Landscape of DNA damage response gene alterations in breast cancer: A comprehensive investigation.

BACKGROUND: DNA damage response (DDR) gene alterations are prevalent in breast cancer (BC) and important for treatment decisions. Intensive studies on DDR alterations in BC are still needed. METHODS: The authors included 438 patients with metastatic breast cancer from their next-generation sequencing database and 1091 patients with early-stage breast cancer from The Cancer Genome Atlas (TCGA) database in the analysis to characterize molecular alterations in the DDR pathway. RESULTS: Germline DDR mutations were more prevalent in younger patients and those with HER2-negative cancers. Tumors with germline DDR mutations more commonly had somatic DDR mutations, especially those with germline Fanconi anemia (FA) pathway mutations. Notably, 66.67% (four of six) of patients with germline PALB2 mutations had tumors that harbored somatic PALB2 mutations. No differences in prognosis were observed in patients with germline or tumor somatic DDR mutations compared to patients and tumors that were wild-type. Compared to early BC, the frequency of somatic DDR mutations in metastatic cancers was significantly higher (24.89% vs. 16.02%, p < .001). Higher tumor mutation burdens were observed in cancers with somatic DDR mutations, but not in cancers with germline DDR mutations. Furthermore, tumors with somatic DDR mutations showed an abundance of anticancer immunological phenotypes. Somatic FA and mismatch repair pathway mutations were associated with increased expression of immune checkpoint molecules. Although most DDR genes were significantly positively associated with expression of proliferation-related genes, PARP3 expression was negatively correlated with MKI67 expression. Lower PARP3 expression was associated with a worse prognosis in TCGA database by multivariate Cox analysis. CONCLUSIONS: Patients with germline FA mutations more frequently have tumors with somatic DDR mutations. Somatic DDR mutations lead to anticancer immunological phenotypes in BC. No differences in prognosis according to germline or somatic DDR mutations were found.

Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer.

BACKGROUND: Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates prompt the identification of the HER2-low subtype. However, the biological significance of HER2-low expression in breast cancer is unclear. METHODS: Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database and genomic analysis of early breast cancer patients from TCGA was also analyzed. FINDINGS: First, the clinicopathological characteristics of HER2-low patients were profoundly influenced by HR status and no difference of prognosis was observed between HER2-low and HER2-zero patients when paired by HR status, but notably HER2-low patients showed similar metastatic patterns to HER2-positive patients in the HR-positive (HR+ ) subgroup, with more brain and initial lung metastases and more cases of de novo stage IV breast cancer than HER2-zero patients. Second, among patients with primary HER2-low or HER2-zero tumors, the discordance of HER2 status between primary and metastatic tumors was significant, with 48.4% of patients with HER2-zero primary tumors exhibiting HER2-low phenotype in metastatic tumors in the HR+ subgroup. Third, within HR+ and HR-negative subtypes, HER2-low and HER2-zero tumors showed no substantial differences in mutation alterations and copy number variations. Forth, germline BRCA2 mutations were observed only in HER2-low patients in our NGS database, especially in HR+ HER2-low tumors. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, which provided novel insights into heterogeneity in HER2-low breast cancer. CONCLUSIONS: After correcting for HR expression, only marginal differences in clinical and molecular phenotypes were determined between HER2-low and HER2-zero breast cancer. Therefore, HER2-low breast cancer is insufficient to be defined as a distinct molecular entity, but rather a heterogenous disease.

Efficacy and safety of mitoxantrone hydrochloride liposome injection in Chinese patients with advanced breast cancer: a randomized, open-label, active-controlled, single-center, phase II clinical trial.

