Zhong Hua Wang

Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial

BACKGROUNDnPlatinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non-inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.nnnMETHODSnFor this open-label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18-70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0-1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1·2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624.nnnFINDINGSnFrom Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16·3 months (IQR 14·4-26·8) in the cisplatin plus gemcitabine group and 15·9 months (10·7-25·4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0·692 (95% CI 0·523-0·915; pnon-inferiority<0·0001, psuperiority=0·009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7·73 months (95% CI 6·16-9·30) in the cisplatin plus gemcitabine group and 6·47 months (5·76-7·18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [<1%]), vomiting (13 [11%] vs one [<1%]), musculoskeletal pain (none vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1-4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1-4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths.nnnINTERPRETATIONnCisplatin plus gemcitabine could be an alternative or even the preferred first-line chemotherapy strategy for patients with metastatic triple-negative breast cancer.nnnFUNDINGnShanghai Natural Science Foundation.

Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer

BackgroundAcidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxelu2009+u2009cisplatin regimen in patients with metastatic breast cancer (MBC).MethodsPatients enrolled were randomly assigned to three arms: Arm A, docetaxel 75xa0mg/m2 followed by cisplatin 75xa0mg/m2 on d4, repeated every 21xa0days with a maximum of 6xa0cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80xa0mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3xa0days on 4xa0days off) was maintained up to maximum 66xa0weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100xa0mg p.o. bid. The primary endpoint was response rate.ResultsNinety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5xa0%, respectively. Median TTP for arm A (nu2009=u200932), B (nu2009=u200931), C (nu2009=u200931) were 8.7, 9.4, and 9.7xa0months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (67.7 % vs. 46.9 %, p = 0.049) and median TTP (9.7xa0months vs. 8.7xa0months, pu2009=u20090.045). Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8xa0months, respectively (pu2009=u20090.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2xa0months, pu2009=u20090.090). No additional toxicity was observed with PPI.ConclusionsThe results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial.Trial registrationClinicaltrials.gov identifier: NCT01069081.

An improved tensile deformation model for in-situ dendrite/metallic glass matrix composites.

With regard to previous tensile deformation models simulating the tensile behavior of in-situ dendrite-reinforced metallic glass matrix composites (MGMCs) [Qiao et al., Acta Mater. 59 (2011) 4126; Sci. Rep. 3 (2013) 2816], some parameters, such as yielding strength of the dendrites and glass matrix, and the strain-hardening exponent of the dendrites, are estimated based on literatures. Here, Ti48Zr18V12Cu5Be17 MGMCs are investigated in order to improve the tensile deformation model and reveal the tensile deformation mechanisms. The tensile behavior of dendrites is obtained experimentally combining nano-indentation measurements and finite-element-method analysis for the first time, and those of the glass matrix and composites are obtained by tension. Besides, the tensile behavior of the MGMCs is divided into four stages: (1) elastic-elastic, (2) elastic-plastic, (3) plastic-plastic (work-hardening), and (4) plastic-plastic (softening). The respective constitutive relationships at different deformation stages are quantified. The calculated results coincide well with the experimental results. Thus, the improved model can be applied to clarify and predict the tensile behavior of the MGMCs.

A clinical analysis of primary testicular diffuse large B-cell lymphoma in China

Abstract The objective of this study was to analyze the clinical behavior and treatment policy of patients with primary testicular diffuse large B-cell lymphoma by retrospective analysis of 32 patients at our institute. All patients underwent orchidectomy. Anthracycline-based chemotherapy was administered to 27 patients (84·38%), six of whom also received rituximab; prophylactic intrathecal chemotherapy was given to seven patients (21·88%); and eight patients (25%) received prophylactic scrotal radiotherapy. Thirteen patients had relapse, among whom 12 cases were extranodal recurrences. Seven patients had central nervous system involvement, and four patients relapsed in the contralateral testis. The presence of B symptoms, poor Eastern Cooperative Oncology Group performance status, left testicular involvement, central nervous system involvement, and first relapse within 1 year were associated with worse progression-free survival using univariate analysis. Poor Eastern Cooperative Oncology Group performance status, left testicular involvement, and surgery alone were negative prognostic factors for overall survival.

