Phase Ib Studies of Benegrastim in Chinese Women with Breast Cancer Receiving Myelotoxic Chemotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4601-4601
Author(s):  
Junning Cao ◽  
Zhongyu Yuan ◽  
Cheng Huang ◽  
Dongmei Ji ◽  
Rujun Peng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Research Funding ◽  
Chinese Women ◽  
Dose Finding ◽  
Chemotherapy Cycle ◽  
Severe Neutropenia ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
Dose Dependent

Abstract Neutropenia is common in patients receiving myelotoxic chemotherapy. BenegrastimTM(F-627), a recombinant human G-CSF dimer, is an once-per-cycle therapy for prophylactic neutropenia in cancer patients after chemotherapy. Two phase I dose finding studies of benegrastim were conducted in Chinese women with stage I-IV breast cancer receiving myelotoxic chemotherapy. The aims of the studies were to evaluate the safety profile and pharmacokinetics (PK) and pharmacodynamics (PD) properties of benegrastim. In the first study, a total of 18 patients were enrolled to receive 3 sequential dose levels of benegrastim at 80, 240 and 360 µg/kg (n=6). The patients received epirubicin/cyclophosphamide (EC) chemotherapy on day one. Benegrastim was administered to patients on day 3 by SC injection once per chemotherapy cycle for up to 4 cycles. In the second study, 15 patients were sequentially assigned to 240 µg/kg (n=7) and 320 µg/kg (n=8) of benegrastim. These patients received doxorubicin, docetaxel and cyclophosphamide (TAC) on day one, benegrastim was administered on day 2 by SC injection for up to 6 cycles. The PK/PD properties of benegrastim were evaluated in cycle one and cycle three. Benegrastim was well tolerated in both clinical studies. The treatment emergent adverse events related to benegrastim were back pain, arthralgia, musculoskeletal pain, and rash, commonly seen in rhG-CSF therapy. The PK/PD result in patients receiving TAC in the first chemotherapy cycle is shown in Fig 1. Dose-dependent benegrastim exposure and ANC increase were demonstrated in these two clinical trials. In breast cancer patients receiving EC or TAC, benegrastim showed a non-linear pharmacokinetics. Benegrastim shortened the duration of neutropenia post chemotherapy in a dose dependent manner. In conclusion, benegrastim may provide an alternative approach to manage neutropenia, especially, severe neutropenia in patients after chemotherapy. Figure 1. PK/PD of F-627 (benegrastim) in Chinese breast cancer patients receiving TAC in the first chemotherapy cycle. Figure 1. PK/PD of F-627 (benegrastim) in Chinese breast cancer patients receiving TAC in the first chemotherapy cycle. Disclosures Cao: Generon (Shanghai) Corporation Ltd.: Research Funding. Yuan:Generon (Shanghai) Corporation Ltd.: Research Funding. Huang:Generon (Shanghai) Corporation Ltd.: Employment. Ji:Generon (Shanghai) Corporation Ltd.: Research Funding. Peng:Generon (Shanghai) Corporation Ltd.: Research Funding. Yan:Generon (Shanghai) Corporation Ltd.: Employment. Tang:Generon (Shanghai) Corporation Ltd.: Employment.

Secondary Myeloid Neoplasms in Older Women with Breast Cancer after Radiotherapy: A Population-Based Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1676-1676
Author(s):  
Amer M. Zeidan ◽  
Jessica B. Long ◽  
Rong Wang ◽  
James B. Yu ◽  
Jane Hall ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Diagnosis ◽  
Research Funding ◽  
Breast Cancer Diagnosis ◽  
Breast Cancer Patients ◽  
Treatment Delivery ◽  
Post Surgery ◽  
Single Modality