PURPOSE: This trial aimed to evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection (Lipo-MIT) in advanced breast cancer (ABC). METHODS: In this randomized, open-label, active-controlled, single-center, phase II clinical trial, eligible patients were randomized in a ratio of 1:1 to receive Lipo-MIT or mitoxantrone hydrochloride injection (MIT) intravenously. The primary endpoint was objective response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and safety outcomes. RESULTS: Sixty patients were randomized to receive Lipo-MIT or MIT. The ORR was 13.3% (95% confidence interval (CI): 3.8-30.7%) for Lipo-MIT and 6.7% (95% CI: 0.8-22.1%) for MIT. The DCR was 50% (95% CI: 31.3-68.7%) with Lipo-MIT vs. 30% (95% CI: 14.7-49.4%) with MIT. The median PFS was 1.92 months (95% CI: 1.75-3.61) for Lipo-MIT and 1.85 months (95% CI: 1.75-2.02) for MIT. The most common toxicity was myelosuppression. Lipo-MIT resulted in an incidence of 86.7% of leukopenia and 80.0% of neutropenia, which was marginally superior to MIT (96.7% and 96.7%, respectively). Lipo-MIT showed a lower incidence of cardiovascular events (13.3% vs. 20.0%) and increased cardiac troponin T (3.3% vs. 36.7%); but higher incidence of anemia (76.7% vs. 46.7%), skin hyperpigmentation (66.7% vs. 3.3%), and fever (23.3% vs. 10.0%) than MIT. Conclusions The clinical benefit parameters of Lipo-MIT and MIT were comparable. Lipo-MIT provided a different toxicity profile, which might be associated with the altered distribution of the drug. Additional study is needed to elucidate the potential benefit of Lipo-MIT in ABC. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (No. NCT02596373) on Nov 4, 2015.

Everolimus-Related Pneumonitis in Patients with Metastatic Breast Cancer: Incidence, Radiographic Patterns, and Relevance to Clinical Outcome.

BACKGROUND: This study investigated the incidence, radiographic patterns, and relevance to clinical outcome of everolimus-related pneumonitis (ERP) in patients with metastatic breast cancer (MBC). MATERIALS AND METHODS: Data of patients with MBC treated with everolimus who had baseline and at least one follow-up chest computed tomography (CT) were obtained from a medical electronic database system. An independent review of the CT scans of these patients was conducted by two radiologists (NCT03730428). Log-rank and Cox proportional hazard regression analyses were used for time-to-event analyses. RESULTS: ERP was radiographically detected in 45 of 86 patients (52.3%). In more than 80% of these patients, ERP occurred during the first 4 months of everolimus treatment. Only 14 of the 45 patients with ERP were symptomatic (31.1%). Symptoms included cough, fever, and shortness of breath. Bilateral and lower distribution of the pneumonitis was most common. In most of the cases, ground-glass opacities and reticular opacities were noticed. Elderly patients were more likely to develop ERP. Patients with ERP had significantly longer progression-free survival (PFS; 6.8 vs. 4.1 months, p = .024) and overall survival (OS; 42.8 vs. 21.3 months, p = .016). ERP was a predictor of OS improvement confirmed by multivariate Cox analysis (hazard ratio, 0.49; 95% confidence interval, 0.25-0.97; p = .040). CONCLUSIONS: ERP was noted in half of the patients with MBC treated with everolimus. Our data suggested that ERP was associated with improved prognosis and may be used as a biomarker for the efficacy of everolimus in MBC. Close monitoring, prompt diagnosis, and proper treatment for ERP are essential to maintain the quality of life of patients and achieve maximum treatment benefits. IMPLICATIONS FOR PRACTICE: Everolimus-related pneumonitis (ERP) is one of the most worrying drug adverse events, especially in Asian patients. However, little has been known about the clinical and radiographic details of ERP in patients with metastatic breast cancers (MBCs) treated with everolimus. The present study investigated the clinical characteristics, radiographic patterns, and its correlation with treatment outcome in patients with MBC. ERP was identified in more than half of patients with MBC during everolimus therapy and was associated with improved outcome. Close monitoring and prompt diagnosis and appropriate treatment for ERP are critical for the preservation of patients' quality of life and achievement of maximal treatment benefits.

Phase II trail of nab-paclitaxel in metastatic breast cancer patients with visceral metastases.

