks. The median time to progression, the primary endpoint of the study, was 4.4 months (95% confidence interval, 3.4-5.4 months). Fifty-nine patients were evaluable for response. Capecitabine maintenance therapy produced an objective response rate of 5.1% (95% confidence interval, 3.9-6.3%). The incidence of grade 3/4 leukopenia (3.1%) and neutropenia (4.7%) was significantly lower (P<0.001) with capecitabine monotherapy than with combination chemotherapy (46.9 and 54.7%, respectively). Conversely, the incidence of grade 3 hand-foot syndrome was higher with capecitabine maintenance therapy than with combination therapy (14.1 vs. 0%, respectively; P=0.003). Capecitabine monotherapy is an effective maintenance treatment after response to capecitabine-based combination chemotherapy in MBC with a favorable safety profile.
[Show abstract][Hide abstract] ABSTRACT: Overinduced CD4(+)CD25(+high) regulatory T cells (Treg) and downregulated NK cells contribute to tumor-relevant immune tolerance and interfere with tumor immunity. In this study, we aimed to design a novel strategy with cytokine combination to correct the dysregulated Treg and NK cells in malignant patients. Initially, a total of 58 healthy individuals and 561 malignant patients were analyzed for their cellular immunity by flow cytometry. The average percentages of CD4(+)CD25(+high)/lymphocyte were 1.30 ± 1.19 % ([Formula: see text] ± SD) in normal adults and 3.274 ± 4.835 % in malignant patients (p < 0.001). The ratio of CD4(+)CD25(+high) to CD4(+) was 3.58 ± 3.19 % in normal adults and 6.01 ± 5.89 % to 13.50 ± 23.60 % in different kinds of malignancies (p < 0.001). Of normal adults, 15.52 % had >3 % Treg and 12.07 % had <10 % NK cells. In contrast, the Treg (>3 %) and NK (<10 %) percentages were 40.82 and 34.94 % in malignant patients, respectively. One hundred and ten patients received the immunomodulation therapy with IFN-α and/or IL-2. The overinduced Treg in 86.3 % and the reduced NK cells in 71.17 % of the patients were successfully modulated. In comparison, other lymphocyte subpopulations in most patients were much less affected by this treatment. No other treatment-relevant complications except slight pyrexia, fatigue, headache, and myalgia were observed. In conclusion, dysregulated Treg and/or NK cells were common in malignant patients. Different from any regimens ever reported, this strategy was simple and effective without severe complications and will become a basic regimen for other cancer therapies.
Cancer Immunology and Immunotherapy 06/2012; · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The primary objective of this multicenter, open-label, randomized, parallel, phase II selection trial was to compare the objective tumor response to biweekly (every 2 weeks) gemcitabine/paclitaxel, gemcitabine/carboplatin, and gemcitabine/cisplatin as first-line treatment for metastatic breast cancer.
Eligible patients with stage IV disease who relapsed after anthracycline failure were randomly assigned in a 1:1:1 ratio to gemcitabine (2,500 mg/m2) plus paclitaxel 150 mg/m2 (n = 49); plus carboplatin, area under the curve = 2.5 mg/mL × min (n = 47); or plus cisplatin 50 mg/m2 (n = 51). Study therapy continued up until a maximum of 8 cycles and follow-up continued for 24 months.
All patients were analyzed for efficacy and one patient was excluded from the safety analyses. The objective response was 26.5% [95% confidence interval (CI) 14.9-41.1] for gemcitabine/paclitaxel, 17.0% (95% CI 7.6-30.8) for gemcitabine/carboplatin, and 15.7% (95% CI 7.0-28.6) for gemcitabine/cisplatin. The adjusted odds ratio for tumor response was 0.33 (95% CI 0.10-1.06), P = 0.063 for gemcitabine/carboplatin versus gemcitabine/paclitaxel; 0.26 (95% CI 0.08-0.86), P = 0.027 for gemcitabine/cisplatin versus gemcitabine/paclitaxel; and 0.77 (95% CI 0.24-2.52), P = 0.671 for gemcitabine/cisplatin versus gemcitabine/carboplatin. There were no significant differences in overall survival or progression-free survival (P > 0.05). Grade 3 or 4 drug-related adverse events varied between groups and the majority of deaths (94.9%; 74/78) were related to disease progression.
The gemcitabine-based treatments had comparable activity and tolerability. Similar survival characteristics and different toxicity profiles suggested that gemcitabine-platinum may be evaluated further in patients after anthracycline failure.