Abstract BACKGROUND: Chemotherapy and combined chemo-radiotherapy are well-documented risk factors for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), collectively referred to in this setting as therapy-related myeloid neoplasms (t-MN). While single-modality radiotherapy post-lumpectomy has been shown to reduce local recurrence among breast cancer patients, data regarding the impact on development of t-MN are limited and inconsistent. METHODS: We conducted a retrospective cohort study of elderly female breast cancer patients (aged 67-94 years at diagnosis) who were diagnosed with in situ or stage 1-3 breast cancer between 1/1/2004 and 12/31/2011 using the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Eligibility criteria included 1) enrollment in Medicare Parts A and B continuously through death or end of study (12/31/2013); 2) underwent surgery for breast cancer within 9 months of diagnosis; and 3) were not diagnosed with other neoplasms prior to breast cancer diagnosis. Delivery of radiation therapy was ascertained using the Healthcare Common Procedural Coding System codes. In order to be considered a recipient of radiotherapy, the patient had to receive radiotherapy within 9 months of diagnosis and had any treatment delivery code for brachytherapy or ≥ 4 treatment delivery codes for external bream radiotherapy. Competing-risk analysis was used to assess the risk of developing t-MN in radiotherapy-treated patients compared to those treated with surgery alone. Patients were censored at the time of receiving chemotherapy or at development of another malignancy (aside of t-MN) during follow-up. Competing-risk analysis was used to assess the risk of developing secondary MN women who received radiation therapy compared to those who did not. These models included adjustment for breast cancer diagnosis age and year, number of comorbidities, anemia, functional status prior to breast cancer diagnosis and breast cancer stage. RESULTS: A total of 63,543 patients were included in the study. Median follow-up for all participants was 48 months. A total of 32,809 patients (51.6%) received radiotherapy post-surgery while 30,734 patients (48.4%) were not treated with radiotherapy post-surgery. Patients who received radiotherapy had significantly better overall survival than those who did not (median overall survival [OS] 107 vs. 89 months, p<0.001). During follow-up, a total of 167 patients were diagnosed with MDS or AML (89 cases among those who received radiotherapy and 78 among those who did not receive radiotherapy). The median time to develop MDS/AML was 24 months. In the unadjusted model, there was no significantly increased risk of subsequent AML/MDS among breast cancer patients who received single-modality radiotherapy compared to those who underwent surgery alone (hazard ratio [HR] = 1.11, 95% confidence interval [CI]: 0.82-1.51, p=0.49). Similarly, no significant difference in subsequent MDS/AML according to receipt of radiotherapy was observed in the adjusted analysis (HR = 1.16, 95% CI: 0.84-1.59, p=0.36). CONCLUSIONS: Older patients with early breast cancer who were treated with single-modality radiotherapy post-surgery did not have a higher risk of subsequent MDS/AML compared to patients who did not receive radiotherapy, and the overall rate of MN was low.While additional studies with a longer duration of follow-up are warranted, these results suggest that the single-modality radiotherapy administered in the contemporary management of early breast cancer is not a risk factor for t-MN in this population. Disclosures Yu: 21st-Century Oncology LLC: Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Gross:Johnson and Johnson: Research Funding; Medtronic: Research Funding; 21st-Century Oncology LLC: Research Funding. Ma:Celgene Corp: Consultancy; Incyte Corp: Consultancy. Davidoff:Celgene: Consultancy, Research Funding.

Efficacy and safety of balugrastim in chemotherapy-induced neutropenia: Integrated analysis of two randomized phase III studies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e17572-e17572
Author(s):  
Oleg Gladkov ◽  
Constantin D. Volovat ◽  
Steven Barash ◽  
Anton Buchner ◽  
Noa Avisar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Medical Condition ◽  
Phase Iii ◽  
Severe Neutropenia ◽  
Integrated Analysis ◽  
Efficacy And Safety ◽  
Breast Cancer Patients ◽  
Myelosuppressive Chemotherapy ◽  
Phase Iii Studies