BACKGROUND: Visceral metastases account for 48-67% of metastatic breast cancer (MBC) patients and presage a worse overall survival. Previous study suggested potential effect of nab-paclitaxel on patients with visceral metastases subgroups. This phase II trial was conducted to explore the efficacy and safety of nab-paclitaxel in such a high-risk group of patients. METHODS: In this prospective, single-center, open-label, phase II study, MBC patients with visceral metastases (N = 80) received nab-paclitaxel (Abraxane, 125 mg/m2, D1, D8, D15 every 28 days). RESULTS: The median PFS was 5.1 months (95% CI: 4.2-6.0 months), with an ORR of 33.8% (95% CI 21.3-43.8%) and CBR of 66.2% (95% CI 56.3-75.0%). In univariate analysis, patients with premenopausal status had a trend of better treatment outcome. Multivariate analysis demonstrated non brain metastasis (adjusted HR 0.31, 95% CI 0.12-0.83, P = 0.019) and first line treatment (adjusted HR 0.37, 95% CI 0.17-0.81, P = 0.013) as independent predictors of longer PFS. The overall safety was acceptable with most common treatment-related, grade ≥ 3 toxicities of neutropenia (16.3%) and sensory neuropathy (3.7%). CONCLUSIONS: This phase II trial documented satisfactory efficacy and safety of nab-paclitaxel in MBC patients with visceral metastases, providing evidence for relative clinical practice. Patients in first line therapy had better treatment outcome. For patients with premenopausal status or brain metastasis, further alternatives (for example, combined chemotherapy or targeting therapy) might be required. This study also demonstrated the efficacy and safety of 125 mg/m2 nab-paclitaxel among Asian patients. TRIAL REGISTRATION: This research is registered under clinicaltrials.gov (NCT02687490, February 22, 2016).

Cisplatin given at three divided doses for three consecutive days in metastatic breast cancer: an alternative schedule for one full dose with comparable efficacy but less CINV and hypomagnesaemia.

PURPOSE: Cisplatin, an effective medication for metastatic breast cancer (MBC), is recommended to be applied at the dose of 75 mg/m2 on day 1 every 3 weeks. However, the 75 mg/m2 schedule is often associated with a variety of side effects (such as vomiting and kidney toxicity), and time-consuming hydration treatment is usually needed. Divided dose (25 mg/m2 on day 1-3) without hydration is an alternative. This study aimed to compare the efficacy and toxicity profiles between these two dosage regimens. METHODS: Patients with MBC treated with cisplatin-based regimens in Fudan University Shanghai Cancer Center between December 2008 and June 2019 were retrospectively analyzed. Objective response rate (ORR), progression-free survival (PFS), and toxicity profiles were analyzed. RESULTS: 227 patients receiving a 1-day schedule and 256 patients receiving a 3-day schedule were included. Median PFS was 6.68 (5.66-7.70) months for patients in the 1-day schedule group and 6.70 (5.89-7.52) months for patients in the 3-day schedule group. There was no statistically significant difference in PFS between the two treatment groups (hazard ratio, 0.942; 95% CI 0.759 to 1.170; P = 0.589). The ORRs were comparable between the two groups. ORRs were 44.9% in 1-day schedule group and 44.5% in 3-day schedule group, respectively (P = 0.929). Compared with patients in the 3-day schedule group, patients in the 1-day schedule group experienced higher rates of chemotherapy-induced nausea and vomiting (CINV) (139 [61.2%] vs. 132 [51.6%], P = 0.033). The risk of hypomagnesaemia was also significantly higher (43.2% vs. 28.3%, P = 0.016) among patients receiving 1-day schedule (without magnesium supplementation). No other differences in adverse events were observed between the two groups. CONCLUSIONS: Cisplatin given at three divided doses with no hydration in MBC is a less toxic (less CINV and hypomagnesaemia) schedule with comparable efficacy. Thus, it may be a good alternative for one full-dose (75 mg/m2) schedule.

Mirtazapine, a dopamine receptor inhibitor, as a secondary prophylactic for delayed nausea and vomiting following highly emetogenic chemotherapy: an open label, randomized, multicenter phase III trial.

