Qunling Zhang

Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer

Apatinib is an oral, highly potent tyrosine‐kinase inhibitor targeting VEGFR2. Phase I study showed the recommended dose of 750 mg/day with substantial antitumor activity. This phase II study aims to evaluate the optimum dose level for the efficacy and safety of apatinib monotherapy in heavily pretreated patients with metastatic triple negative breast cancer (mTNBC) in China. Phase IIa was first performed among 25 patients previously treated with anthracycline and/or taxane. All patients received apatinib 750 mg/day p.o. in a 4‐week cycle. Subsequently, a phase IIb study of 59 patients was activated, with the endpoint progression‐free survival (PFS). The dosage of drug for the Phase IIb was determined according to safety, tolerability and efficacy from the phase IIa study. As a result of toxicity associated with the 750 mg dose in phase IIa, the recommended initial dose of apatinib in the phase IIb was 500 mg/day. In phase IIb, grade 3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), neutropenia (3.4%) and anemia (1.7%). The most frequent grade 3/4 nonhematologic toxicities were hand–foot syndrome, proteinuria, hypertension, and increased ALT. In the 56 evaluable patients, overall response rate and clinical benefit rate (CBR) were 10.7 and 25.0%, respectively. Median PFS and overall survival were 3.3 (95% CI 1.7–5.0) and 10.6 (95% CI 5.6–15.7) months, respectively. Our results indicate that apatinib dose of 500 mg rather than 750 mg is the recommended starting dose for the heavily pretreated mTNBC patients with measurable rate of partial response and PFS.

Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-κB pathway

BackgroundThere are a lot of unmet needs in patients with triple-negative breast cancer (TNBC). Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, has been used for decades to treat hypertriglyceridaemia and mixed dyslipidaemia. Recent studies show that it might have anti-tumor effects, however, the mechanism remains unclear. Here, we assessed the ability of fenofibrate to induce apoptosis of TNBC in vitro and in vivo and explored involved mechanisms.MethodsMTT method was used to evaluate the anti-proliferation effect of fenofibrate, and invert microscope to observe the apoptotic morphological changes. The percentage of apoptotic cells and distribution ratios of cell cycle were determined by flow cytometric analysis. The related protein levels were measured by Western blot method. The changes of genes and pathways were detected by gene expression profiling. The tumor growth in vivo was assessed by MDA-MB-231 xenograft mouse model. Terminal deoxytransferase-catalyzed DNA nick-end labeling (TUNEL) assay was employed to estimate the percentage of apoptotic cells in vivo. In order to evaluate the safety of fenofibrate, blood sampled from rat eyes was detected.ResultsWe found that fenofibrate had anti-proliferation effects on breast cancer cell lines, of which the first five most sensitive ones were all TNBC cell lines. Its induction of apoptosis was independent on PPAR-α status with the highest apoptosis percentage of 41.8 ± 8.8%, and it occurred in a time- and dose-dependent manner accompanied by up-regulation of Bad, down-regulation of Bcl-xl, Survivin and activation of caspase-3. Interestingly, activation of NF-κB pathway played an important role in the induction of apoptosis by fenofibtate and the effect could be almost totally blocked by a NF-κB specific inhibitor, pyrrolidine dithiocarbamate (PDTC). In addition, fenofibrate led to cell cycle arrest at G0/G1 phase accompanied by down-regulation of Cyclin D1, Cdk4 and up-regulation of p21, p27/Kip1. In vivo, fenofibrate slowed down tumor growth and induced apoptosis with a good safety profile in the MDA-MB-231 xengograft mouse model.ConclusionsIt is concluded that fenofibrate induces apoptosis of TNBC via activation of NF-κB pathway in a PPAR-α independent way, and may serve as a novel therapeutic drug for TNBC therapy.

