Xichun Hu

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.

MiRNA-21 induces epithelial to mesenchymal transition and gemcitabine resistance via the PTEN/AKT pathway in breast cancer

Acquisition of gemcitabine resistance in breast cancer has not been fully clarified. Prior studies suggest that miRNAs are important to chemoresistance in solid tumors and we confirmed that miR-21 is involved in the development of gemcitabine resistance. Epithelial-to-mesenchymal transition (EMT) and AKT pathway activation were noted to be important to this resistance as well. PTEN, a direct target gene of miR-21, was significantly downregulated in gemcitabine-resistant breast cancer cells and restoration of PTEN expression blocked miR-21-induced EMT and gemcitabine resistance. Our data offer novel insight into gemcitabine resistance in breast cancer and suggest that miR-21 may be used to predict optimal breast cancer therapy and may be a potential therapeutic target for reversing gemcitabine resistance.

Circulating tumor cells predict progression-free and overall survival in Chinese patients with metastatic breast cancer, HER2-positive or triple-negative (CBCSG004): a multicenter, double-blind, prospective trial

BACKGROUND The aim of this multicenter, double-blind, prospective study was to evaluate the potential utility of circulating tumor cell (CTC) measurements in predicting responses to anticancer therapies, including response to human epidermal growth factor receptor-2 (HER-2)-targeted agents, progression-free survival (PFS), and overall survival (OS) in Chinese women with metastatic breast cancer (MBC). PATIENTS AND METHODS Three hundred MBC patients planned to complete three CTC blood draws and two imaging studies. RESULTS A total of 294 of the 300 MBC patients enrolled from six leading Chinese cancer centers were assessable. In multivariate Cox regression analyses, the baseline CTC number remained an independent prognostic factor for PFS [hazard ratio (HR) = 1.93; 95% confidence interval (CI) = 1.39-2.69; P < 0.001) and OS (HR = 3.76; 95% CI = 2.35-6.01; P < 0.001). Similar results were observed for CTC counts at the first follow-up visit for both PFS (P = 0.049) and OS (P < 0.001). CONCLUSIONS Enumeration of CTCs in Chinese MBC patients provides substantial prognostic information and is an independent factor associated with PFS and OS. Moreover, we demonstrated the prognostic value in the various disease subtypes, including HER-2-positive disease irrespective of therapy.

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.

Cisplatin and gemcitabine as the first line therapy in metastatic triple negative breast cancer

No standard first‐line treatment exists for patients with metastatic triple‐negative breast cancer (mTNBC). In this single‐arm, phase II study (NCT00601159), we evaluated the efficacy and tolerability of cisplatin and gemcitabine (GP) as the first‐line therapy in mTNBC. Eligible women were those who had measurable disease with no prior chemotherapy for mTNBC. All patients received 21‐day‐cycle of cisplatin 25 mg/m2 on days 1–3 and gemcitabine 1,000 mg/m2 on days 1 and 8. Treatment was continued until disease progression, unacceptable toxicity or up to 8 cycles. BRCA1/2 mutation status and immunohistochemical basal markers were included in the correlative studies. Sixty‐four patients with the median age of 49 years were enrolled. Thirty patients (46.9%) had ≤1 year from diagnosis to recurrence. The median progression free survival (PFS) was 7.2 months (95%CI, 5.6–8.9 months) and overall survival (OS) was 19.1 months (95%CI, 12.4–25.8 months) with median follow‐up 42 months. Patients received treatment for a median of six cycles. The overall response rate was 62.5%. The most common grades 3/4 toxicities were neutropenia (42.2%), thrombocytopenia (29.7%), anemia (18.8%) and nausea/vomiting (15.6%).No specific BRCA1/2 mutation carriers were identified. The efficacy of responses and basal‐like subtype were independent favorable factors for PFS and OS, respectively. We conclude that the combination of GP has significant activity and a favorable safety profile as the first‐line chemotherapy in mTNBC patients, in particular patients with basal‐like subtype. The promising role of this combination as the front‐line treatment for mTNBC continued to be evaluated in our ongoing phase III trial (CBCSG006).

Guidelines on the diagnosis and treatment of breast cancer (2011 edition)

As the most common malignancy among women, breast cancer seriously endangers the physical and mental health of women. So far, the application of multidisciplinary treatment has made breast cancer one of the most treatment-responsive solid tumors.

The effect of remifentanil on cough suppression after endoscopic sinus surgery: a randomized study

Background: Excessive coughing may increase the risk of complications after sinus surgery. We hypothesized that remifentanil would decrease the incidence and severity of coughing after endoscopic sinus surgery with propofol and remifentanil anaesthesia.

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

Randomized phase II non-inferiority study (NO16853) of two different doses of capecitabine in combination with docetaxel for locally advanced/metastatic breast cancer

BACKGROUND This phase II study investigated whether a lower-than-approved dose of capecitabine, plus docetaxel (XT), would improve tolerability versus standard-dose XT without compromising efficacy. PATIENTS AND METHODS Women aged ≥18 years with locally advanced/metastatic breast cancer resistant to anthracycline-based chemotherapy in the (neo)adjuvant, first- or second-line metastatic setting were eligible. Patients were randomly assigned to receive standard-dose XT (capecitabine 1250 mg/m2 twice daily, days 1-14; docetaxel 75 mg/m2, day 1 every 3 weeks) or low-dose XT (capecitabine 825 mg/m2 twice daily, days 1-14; docetaxel as above). The primary objective was to demonstrate non-inferiority of low-dose to standard-dose XT in terms of progression-free survival (PFS). RESULTS 470 patients were randomly allocated in a 1:1 ratio to standard-dose or low-dose XT. Median PFS was 7.9 versus 5.8 months [hazard ratio 1.16, 95% confidence interval (CI) 0.95-1.43] in the standard-dose and low-dose arms, respectively. The upper limit of the 95% CI was above the predefined non-inferiority margin (1.35, P = 0.078). Secondary efficacy end points were consistent with PFS. The frequency and severity of adverse events was similar in both treatment arms. CONCLUSIONS Non-inferiority of low-dose to standard-dose XT in terms of PFS was not demonstrated; this may be due to regional subgroup effects.BACKGROUND This phase II study investigated whether a lower-than-approved dose of capecitabine, plus docetaxel (XT), would improve tolerability versus standard-dose XT without compromising efficacy. PATIENTS AND METHODS Women aged ≥18 years with locally advanced/metastatic breast cancer resistant to anthracycline-based chemotherapy in the (neo)adjuvant, first- or second-line metastatic setting were eligible. Patients were randomly assigned to receive standard-dose XT (capecitabine 1250 mg/m(2) twice daily, days 1-14; docetaxel 75 mg/m(2), day 1 every 3 weeks) or low-dose XT (capecitabine 825 mg/m(2) twice daily, days 1-14; docetaxel as above). The primary objective was to demonstrate non-inferiority of low-dose to standard-dose XT in terms of progression-free survival (PFS). RESULTS 470 patients were randomly allocated in a 1 : 1 ratio to standard-dose or low-dose XT. Median PFS was 7.9 versus 5.8 months [hazard ratio 1.16, 95% confidence interval (CI) 0.95-1.43] in the standard-dose and low-dose arms, respectively. The upper limit of the 95% CI was above the predefined non-inferiority margin (1.35, P = 0.078). Secondary efficacy end points were consistent with PFS. The frequency and severity of adverse events was similar in both treatment arms. CONCLUSIONS Non-inferiority of low-dose to standard-dose XT in terms of PFS was not demonstrated; this may be due to regional subgroup effects.

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.