Background We examined the efficacy of mirtazapine in preventing delayed nausea and vomiting following highly emetogenic chemotherapy (HEC). Patients and methods Patients who had experienced delayed emesis and would be subsequently scheduled for at least three more cycles of the same chemotherapy were randomly assigned to either a mirtazapine (15 mg daily on days 2-4) or a control group. In addition, both groups received a standard triplet regimen comprising aprepitant, a 5-HT3 receptor antagonist, and dexamethasone (7.5 mg on days 2-4). The chemotherapy regimens were either an epirubicin plus cyclophosphamide regimen or cisplatin-containing regimens. The primary end point was a complete response (no emesis and no rescue treatment) to the delayed phase (25-120 h post-chemotherapy) during Cycle 1. The impact on quality of life (QOL) was assessed using the Functional Living Index-Emesis (FLIE) questionnaire. Results Of 95 enrolled patients, 46 were assigned to the mirtazapine group and 49 to the control group. The complete response rate in the delayed phase during Cycle 1 was significantly higher with mirtazapine than in the control group (78.3% versus 49.0%, P = 0.003). The main adverse effects of mirtazapine were mild to moderate somnolence and weight gain. Mean total FLIE scores were similar between the two arms. Conclusions This is the first randomized prospective study to show that adding mirtazapine has a substantial and statistically significant benefit with good tolerance in patients with breast cancer who have experienced delayed emesis following the same prior HEC. (Trial registration: ClinicalTrials.gov NCT02336750).

Clinical Outcomes of 130 Patients with Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Treated with Palbociclib plus Endocrine Therapy and Subsequent Therapy: A Real-World Single-Center Retrospective Study in China.

BACKGROUND This retrospective single-center study conducted in China aimed to investigate the clinical outcomes of patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) treated with palbociclib plus endocrine therapy (ET) and subsequent therapy. MATERIAL AND METHODS Eligible patients were women with HR+ and HER2- MBC who initiated palbociclib plus ET between September 2016 and August 2019 at Fudan University Shanghai Cancer Center. Clinical characteristics and efficacy data were retrospectively recorded from the electronic medical record system. RESULTS In total, 130 patients were included in the study, of whom 87.0% of patients started palbociclib on 125 mg/day, 8.5% of patients had dose reduction, and 2.3% of patients discontinued the treatment because of toxicity. Overall, the disease control rate was 77.4% and clinical benefit rate was 63.4%. After a median follow-up period of 10.6 months, the median progression-free survival was 9.2 months. There was limited efficacy in patients who received palbociclib as no less than a fourth line of ET, except for patients who added palbociclib to the ET, which they had acquired resistance to. After disease progression on palbociclib, further treatment with chemotherapy and ET had similar efficacy (P=0.571). CONCLUSIONS The findings from this real-world single-center study in China showed that treatment with palbociclib plus ET exhibited favorable efficacy and good tolerance in patients with HR+ and HER2- MBC, even in patients who were initially resistant to endocrine therapy, and there was no difference in outcomes between subsequent treatment with chemotherapy and ET.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

Incidence, pattern and prognosis of brain metastases in patients with metastatic triple negative breast cancer.

BACKGROUND: To identify the incidence, recurrence pattern and prognosis of brain metastases (BM) among women with metastatic triple negative breast cancer (mTNBC) treated consecutively at a single institution during a 7-year period. METHODS: Patients with histologically confirmed mTNBC were retrospectively identified. The incidence of BM as first site of recurrence and the cumulative BM incidence were computed. We used the Cox proportional hazards model to identify the univariate and multivariate factors associated with survival. RESULTS: Four hundred thirty three patients were included with a median overall survival (OS) of 21.6 months after median follow-up for 48.1 months. BM was found in 29% (127/433) of the patients and about a quarter (32/127) of BM was first recurrence. The cumulative incidence of BM at 1 and 2 years was 17 and 25%, respectively. The median time from the diagnosis of extracranial metastases to BM was 10 months. Median OS following a diagnosis of BM was 7.3 months. The longer median OS from time of first recurrent BM was noted compared with those of subsequent recurrent (17.3 vs 6.3 months, p = 0.008). However, patients with first recurrent BM were associated with shorter OS compared with those without BM (17.3 vs 22.1 months, p = 0.006). The independent factors that increased BM death risk were > 3 brain lesions, no BM-directed treatment, subsequent recurrent BM, symptomatic BM and uncontrolled extracranial metastasis. CONCLUSIONS: Patients with mTNBC have a high incidence of early BM with subsequent poor survival. The findings lend support to consideration of screening imaging of the brain for mTNBC patients.