e17572 Background: Balugrastim is a recombinant fusion protein composed of human serum albumin and human granulocyte colony-stimulating factor, which allows for once-per-chemotherapy cycle administration. We present a combined analysis of two double-blind, randomized Phase III studies comparing efficacy and safety of balugrastim vs pegfilgrastim in breast cancer patients receiving myelosuppressive chemotherapy (CTx). Methods: All patients were treated with doxorubicin 60 mg/m2 followed by docetaxel 75 mg/m2 administered by i.v. infusion on Day 1 of a 21-day cycle for up to 4 cycles. For each cycle, patients received a single s.c. injection of balugrastim approximately 24 hours after administration of CTx. The primary endpoint for both studies was duration of severe neutropenia (DSN) in Cycle 1. Safety of balugrastim was assessed by evaluating the type, frequency, and severity of adverse events (AEs); changes in laboratory parameters and vital signs, and immunogenicity over time. Analyses were performed in the per-protocol population. Results: A total of 469 patients were randomized to receive balugrastim 40 mg (N=235) or pegfilgrastim 6 mg (N=234). Mean DSN in Cycle 1 was 1.1±1.11 days in patients receiving balugrastim (n=236) and 1.0±1.14 days in patients receiving pegfilgrastim (n=234). Non-inferiority was demonstrated by statistical analysis for balugrastim vs pegfilgrastim for reduction in DSN across studies. Patients treated with balugrastim had a significantly shorter time to ANC recovery in Cycle 1 vs pegfilgrastim (2.0 vs 2.3 days; P=0.015). No other significant differences were seen between treatment groups in either study for any other secondary endpoints in Cycles 1–4. The safety profile was similar for both drugs, with the incidence of AEs consistent with the underlying medical condition and administration of myelosuppressive CTx. Conclusions: In both Phase III studies, non-inferiority was clearly demonstrated for balugrastim 40 mg vs pegfilgrastim 6 mg. Balugrastim is a safe and effective alternative to long-acting pegfilgrastim for reducing DSN in breast cancer patients receiving myelosuppressive chemotherapy. Clinical trial information: 2010-019001-42.

A nomogram based on genetic and clinicopathologic features to predict the nonsentinel lymph node metastases in Chinese women breast cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12577-e12577
Author(s):  
Liling Zhu ◽  
Ke Liu ◽  
Fengyun Li ◽  
Wentao Liang ◽  
Wenzhao Shi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Sentinel Lymph Node ◽  
Cancer Patients ◽  
Chinese Women ◽  
Lasso Regression ◽  
Breast Cancer Patients ◽  
Internal Validation ◽  
Genetic Features ◽  
Clinicopathologic Factors

e12577 Background: Sentinel lymph node biopsy (SLNB) is the standard treatment for breast cancer patients with clinically negative axilla. However, axillary lymph node dissection (ALND) is still the standard care for sentinel lymph node (SLN) positive patients. Clinical data reveals 20–60 % of patients without non-sentinel lymph node metastasis (NSLNM) after ALND. Unnecessary ALND increases the risk of lymphedema and detracts from quality of life. In this study, we expect to develop a nomogram based on genetic and clinicopathologic features to predict the risk of NSLN metastasis in SLN-positive Chinese women breast cancer patients. Methods: This retrospective study collected data from 310 women breast cancer patients who underwent SLNB followed by ALND and without any neo-adjuvant therapy in Chinese PLA General Hospital, China, between 2016 and 2017. Genetic features contain 96 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility and prognosis based on the GWAS studies and clinical information. SNP genotyping was identified by the quantitative PCR detection platform. The genetic features were divided into two clusters by the gene functions and signaling pathways. The polygenic risk score (PRS) was used to evaluate the combined effect of each SNP cluster. Least absolute shrinkage and selection operator (LASSO) regression model was adopted for feature selection and nomogram construction. Internal validation was performed and the area under ROC curve (AUC) was assessed. Results: 81 patients of 310 patients (26%) had a positive axillary NSLNM. The LASSO regression analysis identified the clinicopathologic characteristics including molecular subtype, cN-stage, number of positive SLNs and number of negative SLNs as significant predictors of NSLNM. Furthermore, two SNP clusters were also showed statistically significant in the prediction of NSLNM. In internal validation, the average AUC of the nomogram was 0.795 and the model was well calibrated. Conclusions: We present a new nomogram by combining genetic and clinicopathologic factors to achieve higher sensitivity and specificity comparing with traditional clinicopathologic factors to predict NSLNM in Chinese women breast cancer. It is recommended that more validations are required in prospective studies among different patient populations.

scholarly journals A Precision Medicine Approach to Metabolic Therapy for Breast Cancer in Mice

2021 ◽  
Author(s):  
Ngozi D Akingbesote ◽  
Aaron Norman ◽  
Wanling Zhu ◽  
Alexandra A Halberstam ◽  
Xinyi Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Precision Medicine ◽  
Cancer Patients ◽  
Insulin Signaling ◽  
Breast Tumors ◽  
Sglt2 Inhibitors ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
Metabolic Therapy ◽  
Response To Chemotherapy