Erratum: Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer (Journal of Experimental and Clinical Cancer Research (2015) 34:85 DOI: 10.1186/s13046-015-0194-x)

Unfortunately, the original version of this article [1] contained an error. The original article was published containing two incorrect sentences. This sentence appeared in the abstract as follows “A significant difference was observed between patients who had taken PPI and who not with ORR (46.9 vs. 67.7 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045).” This should have read as “A significant difference was observed between patients who had taken PPI and who not with ORR (67.7 vs. 46.9 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045).” The following sentence which appeared in the main text was also incorrect. In the original article it read as “As planned, we compared the pool of patients receiving PPI to those treated exclusively with chemotherapy and the statistical analysis showed a significant difference in term of ORR between patients who received PPI, as compared to those treated with chemotherapy alone (46.9 vs. 67.7 %, p = 0.049).” However this should have read as “As planned, we compared the pool of patients receiving PPI to those treated exclusively with chemotherapy and the statistical analysis showed a significant difference in term of ORR between patients who received PPI, as compared to those treated with chemotherapy alone (67.7 vs. 46.9 %, p = 0.049).” Both sentences have now been corrected in the original article. The author apologizes for any inconvenience caused. Author details Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Anti-Tumour Drugs Section, Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Rome, Italy.

Biomarker assessment of the CBCSG006 trial: A randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.

BackgroundnCBCSG006 trial reported the superior efficacy of cisplatin plus gemcitabine (GP) regimen than paclitaxel plus gemcitabine (GT) regimen as first-line treatment of metastatic triple-negative breast cancer (mTNBC). This study focused on the updated survival data and the explorations of potential biomarkers for efficacy.nnnPatients and methodsnGerm-line mutations of homologous recombination (HR) panel, BRCA1/2 included, were evaluated in 55.9% (132/236) patients. PD-L1 expression was evaluated in 48.3% (114/236) patients. A nonparametric sliding-window subpopulation treatment effect pattern plot (STEPP) methodology was used to analyze the absolute survival benefits. All statistical tests were two-sided.nnnResultsnMedian progression-free survival (PFS) was 7.73 [95% confidence interval (CI) 6.46-9.00] months for GP arm and 6.07 (95% CI 5.32-6.83) months for GT arm (Pu2009=u20090.005). No significant difference in overall survival (OS) was observed. There was significant interaction between HR status and treatment for PFS and status of HR deficient significantly correlated with higher objective response rate (ORR) and longer PFS in GP arm than in GT arm (71.9% versus 38.7%, Pu2009=u20090.008; 10.37 versus 4.30u2009months, Pu2009=u20090.011). There was no significant interaction between germ-line BRCA1/2 (gBRCA1/2) status and treatment for PFS. Patients with gBRCA1/2 mutation had numerically higher ORR and prolonged PFS in GP arm than in GT arm (83.3% versus 37.5%, Pu2009=u20090.086; 8.90 versus 3.20u2009months, Pu2009=u20090.459). There was no significant interaction between PD-L1 status and treatment for PFS, and no significant differences in ORR, PFS or OS between two arms regardless of PD-L1 status. In STEPP analysis, patients with lower composite risks had more absolute benefits in PFS than those with higher composite risks.nnnConclusionsnGP regimen has superior efficacy than GT regimen as first-line chemotherapy for mTNBC patients. Germ-line mutations of BRCA1/2 and HR panel are possible biomarkers for better performance of cisplatin-based regimens. A composite risk model was developed to guide patient selection for GP treatment in TNBC patients.nnnTrial registrationnClinicalTrials.gov, NCT01287624.

Impact of hormone receptor status and distant recurrence-free interval on survival benefits from trastuzumab in HER2-positive metastatic breast cancer

We sought to investigate the impact of hormone receptor (HR) status and distant recurrence-free interval (DRFI) on the degree of overall survival (OS) benefit from palliative trastuzumab-containing treatment in HER2-positive metastatic breast cancer (MBC). Here, we retrospectively identified 588 eligible HER2-positive patients with postoperative distant recurrence. DRFI of HR+HER2+ MBC patients (median: 30.7 months, IQR: 18.5–45.9, Pu2009<u20090.001) was significant longer compared with HR−HER2+ patients. Patients were categorized into four subgroups based on HR status and palliative trastuzumab (trast+) received. The most superior outcome was observed in the HR+HER2+trast+ subgroup, with a median OS of 48.3 months. Moreover, DRFIu2009>u200924 months is an independent favourable prognostic factor for both HR−HER2+ patients (Hazard Ratio (HzR)u2009=u20090.55, 95%u2009CI: 0.39–0.76, Pu2009<u20090.001) and HR+HER2+ patients (HzRu2009=u20090.45, 95%u2009CI: 0.32–0.64, Pu2009<u20090.001). Upon further analysis of the interaction between trastuzumab and DRFI, the degree of trastuzumab benefits in HR−HER2+ MBC patients remained basically unchanged regardless of DRFI length. Unlikely, the degree in HR+HER2+ MBC patients decreased gradually along with DRFI extending, indicating that trastuzumab failed to translate into an OS benefit for late recurrent (DRFIu2009>u20095years) HR+HER2+ MBC patients.