Caveolin-1 expression predicts efficacy of weekly nab-paclitaxel plus gemcitabine for metastatic breast cancer in the phase II clinical trial.

BACKGROUND: Nanoparticle albumin-bound (nab)-paclitaxel has better efficacy, safety profiles, and no need to use prophylactic steroids compared with solvent-based paclitaxel. We performed a single arm, phase II study to evaluate the efficacy and safety of weekly nab-paclitaxel and gemcitabine combination in patients with metastatic breast cancer (MBC) and explored role of tumor/stromal Caveolin-1 (Cav-1) as a predictive biomarker for the efficacy. METHODS: Nab-paclitaxel (125 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1, 8, and 15 in a 4-week cycle. The primary end point was objective response rate (ORR). Secondary end points were progression free survival (PFS), overall survival (OS) and safety profile. Exploratory study included immunohistochemical detection of Cav-1. RESULTS: Among 85 patients enrolled in the study, ORR was 52.4%. After a median follow-up of 17.2 months, median PFS was 7.9 months (95%CI, 6.6-9.2) and median OS was 25.8 months (95% CI, 20.4-31.1). The most common toxicities were neutropenia (75.0% for all grades; 45.2% for grade 3 or worse) and the most common non-hematologic toxicity was peripheral neuropathy (50.0% for all grades, 7.14% for grade 3 or worse). Higher tumor Cav-1 level and lower stromal Cav-1 level were significantly associated with longer PFS of nab-paclitaxel and gemcitabine. CONCLUSIONS: The regimen had substantial antitumor activity and was well tolerated in MBC patients. Tumor/stromal Cav-1 level may be a good predictor for the efficacy of nab-paclitaxel and gemcitabine. TRIAL REGISTRATION: NCT01550848 . Registered 12 March 2012.

Apatinib for metastatic breast cancer in non-clinical trial setting: Satisfying efficacy regardless of previous anti-angiogenic treatment.

Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2. This study aimed to evaluate the efficacy and safety of apatinib in metastatic breast cancer (MBC) under non-clinical trial setting, and to study the impact of previous antiangiogenic treatment to the efficacy of apatinib. 52 MBC patients treated with apatinib under non-clinical trial setting in Fudan University Shanghai Cancer Center between January 1st 2015 and October 1st 2016 were included. All patients were included in time-to-treatment failure (TTF) analysis, while 45 patients were enrolled for progression-free survival (PFS) and overall survival (OS) analysis because 7 of the patients with treatment discontinuation due to intolerable toxicities had too short time for efficacy assessment. Impact of previous exposure to antiangiogenic treatment and other factors to patients' survival were analyzed by Log-rank analysis and Cox multivariate analysis. The median PFS, median OS, and median TTF were 4.90 (95% confidence interval [CI] 3.44 - 6.36), 10.3 (unable to calculate 95% CI), and 3.93 (95% CI 1.96 - 5.90) months, respectively. Previous treatment of bevacizumab did not affect the efficacy of apatinib. Previous exposure to anthracycline, age of 60 years or older and palmar-plantar erythrodysesthesia syndrome were independent predictors for prolonged PFS. Discontinuation of treatment was more common in age group of 60 years or older than that in younger group, although the difference was not significant. Although toxicities were generally managable, a previously unrecorded grade 3~4 adverse event of dyspnea has been observed. This study confirmed the encouraging efficacy and manageable safety of apatinib on pretreated MBC patients in non-clinical trial setting. For the first time to our knowledge, this study found that previous treatment of bevacizumab did not affect the efficacy of apatinib, and reported an undocumented severe adverse effect of dyspnea.

Overall survival of cancer patients with serum lactate dehydrogenase greater than 1000 IU/L.