Prognostic and predictive value of clinical and biochemical factors in breast cancer patients with bone metastases receiving "metronomic" zoledronic acid

BackgroundTo assess prognostic and predictive effects of clinical and biochemical factors in our published randomized study of a weekly low dose (metronomic arm) versus a conventional dosage of zoledronic acid (conventional arm) in breast cancer patients with bone metastases.MethodsTreatment outcome of 60 patients with bone metastases were used to assess impacts of following potential prognostic factors, estrogen receptor status, lymph node status, 2 year-disease free interval (DFI), numbers of chemotherapy regimens administered, interventions, and serum levels of VEGF, N-telopeptide of type I collagen (NTx), CEA, and CA 15-3.ResultsIn univariate analyses, patients pretreated with 2 or fewer chemotherapy regimens, ER-positive tumors, 3 or fewer lymph nodes, DFI of more than 2 years, serum VEGF of less than 500 pg/mL after 3 months of intervention, serum CEA and CA 15-3 of less than ULN, and baseline serum NTx of less than 18 nM BCE had significantly longer progression free survival (PFS). The multivariate analysis showed that ER positivity (hazard ratio [HR], 0.295; 95% confidence interval [CI], 0.141-0.618; P = 0.001), serum VEGF of less than 500 pg/mL after 3 months of intervention (HR, 2.220; 95% CI, 1.136-4.338; P = 0.020), baseline serum NTx of less than 18 nM BCE (HR, 2.842; 95% CI, 1.458-5.539; P = 0.001), and 2 or fewer chemotherapy regimens received (HR, 7.803; 95% CI, 2.884-21.112; P = 0.000) were associated with a better PFS. When evaluating the predictive effect of the biochemical factors, an interaction between NTx and zoledronic acid intervention was shown (P = 0.005). The HR of weekly low dose versus a conventional dosage of zoledronic acid was estimated to be 2.309 (99% CI, 1.067-5.012) in patients with baseline serum NTx of more than 18 nM BCE, indicating a superiority of weekly low dose of zoledronic acid.ConclusionsER, serum VEGF level after intervention, and numbers of chemotherapy regimens administered are prognostic but not predictive factors in breast cancer patients with bone metastases. Patients with baseline serum NTx of more than 18 nM BCE might benefit more from weekly low-dose of zoledronic acid.Trial registrationClinicalTrials.gov unique identifier: ClinicalTrials.gov: NCT00524849

Cisplatin improves antitumor activity of weekly nab-paclitaxel in patients with metastatic breast cancer

Although nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved to be given every 3 weeks, weekly use of this drug is becoming a new standard of care in patients with metastatic breast cancer (MBC). This prospective Phase II study was conducted to improve the efficacy of weekly nab-paclitaxel with cisplatin in MBC patients. Seventy-three women with recurrent or MBC were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m2 on day 1, day 8, and day 15, followed by cisplatin 75 mg/m2 on day 1, repeated every 28 days with a maximum of 6 cycles. The primary objective was investigator-assessed overall response rate (ORR). A high ORR of 67.1% was obtained, with rates of 80.6% for the first-line patients and 80% for patients not pretreated with taxanes. Among those who had objective responses, a large percentage of patients (83.7%) showed quickly remarkable tumor shrinkage during the first two cycles. The median progression-free and overall survival times were 9.8 and 26.9 months, respectively. For the patients receiving first-, second-, and third-line therapy or beyond, median progression-free survival was 11.7, 7.7, and 7.6 months, respectively (P=0.005). Molecular subtype was not significantly associated with ORR or disease progression. Grade 4 neutropenia occurred in 46 patients (63.0%), with febrile neutropenia found in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%). Efficacy of weekly nab-paclitaxel can be improved by adding cisplatin. The doublet is highly effective, with quick response, manageable toxicity, and possible equivalence across molecular subtypes in MBC patients.

Recombinant human endostatin in combination with CHOP regimen for peripheral T cell lymphoma.

Peripheral T cell lymphoma (PTCL) has a poor prognosis. Overexpression of vascular endothelial growth factor (VEGF) might contribute to the poor prognosis of PTCL and could be the target of novel therapy. The efficacy and safety of recombinant human endostatin (Endostar) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (ECHOP) have been explored in 15 PTCL patients. The objective response rate was 80%, with 53.3% patients having achieved complete response (CR) rate. The CR rate was 100% (3/3) in angioimmunoblastic T cell lymphoma (AITL) patients compared to only 36.4% (4/11) in PTCL not otherwise specified (PTCL-NOS) patients. With a median follow-up of 69 months, the 5-year progression-free survival and overall survival (OS) were 53% and 60%, respectively. The 5-year OS was 100% in AITL but was only 45% in PTCL-NOS. Seven out of 11 patients showed overexpression of VEGFR2 in their tumor vessels and had a better efficacy than those with low expression of VEGFR2. Grade 3 or 4 neutropenia is the most common toxicity observed. ECHOP was safe and might display potential benefit in AITL patients.