Increasing evidence highlights the possibility for approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic therapies and have recently been highlighted as a novel therapeutic approach to breast cancer. To our knowledge, however, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach to combining metabolic therapy with standard of care therapy for this devastating disease. In this study, we combine the SGLT2 inhibitor dapagliflozin with paclitaxel chemotherapy in both lean and obese mice. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival in an insulin-dependent manner in some but not all breast tumors. Our data find a genetic signature for breast tumors most likely to respond to dapagliflozin in combination with paclitaxel. Tumors driven by mutations upstream of canonical insulin signaling pathways are likely to respond to such treatment, whereas tumors driven by mutations downstream of canonical insulin signaling are not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that breast cancer patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach. A clinical trial is currently in preparation, with an application recently submitted for Yale Human Investigations Committee approval, to test this hypothesis in breast cancer patients.

scholarly journals Global and Regional Longitudinal Strain Reduction in Breast Cancer Patients After First Chemotherapy Cycle With Fluorouracil, Adriamycin, and Cyclophosphamide Regimen

2021 ◽  
Vol 12 (4) ◽  
pp. 238-243
Author(s):  
Astri Astuti ◽  
Erwinanto Erwinanto ◽  
Muhammad Rizki Akbar ◽  
Erwan Martanto ◽  
Dharmayanti Fransisca Badudu
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Longitudinal Strain ◽  
Chemotherapy Cycle ◽  
Breast Cancer Patients

Somatic and germline mutation profiles of Chinese breast cancer patients younger than 35.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 554-554
Author(s):  
Ning Liao ◽  
Guo-Chun Zhang ◽  
Xiaoqing Chen ◽  
Weikai Xiao ◽  
Jianguo Lai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Patients ◽  
Germline Mutation ◽  
Early Onset ◽  
Chinese Women ◽  
Germline Mutations ◽  
Breast Cancer Patients ◽  
Early Onset Breast Cancer ◽  
Younger Women

554 Background: Limited studies have investigated the molecular underpinnings driving breast cancer development in Chinese younger women. Based from our previous data, more Chinese women are diagnosed with early-onset breast cancer than in the West. In our study, we aim to investigate the comprehensive mutational profile of Chinese women 35 years old and younger (≤35y) diagnosed with breast cancer. Methods: Targeted sequencing was performed on surgically-removed tumor tissues and blood samples collected from 589 women diagnosed with stage I-III breast cancer of various molecular subtypes at the Guangdong Provincial People’s Hospital (GPDH) using a gene panel interrogating 520 cancer-related genes. We compared the data of 53 women aged ≤35y from our cohort to the data from 33 breast cancer patients aged ≤35y included in The Cancer Genome Atlas (TCGA) dataset. Results: Among the women aged ≤35y with early-stage breast cancer from both cohorts, our cohort had more number of hormone receptor-positive (HR+) patients (GPDH, 72% vs. TCGA, 61%, P< 0.001). Analysis revealed an overall mutation detection rate of 98% in our cohort, with mutations affecting genes involved in the PI3K pathway (47%) and cell cycle pathway (23%). TP53 and PIK3CA were the most commonly mutated genes, with mutation rates of 51% and 25% from our cohort. No statistical difference in mutation profile was found between GPDH and TCGA cohorts. Moreover, germline mutations considered as pathogenic and likely pathogenic (P/LP) in breast cancer susceptibility genes including BRCA1 (n = 4), BRCA2 (n = 2), PALB2 (n = 1), PMS2 (n = 1), PTEN (n = 1), and ATM (n = 1) were detected from 18.9% (10/53) of the patients from our cohort. Women aged ≤35y had significantly more germline BRCA1 mutations than patients > 35y from our cohort (7.5%, 4/53 vs. 2.1%, 11/536 P= 0.049). Conclusions: Our study has identified the involvement of PI3K and cell cycle as the two key pathways in the early development of breast tumors in younger women. In addition, our results also support the role of P/LP germline mutations in breast oncogenesis in Chinese patients with early-onset breast cancer, indicating the need to include a more comprehensive germline mutation screening in our population.

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