A Quantitative Systems Pharmacology Framework for Optimal Doxorubicin Granulocyte Colony-Stimulating Factor Regimens in Triple-Negative Breast Cancer

Pharmacology ◽  
2021 ◽  
pp. 1-9
Author(s):  
Rosalba Vivian Paredes Bonilla ◽  
Fahima Nekka ◽  
Morgan Craig
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Tumour Growth ◽  
Triple Negative ◽  
Effective Control ◽  
Systems Pharmacology ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Quantitative Systems Pharmacology ◽  
Stimulating Factor

<b><i>Introduction:</i></b> To mitigate the risk of neutropenia during chemotherapy treatment of triple-negative breast cancer, prophylactic and supportive therapy with granulocyte colony-stimulating factor (G-CSF) is administered concomitant to chemotherapy. The proper timing of combined chemotherapy and G-CSF is crucial for treatment outcomes. <b><i>Methods:</i></b> Leveraging our established mathematical model of neutrophil production by G-CSF, we developed quantitative systems pharmacology (QSP) framework to investigate how modulating chemotherapy dose frequency and intensity can maximize antitumour effects. To establish schedules that best control tumour size while minimizing neutropenia, we combined Gompertzian tumour growth with pharmacokinetic/pharmacodynamic models of doxorubicin and G-CSF, and our QSP model of neutrophil production. <b><i>Results:</i></b> We optimized a range of chemotherapeutic cycle lengths and dose sizes to establish regimens that simultaneously reduced tumour burden while minimizing neutropenia. Our results suggest that cytotoxic chemotherapy with doxorubicin 45 mg/m<sup>2</sup> every 14 days provides effective control of tumour growth while mitigating neutropenic risks. <b><i>Conclusion:</i></b> This work suggests future avenues for optimal regimens of chemotherapy with prophylactic G-CSF support. Importantly, the algorithmic approach that we developed can aid in balancing the anticancer and the neutropenic effects of both drugs, and therefore contributes to rational considerations in clinical decision-making in triple-negative breast cancer.

Case report of sacituzumab govitecan-hziy-induced neutropenia in a patient with metastatic triple-negative breast cancer and a uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizer genotype

2021 ◽  
pp. 107815522110574
Author(s):  
Grace Baek ◽  
Lindsey Jung ◽  
Arianne Duong ◽  
Julie Gralow
Keyword(s):  
Breast Cancer ◽  
Case Report ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Uridine Diphosphate ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Uridine Diphosphate Glucuronosyltransferase ◽  
Increased Risk ◽  
Stimulating Factor

Introduction Sacituzumab govitecan-hziy, approved in 2020 for treatment of metastatic triple-negative breast cancer, provides a new option for a population with a historically poor prognosis with standard chemotherapy. Uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers are at increased risk for profound neutropenia. This case discusses clinical implications of the uridine diphosphate glucuronosyltransferase family 1 member A1*28/*28 genotype in patients receiving sacituzumab govitecan-hziy. Case report A 38-year-old otherwise healthy pre-menopausal female of South Asian descent was diagnosed with non-metastatic, hormone receptor-positive, and human epidermal growth factor receptor 2-negative breast cancer. This was treated with neoadjuvant chemotherapy and multiple lines of subsequent therapies. Upon finding bone metastasis, an additional six lines of therapy ensued. In total, 3.5 years post-diagnosis, sacituzumab govitecan-hziy was started for disease transformation to triple-negative status. Management and outcome Sacituzumab govitecan-hziy was initiated at the Food and Drug Administration-approved 10 mg/kg/dose on days 1 and 8 of a 21-day cycle. Grade 4 neutropenia occurred after one dose. Pharmacogenomics testing identified the patient as a uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressor. Sacituzumab govitecan-hziy was dose-reduced, and granulocyte colony-stimulating factor was administered due to the severity of neutropenia. The patient continued on sacituzumab govitecan-hziy until disease progression. Discussion Sacituzumab govitecan-hziy's propensity to cause neutropenia is multifactorial. Although incidence of all-grade neutropenia from sacituzumab govitecan-hziy is elevated for uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressors, this does not translate to increased risk for febrile neutropenia. Detailed guidance is lacking regarding empiric dose adjustments or prophylactic granulocyte colony-stimulating factor for these patients. 1 Currently, pre-sacituzumab govitecan-hziy pharmacogenomics testing to identify uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers is not recommended, and the cost-effectiveness of this approach is unclear.