Cardiotoxicity as indicated by LVEF and troponin T sensitivity following two anthracycline-based regimens in lymphoma: Results from a randomized prospective clinical trial

Anthracycline-induced cardiotoxicity influences treatment selection and may negatively affect clinical outcomes in lymphoma patients. While epirubicin induced cardiotoxicity less often than the same dose of doxorubicin in breast cancer, higher doses of epirubicin are required in lymphoma regimens for equivalent efficacy. Whether a higher dosage of epirubicin also induces cardiotoxicity less often than doxorubicin in lymphoma remains unknown. We therefore administered 6-8 cycles of cyclophosphamide, vincristine and prednisone (CEpOP) +/− rituximab (R) with either epirubicin (CEpOP) or doxorubicin (CHOP) to patients (N=398) with untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3 (FLG3). Left ventricular ejection fraction (LVEF) and high-sensitivity serum cardiac troponin T (HsTnT) were assessed at baseline and after 4 cycles of treatment. Epirubicin (70 mg/m2/dose) was equivalent to doxorubicin (50 mg/m2/dose) in terms of 3-year progression-free survival. The risk of decreased LVEF was similar between the two regimens. CEpOP+/−R induced HsTnT elevation less often than CHOP+/−R. We conclude that CEpOP+/−R is a more acceptable regimen with short-term efficacy similar to CHOP+/−R in lymphoma patients. Longer follow-up is needed to monitor the risk of cardiac dysfunction and determine whether differences in the induction of elevated HsTnT between epirubicin and doxorubicin justify changes in clinical practice.

Role of radiotherapy in patients with limited diffuse large B-cell lymphoma of Waldeyer's ring in remission after R-CHOP immunochemotherapy

The standard treatment of waldeyers ring DLBCL remains controversial. This retrospective study was designed to evaluate the role of consolidation radiotherapy (RT) in patients with stage I/II diffuse large B-cell lymphoma (DLBCL) limited in Waldeyers ring (WR). We included 72 patients, 42 were treated with immunochemotherapy alone (CT group) and 30 were treated with immunochemotherapy followed by radiotherapy (CT + RT group). All patients received at least 3 cycles of R-CHOP regimen and achieved complete remission (CR) after immunochemotherapy. After 53 months median follow-up time, the 5-year progression-free survival (PFS) rates in CT + RT group vs. CT group were 93.3% vs. 92.5% (P = 0.896), the 5-year overall survival (OS) rates were 96.7% vs. 94.4% (P = 0.649). Patients with oropharyngeal primary had relatively better 5-year PFS and OS rates compared to nasopharyngeal primary (PFS: 98.2% vs. 73.3%, p = 0.001; OS: 100% vs. 79.0%, p < 0.001). Moreover, the primary site was the only independent prognostic factor for PFS in the multivariate analysis (p = 0.012, HR 16.858 [95% CI: 1.883-150.933]).

The size and depth of lesions measured by endoscopic ultrasonography are novel prognostic factors of primary gastric diffuse large B-cell lymphoma

Abstract Diffuse large B cell lymphoma is one of the predominant histological subtypes of primary gastric lymphomas. Factors that contribute to precise stratification and guide the treatment of this disease are still not well understood. We analyzed 73 primary gastric diffuse large B cell lymphoma patients retrospectively, and found that patients characterized by late stage, multiple localization, B symptoms, lower serum albumin level and elevated LDH level had a shorter overall survival through Univariate Cox regression analysis. Multivariate Cox regression analysis demonstrated that ALB ≤ 35g/L, staging ≥ IIE and multiple sites localization were independent adverse prognostic factors. Significantly, in 35 patients who received endoscopy at diagnosis, Kaplan–Meier analyses indicated that patients with large (≥3 cm) and deep lesions (≥11 mm) had an inferior OS (p = .01 and .039). These findings implicated that tumor size and depth are two indicators of prognosis under ultrasonography. Further randomized studies with large number of cases are needed.