Breast Cancer 04/2011; 18(3):203-12. · 1.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was conducted to evaluate the response rate of gemcitabine and cisplatin as second-line combination chemotherapy in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Thirty-eight eligible women with measurable disease and anthracycline- and taxane-pretreated MBC were enrolled. The chemotherapy treatment consisted of gemcitabine (1,250 mg/m(2) by intravenous infusion over 30 min on days 1 and 8) and cisplatin (75 mg/m(2) by intravenous infusion over 1 h on day 1), which were administered every 21 days. Thirty-seven of 38 (97.4%) of patients were assessable for response. The objective response rate was 42.1% (95% CI, 26.4-57.8%) with 16 partial responses. The median time to progression (TTP) and overall survival (OS) for all patients were 5.4 months (95% CI, 2.7-8.1 months) and 13.9 months (95% CI, 9.4-18.4 months), respectively. The most frequent hematologic-related adverse events were grade 3/4 leucopenia and thrombocytopenia, observed in 10 patients (27.0%) and 11 (29.7%), respectively. Grade 3 stomatitis was observed in 3 (8.1%) patients. No grade 4 nonhematologic toxicity was observed in this study. No treatment-related deaths occurred during the study. In conclusion, the combination of gemcitabine and cisplatin is a safe and tolerable regimen as second-line combination for patients with anthracycline- and taxane-pretreated MBC.
Medical Oncology 01/2011; 29(1):56-61. · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the efficacy and safety of gemcitabine-paclitaxel in Chinese patients with metastatic breast cancer following anthracycline failure in a multicenter, open-label, single-arm, phase II clinical trial.
Chinese female patients with unresectable, locally recurrent or metastatic breast cancer who had relapsed after neo-adjuvant anthracycline-based chemotherapy were included. All patients had measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 at baseline. Gemcitabine (1250 mg/m(2) )-paclitaxel (175 mg/m(2) ) was administered on a 3-weekly schedule until disease progression, and patients were followed up for 12 months (post-enrollment). The primary end point was objective response rate; secondary end points included duration of response, progression-free survival and overall survival.
Overall 60 patients were enrolled. Their mean age was 46.9 (SD ± 9.0) years and 90% of patients had metastatic disease. All patients had previously received chemotherapy. A total of 48 patients (80%) completed the 12-month follow up, and 40 patients (67%) completed at least six cycles of study therapy. The objective response rate (complete response + partial response) was 50% (95% CI: 36.6-63.4). Median duration of response was 5.6 months (95% CI: 4.4-7.6) and median progression-free survival was 7.6 months (95% CI: 5.8-8.8). Overall survival at 12 months was 87% (95% CI: 77.9-95.2). Laboratory toxicities were primarily hematologic, including Grade 3 and 4 neutropenia (n = 27 [45%]) and leukopenia (n = 18 [30%]). Eight patient deaths (13%) were not treatment-related.
Gemcitabine-paclitaxel combination therapy is an active and well-tolerated chemotherapy regimen, with expected and manageable toxicity in Chinese patients with metastatic breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Fulvestrant, an oestrogen receptor (ER) antagonist with no known agonist effects, has shown activity in postmenopausal patients with ER-positive advanced breast cancer recurring or progressing following prior endocrine therapy. This double-blind, double-dummy, randomised phase III study (NCT00327769) was designed to compare the efficacy and safety of fulvestrant versus anastrozole in advanced breast cancer of Chinese postmenopausal women whose disease has progressed following prior endocrine treatment.
A total of 234 patients were randomised to fulvestrant 250 mg/month (n = 121) or 1 mg/day anastrozole (n = 113), together with matching placebo. The primary endpoint was time to progression (TTP). Secondary endpoints included objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR) and time to treatment failure (TTF).
Baseline characteristics were similar, with the possible exception that a higher number of fulvestrant patients had received two prior chemotherapy regimens. Median TTP was 110 days in the fulvestrant group versus 159 days in the anastrozole group (hazard ratio [HR], 1.314; 95% confidence intervals [CI], 0.948, 1.822; P = 0.101). ORR was 10% in the fulvestrant group and 14% in the anastrozole group. Median DoR from randomisation to progression was 436 days versus 432 days for the fulvestrant and anastrozole groups, respectively. CBR for fulvestrant (36.1%) versus anastrozole (48.2%) was not statistically different between the groups. TTF (110 days versus 147 days for the fulvestrant and anastrozole groups, respectively) was not statistically different between the treatments (HR, 1.307; 95% CI, 0.961, 1.778; P = 0.088). Both treatments were well tolerated, with only two patients treated with fulvestrant and four patients treated with anastrozole withdrawn from study treatment due to adverse events.
These data demonstrate that fulvestrant 250 mg and anastrozole were similarly effective and well tolerated in the treatment of postmenopausal Chinese women with advanced breast cancer whose disease had progressed or recurred on prior endocrine treatment.
Cancer Chemotherapy and Pharmacology 10/2010; 67(1):223-30. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ObjectiveThe aim of this study was to investigate renal insufficiency in patients with chemotherapy.
MethodsPrescribing chemotherapy in a regular hemodialysis patient with renal failure, and monitoring of serum drug concentrations
to determine its safety and effectiveness.
ResultsChemotherapy assessment efficiency: SD (better), hemodialysis did not affect THP treatment, their safety was guaranteed.
ConclusionThe chemotherapy of renal dysfunction is not an absolute contraindication to fully assess the patient’s adverse effects and
tolerability, the reasonable arrangements for hemodialysis and the timing of administration can be safe and effective chemotherapy.
Key wordsbreast cancer-renal dysfunction-chemotherapy
The Chinese-German Journal of Clinical Oncology 01/2010; 9(10):594-596.