360PDGEMCITABINE WITH CISPLATIN OR PACLITAXEL IN METASTATIC TRIPLE-NEGATIVE BREAST CANCER

ABSTRACT Aim: There is still no standard first-line chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). This study compared the first-line use of gemcitabine/cisplatin (GP) with one standard regimen containing gemcitabine/paclitaxel (GT) for patients with mTNBC in terms of efficacy and safety. Methods: A hybrid trial design incorporating a formal test of superiority as well as non-inferiority was applied to compare the GP and GT regimens as first-line treatment on PFS of mTNBC in the Chinese Breast Cancer Study Group (CBCSG) 006 trial (clinicaltrials.gov Identifier: NCT01287624).We randomly assigned 240 mTNBC patients with no previous exposure to palliative chemotherapy to receive GP regimen (1250u2003mg/m2 d1,8/ 75u2003mg/m2 d1) or GT regimen (1250u2003mg/m2 d1,8 /175u2003mg/m2 d1) with expected median PFS improvement of 1.2 months. Results: Between Jan. 2011 and Nov. 2013, 236 patients received at least one dose of assigned chemotherapy with 118 patients in each arm and were all put in the intent-to-treat analysis. As of Mar. 20, 2014, there were 201 PFS events and 97 overall survival events. The GP regimen was different from the GT regimen in terms of objective response rates (67.9% vs. 50.4%, P= 0.008), PFS (median 232 vs.194 days, P= 0.009; HR 0.692, 95%CI 0.523-0.915), and overall survival (median 672 vs.556 days, P= 0.611). Delivered relative dose intensity for the three drugs was all more than 90%, with the number of total delivered cycles per arm at 654 and 648 for GP and GT, respectively. Significant differences in grade 3/4 adverse events between the GP and GT arms were nausea (6.8% and 0.8%), vomiting (11.0% and 0.8%), anemia (33.1% and 5.1%), thrombocytopenia (32.2% and 2.5%). For adverse events of all grades, the GP regimen had significantly more nausea, vomiting, anorexia, constipation, hypomagnesemia, hypokalemia, anemia, and thrombocytopenia while GT regimen had significantly more alopecia and peripheral neuropathy. Conclusions: The GP regimen is better than the GT regimen in terms of objective response and PFS in the first-line treatment of mTNBC patients. The toxicity profiles of the two regimens were different without any unexpected findings. Disclosure: All authors have declared no conflicts of interest.

Abstract P3-13-06: A prospective phase II trial of vinorelbine plus oxaliplatin in second- or third-line metastatic triple-negative breast cancer

Purpose: Patients with metastatic triple-negative breast cancer (mTNBC) typically have a poor prognosis and limited treatment options. Previous study showed biweekly combination of vinorelbine and oxaliplatin (NVBOX) at doses of 30 mg/m2 and 90 mg/m2, respectively, is highly active and well tolerated as first-line treatment for patients with metastatic breast cancer. The purpose of this study (NCT 01528826) was to prospectively evaluate the efficacy and toxicity of NVBOX in second- or third-line mTNBC. Methods: Eligible patients were female with 18–70 years old and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and had mTNBC that had progressed after 1or 2 prior chemotherapy regimens in the metastatic setting. A period of 4 weeks (NVBOX twice) was considered as one treatment cycle and the maximum cycles were 6. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between Dec 2011 and Nov 2012, forty-four patients were recruited [median age 47; 77.3% with viceral metastasis, 100% had been exposed to anthracyclines and/or taxanes; 56.8% cis/carbo-platin pretreated for MBC; 38.6% with time to progression (TTP) of 1-2 previous regimens before recruitment ≤ 3 months]. The overall response rate was 31.6% (1 complete response, 11 partial responses) and 10 achieved stable diseases (7 lasting more than 6 months) in 38 evaluable patients. After a median follow-up of 12.8 months, the median PFS and OS were 4.3 (95% CI, 3.6–5.0) months and 12.6 (95% CI, 8.1–17.0) months, respectively. PFS was significantly shorter in patients with disease free interval (DFI) ≤ 1year (HR = 2.10; 95% CI, 1.05–4.21; P = 0.037) and TTP of 1-2 previous regimens before recruitment ≤ 3 months (HR = 3.39; 95% CI, 1.66–6.89; P Conclusion: We conclude that biweekly NVBOX regimen is effective with a good safety profile in the second- or third-line mTNBC, which warrants further investigation in a phase III study. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-06.