Response-adapted therapy for limited stage diffuse large B-cell lymphoma based on interim PET-CT: preliminary results of a phase 2 study

Abstract Background Limited stage diffuse large B-cell lymphoma is curable with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) immunochemotherapy. For patients achieving complete response by interim 18F-fluorodeoxyglucose PET-CT, a previous study showed therapy could be safely de-escalated by omitting the subsequent chemotherapy or radiotherapy. We aimed to adapt the therapy on the basis of the response as assessed by the interim PET-CT. Methods We did this phase 2 study in patients with low risk (International Prognostic Index 0–2), limited stage diffuse large B-cell lymphoma. Patients were initially treated with four cycles of R-CHOP. PET-CT scans were done at baseline and after four cycles. Patients with negative PET (Deauville scores 1–2) received two cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, primary extranodal non-Hodgkin lymphoma, and bulky disease). Patients with these risk factors received another two cycles of R-CHOP as routine practice. Patients with partial response received another four cycles of R-CHOP and a repeated PET-CT scan at the end of treatment. Patients with stable and progressive disease were managed by salvage chemotherapy. The primary endpoint was progression-free survival at 3 years. The trial is registered with ClinicalTrials, number NCT0180412 . Findings From December, 2012, to September, 2015, a total of 143 patients were enrolled and we analysed the 129 patients with baseline and interim PET-CT scans for efficacy. By local assessment, 114 PET-CT scans (88%) were reported as negative and 15 (12%) as positive. With a median follow-up time of 28·2 months (range 15·0–47·4), the estimated 3-year progression-free survival was 91%. Patients with negative interim PET-CT scans had a 3-year progression-free survival of 93% compared with 79% for patients with positive results (p=0·062). The estimated 3-year progression-free survival did not differ between patients with nodal and extranodal primaries (92% vs 91%, p=0·978). Interpretation For patients with limited stage diffuse large B-cell lymphoma, the results of interim PET-CT might predict progression-free survival and adapt the subsequent treatment. For complete response patients without risk factors, the extra two cycles of CHOP might be safely omitted without compromising the efficacy, which needs to be confirmed in a randomised study. Funding None.

Abstract P2-09-13: Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-kB pathway

Introduction: There are a lot of unmet needs in patients with triple-negative breast cancer (TNBC). Fenofibrate, a PPAR-α (Peroxisome proliferator-activated receptor alpha) agonist, has been used for decades to treat hypertriglyceridaemia and mixed dyslipidaemia and recent studies showed that it may have anti-tumor effects, however, the mechanism remains unclear. Here, we assessed the ability of fenofibrate to inhibit TNBC cells proliferation and to induce apoptosis in vitro and in vivo and explored possible involved mechanisms. Methods: Utilization of cell count kit-8 method was to evaluate the anti-proliferation effect of fenofibrate. The percentage of apoptotic cells and distribution ratio of cell cycle was determined by flow cytometric analysis. The related protein levels were measured with Western Blotting methods. The inhibition of tumor growth in vivo was assessed using MDA-MB-231 xenograft mouse model. Terminal deoxytransferase-catalyzed DNA nick-end labeling assay was employed to estimate the proportion of apoptotic cells in tumor tissue sections. In order to evaluate the safety of fenofibrate, counts of leukocyte, erythrocyte, hemoglobin, platelet, aspartate transaminase,alanine transaminase and blood urea nitrogen in peripheral blood were detected. Results: Fenofibrate had anti-proliferation effects on the twelve different subtype breast cancer cell lines we studied, of which the first five most sensitive ones were all TNBC cell lines. Its induction of apoptosis of MDA-MB-231 cell lines was independent on PPAR-α status with the highest apoptosis percentage of 48.0% when compared with 4.8% in the control group. It occurred in a both time- and dose-dependent manner accompanied by up-regulation of Bad, down-regulation of Bcl-xl, Survivin and activation of caspase-3 and NF-κB pathway. Interestingly, activation of NF-κB pathway played an important role in the induction of apoptosis by fenofibtate and the apoptosis effect can be almost totally blocked by a NF-κB specific inhibitor, that is pyrrolidine dithiocarbamate(PDTC). In addition, fenofibrate led to cell cycle arrest at G1 phase accompanied by down-regulation of Cyclin D1, Cyclin-dependent kinase4(Cdk4) and up-regulation of p21, p27/Kip1.In vivo, fenofibrate significantly inhibited tumor growth in the MDA-MB-231 xengograft mouse model and induced apoptosis with a good safety profile. Conclusions: Fenofibrate can induce apoptosis in TNBC in vitro and in vivo, and the mechanism is the activation of NF-κB pathway in a PPAR-α independent way, which may serve as a novel therapeutic drug for TNBC therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-13.