High level of serum lactate dehydrogenase (LDH) is a well-known poor prognostic factor in patients with malignancies. However, there was no data on overall survival (OS) in cancer patients with serum LDH level > 1000 IU/L, and the prognostic value of the changes in LDH over time for OS had not been reported. Clinical data of 311 cancer patients with metastatic disease with serum LDH >1000 IU/L (four times upper limit of normal) admitted consecutively to a single center were reviewed in this retrospective study. LDH level ranged from 1002 to 8235 U/L with a mean of 1689 U/L. The median OS was 1.7 months (95 % CI: 1.4-2.0). About half of patients (n = 163, 52 %) died within 2 months with the median OS of 0.5 months (95 % CI: 0.3-0.7). Only 173 patients were indicated for salvage treatment. Fifty-one patients' serum LDH level decreased to normal at 2 months following chemotherapy; OS was significantly longer in these patients (22.6 months, 95 % CI: 10.9-34.3, p < 0.001) compared to those with persistently abnormal serum LDH at 2 months (4.0 months, 95 % CI: 3.4-4.6). The independent factors that increased the death risk were ECOG performance status 3-4 (HR: 2.05, 95 % CI: 1.42-2.97, p < 0.001), supportive care only (HR: 2.91, 95 % CI: 2.06-4.10, p < 0.001), and persistently abnormal serum LDH at 2 months (HR: 2.72, 95 % CI: 1.67-4.42, p < 0.001). In conclusion, serum LDH level > 1000 IU/L predicted a terminal stage in metastatic cancer patients. OS was significantly prolonged in patients indicated for effective palliative treatment and LDH level decreased to normal at 2 months.

Abraxane® versus Taxol® for patients with advanced breast cancer: A prospective time and motion analysis from a Chinese health care perspective.

BACKGROUND: Abraxane® and Taxol® are both effective drugs for the treatment of advanced stage breast cancer. However, each agent possesses unique drug delivery characteristics with the former not requiring premedication and having a considerably shorter recommended infusion time (i.e. 30 min vs. 2-4 h). To measure the overall efficiency and cost-saving potential associated with Abraxane® relative to Taxol®, a time and motion study was undertaken in breast cancer patients treated in China. METHODS: Baseline patient data collection included age, disease stage, number and sites of metastatic disease, and performance status. Time and resource use data were then collected from breast patients being treated with Abraxane® (n = 12) or Taxol® (n = 15) in one of three cancer clinics located in Jiangsu, Shanghai, and Beijing. Resource use and time impact on clinical staff were quantified using unit cost estimates. This included costs for drug preparation, administration, materials and supplies, premedication, patient chair time, labor costs, and all acute adverse drug reactions. Outcomes were presented as a mean total time and cost for delivering a dose of Abraxane® or Taxol® and were compared using parametric and non-parametric statistical tests where appropriate. All costs were reported in US dollars (US$1 = 6.1 RMB, as of January 2014). RESULTS: Patients were comparable with respect to mean age, number of metastatic sites, and performance status. Approximately 9 of 12 (75%) patients received Abraxane® as on a weekly schedule (vs. every 3 weeks) compared to 6 of 15 (40%) with Taxol®. There were 5 (33.3%) acute adverse drug reactions with Taxol®, 3 of which required a physician visit and the initiation of supportive interventions. In contrast, there was only one minor event with Abraxane® (8.3%), which was easily managed with a temporary stoppage of the infusion. From the time and motion study, the mean total time for Abraxane® and Taxol® delivery (preparation, administration, premedication, total chair time, and adverse effects management) was 84 and 282 min respectively (p < 0.001), with the associated costs being US$59 and US$254 respectively per dose (p < 0.001). CONCLUSION: To our knowledge, this is first such study in breast cancer patients to be undertaken in China. Abraxane® was associated with fewer acute adverse drug reactions and significant reductions in health care resources, physician/nurse time and overall drug delivery costs compared to Taxol®.

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/m(2) on days 1-3 and gemcitabine 1,000 mg/m(2) 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).

Multi-phenotype response and cadmium detection of rice stem under toxic cadmium exposure.

Rice stem is the sole conduit for cadmium translocation from underground to aboveground. The presence of cadmium can trigger responses of rice stem multi-phenotype, affecting metabolism, reducing yield, and altering composition, which is related to crop growth, food safety, and new energy utilization. Exploring the adversity response of plant phenotypes can provide a reliable assessment of growth status. However, the phytotoxicity and mechanism of cadmium stress on rice stem remain unclear. Here, we systematically revealed the response mechanisms of cadmium accumulation, adversity physiology, and morphological characteristic in rice stem under cadmium stress for the first time with concentration gradients of CK, 5, 25, 50, and 100 µM, and duration gradients of Day 5, Day 10, Day 15, and Day 20. The results indicated that cadmium stress led to a significant increase in cadmium accumulation, accompanied by the adversity response in stem phenotypes. Specifically, cadmium can cause fluctuations in soluble protein and disturbance of malondialdehyde (MDA), which reflects lipid peroxidation induced by cadmium accumulation. Lipid peroxidation inhibited rice growth by causing (1) a reduction in stem length, diameter, and weight, (2) suppression of air cavity, vascular bundle, parenchyma, and epidermal hair, and (3) disruption of cell structure. Furthermore, rapid detection of cadmium was realized based on the combination of laser-induced breakdown spectroscopy (LIBS) and machine learning, which took less than 3 min. The established qualitative model realized the precise discrimination of cadmium stress degrees with a prediction accuracy exceeding 92 %, and the quantitative model achieved the outstanding prediction effect of cadmium, with Rp of 0.9944. This work systematically revealed the phytotoxicity of cadmium on rice stem multi-phenotype from a novel perspective of lipid peroxidation and realized the rapid detection of cadmium in rice stem, which provided the technical tool and theoretical foundation for accurate prevention and efficient control of heavy metal risks in crops.

In situ synthesis of porous metal-organic frameworks NH2-UiO-66 on tea stem biochar and application in odours adsorption.

Multiple odour nuisance in livestock farming is a notorious problem that has a significant impact on the living environment of surrounding communities. Adsorbents based on metal-organic framework (MOF) materials show great promise for controlling odour pollution, as they offer a high specific surface area, a controllable structure and an abundance of active sites. However, the MOF formation process is prone to problems such as pore clogging or collapse and reduced porosity, which limits its further application. In this study, a series of odour adsorbents were prepared by in situ growth of NH2-UiO-66 on tea stem biochar (TSBC) using a hydrothermal method and named UiO (Zr)-TSBCx. The physical and chemical properties and composition of UiO (Zr)-TSBCx have been systematically characterized using SEM, TEM, XRD, FT-IR, N2 adsorption-desorption and XPS. The release of odours from the pig farm effluent was monitored using in-situ continuous Proton-Transfer-Reaction Mass Spectrometry (PTR-MS), and the obtained primary compositions were tested for further adsorption. In dynamic adsorption experiments focused on butyric acid, UiO (Zr)-TSBC2 showed a high adsorption capacity of 3.99 × 105 µg/g and exceptional structural stability. UiO (Zr)-TSBC2 showed variable adsorption efficiencies for different odorous gases, with the best performance for the removal of ammonia, toluene and butyric acid. It also demonstrated the ability to rapidly mitigate instantaneous high concentrations of hydrogen sulfide (H2S), methanethiol and toluene resulting from agitation. Additionally, based on the relationship between the adsorption amount and the structural characteristics of the adsorbent as well as the nature of the odours, a possible adsorption mechanism of UiO (Zr)-TSBC2 for a variety of odours released from pig farm effluent was proposed. This work demonstrates a novel approach to promote deodorization applications in livestock and poultry farming environments by the in-situ growth of NH2-UiO-66 on biochar prepared from tea stem.

Phase 1b clinical trial of pucotenlimab (HX008), a novel anti-PD-1 monoclonal antibody, combined with gemcitabine and cisplatin in the first-line treatment of metastatic triple-negative breast cancer.

Background: Pucotenlimab, also called HX008, is a humanized anti-PD-1 antagonist IgG4 mAb. It blocks programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1), and programmed death ligand-2 (PD-L2). In the CBCSG 006 trial, gemcitabine plus cisplatin (GP) has shown impressive antitumor activity as first-line therapy for metastatic triple-negative breast cancer (mTNBC). The phase 1b study was conducted to assess the safety and preliminary antitumor activity of pucotenlimab when combined with GP in patients with mTNBC in the first-line setting. Methods: Eligible patients with mTNBC with ≥6 months of DFI (disease-free interval) who have never received antitumor therapy for metastatic disease were screened. Participants received pucotenlimab at 3 mg/kg (d1, q3w) plus gemcitabine at 1,250 mg/m2 (d1, 8, q3w) and cisplatin at 75 mg/m2 (d1, q3w). Eligible patients received up to six cycles of pucotenlimab along with GP chemotherapy, while pucotenlimab could be maintained until disease progression or unacceptable toxicity occurred or withdrawal of informed consent. This study was registered in China under registration number CTR20191353. Results: Between July 2019 and March 2020, 31 patients were enrolled in this study. The median age was 50 (range 28-68) years. Among 31 patients who were evaluated, 25 (80.6%) experienced objective response and the other six (19.4%) experienced stable disease (SD). As of 4 August, the median progression-free survival (PFS) was 9.0 months (95% CI, 6.2-9.2). The most common grade 3 or 4 treatment-related adverse events included neutropenia (74.1%), anemia (35.5%), thrombocytopenia (32.3%), hypocalcemia (9.7%), hypokalemia (9.7%), and alanine aminotransferase increased (6.5%). There were no treatment-related deaths. Conclusion: Pucotenlimab plus GP demonstrated promising activity and a manageable safety profile in patients with mTNBC in the first-line setting.

Promotional effects of calcination temperature and H2O on the catalytic activity of Al-substituted MnAlO catalysts for low-temperature acetone oxidation.

In order to enhance the role of Al in the materials, Al-substituted MnAlO catalysts were synthesized via the hydrothermal-redox method at different calcination temperatures for acetone oxidation. There were Al-substituted α-MnO2 and amorphous aluminum oxide existed with homogeneous dispersion of elements in the catalysts. The surface property, reaction rate, CO2 yield and water resistance of MnAlO catalysts were greatly affected by calcination temperatures. MnAlO-450 catalyst exhibited the best catalytic performance (acetone conversion of 90% at 165 °C) with CO2 yield higher than 99.7%, which was mainly related to the weaker Mn-O bond strength, lower temperature reducibility and abundant Lewis acid sites. The acetone conversion of MnAlO-450 increased by as much as 16% in the presence of 1 vol% H2O compared to that in the absence of H2O at T50 (the temperature for 50% conversion of acetone). The acceleration consumption of ethanol as the main by-product by H2O improved the catalytic performance. This work would shed light on the Al substitution based catalysts for OVOC oxidation with highly efficient and water resistance.

Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study.

Purpose: The LORDSHIPS study aimed to explore the safety and efficacy of a novel fully oral triplet combination of dalpiciclib (a potent cyclin-dependent kinase 4/6 inhibitor), pyrotinib (a HER2 tyrosine kinase inhibitor) and endocrine therapy letrozole in patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) in the front-line setting. Patients and Methods: Postmenopausal women with HER2-positive, HR-positive MBC were recruited in the dose-finding phase Ib trial. A standard 3 + 3 design was used to determine safety, tolerability, and recommended phase II dose (RP2D) for the combination. Results: A total of 15 patients were enrolled to three dose combination cohorts (letrozole/pyrotinib/dalpiciclib, level/I: 2.5/400/125 mg, n=5; level/L1: 2.5/400/100 mg, n=6; level/L2: 2.5/320/125 mg, n=4). Three patients experienced dose-limiting toxicities (level/I, n=2; level/L1, n=1) and level/L2 was identified as RP2D. The most frequent grade 3-4 adverse events were neutropenia (46.7%), leukopenia (40.0%), oral mucositis (26.7%) and diarrhea (20.0%). The confirmed objective response rate (ORR) was 66.7% (95% CI: 38.4% to 88.2%). The confirmed ORR of study treatment as first line (1L) and second line (2L) HER2-targeted therapy was 85.7% (6/7) and 50.0% (4/8), respectively. Median progression-free survival (PFS) was 11.3 months (95% CI: 5.3 months to not reached). PFS in 1L setting was not reached yet, while PFS in 2L setting was 10.9 months (95% CI: 1.8 to 13.7 months). Conclusions: The fully oral combination of dalpiciclib, pyrotinib and letrozole is a promising chemotherapy-sparing treatment option for HER2-positive, HR-positive MBC patients. The planned dose-expansion phase II study is ongoing. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03772353.