scholarly journals 845 A colony stimulating factor 1 receptor-blocking bifunctional protein simultaneously targets tumor-associated macrophages and exhausted T cells for the treatment of triple-negative breast cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A886-A886
Author(s):  
Pandelakis Koni ◽  
Hung-Kai Chen ◽  
Yao-Wen Chang ◽  
Huey-Wen Hsiao ◽  
Chih-Lun Hsiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Fusion Protein ◽  
Tumor Immunity ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Model ◽  
Colony Stimulating Factor ◽  
Stimulating Factor

BackgroundTumor-associated macrophages (TAMs) are a significantly-poor prognostic factor for patients with triple-negative breast cancer (TNBC). The tumor microenvironment of TNBC features highly-infiltrating TAMs that contribute to tumor progression and metastasis. Therefore, TAM-targeted immunotherapies are recognized as a potential approach for treating TNBC. However, depleting TAMs alone by use of monoclonal antibodies against colony-stimulating factor 1 receptor (CSF1R) was insufficient to cause substantial tumor control. Recent studies revealed that interleukin-10 (IL-10) can directly activate terminally-exhausted CD8+ T cells to boost anti-tumor activity. We set forth to investigate whether a combination of anti-CSF1R antibody with a half-life-extended IL-10-Fc fusion protein (IL-10-Fc) may enhance anti-tumor immunity, and whether synergistic effects could be achieved with bifunctional antibody forms.MethodsAntibodies and recombinant proteins were produced in-house. In vitro CSF1R activity was evaluated by Western blot analysis of CSF1-mediated CSF1R phosphorylation and monocyte proliferation assays. In vitro IL10 activity was evaluated by MC/9 cell proliferation and CD8 T cell activation assays. 4T1 mouse breast tumor studies were performed at the National Yang Ming Chiao Tung University (Taiwan). Other tumor model studies employed the services of Crownbio (China). Methods of RNAseq analysis of 4T1 tumor masses included Cibersort, gene set enrichment analysis (GSEA) and immune gene signature score analysis.ResultsCo-treatment with a recombinant human IL-10-Fc protein significantly improved the anti-tumor efficacy of anti-mouse CSF1R antibody in a mouse CT26 colon tumor model. It was then hypothesized that a better synergistic effect could be achieved by a bifunctional anti-mouse CSF1R-IL-10 fusion protein (anti-mCSF1R-IL-10), to allow targeted-delivery of IL-10 to CSF1R-positive-TAM-rich tumor microenvironments. Indeed, anti-mCSF1R-IL-10 showed greatly increased anti-tumor efficacy in both EMT-6 and 4T1 mouse models of breast cancer. Consistent with the in vivo efficacy, gene expression profiling revealed an enhanced intratumoral interferon-gamma signature by treatment with anti-mCSF1R-IL-10 as compared to either anti-mCSF1R or IL-10-Fc alone. An anti-human CSF1R-IL-10 (hCSF1R-IL-10) was also constructed using a newly-produced anti-human CSF1R antibody and tested in cell-based functional assays, demonstrating that anti-hCSF1R-IL-10 could both inhibit CSF1-dependent cell growth and activate tumor-infiltrating T cells isolated from tumor biopsies of triple-negative breast cancer patients. Further validation of this bifunctional form will be presented.ConclusionsOur findings provide a potential strategy for simultaneously targeting TAM and exhausted T cells to potentiate anti-tumor immunity for treatment of triple-negative breast cancer.Ethics ApprovalThe studies were approved by the institutional animal care and use committee of National Yang Ming Chiao Tung University; approval numbers 1081025 and 109060.

scholarly journals Quantitative systems pharmacology model predictions for efficacy of atezolizumab and nab-paclitaxel in triple-negative breast cancer

2021 ◽  
Vol 9 (2) ◽  
pp. e002100
Author(s):  
Hanwen Wang ◽  
Huilin Ma ◽  
Richard J Sové ◽  
Leisha A Emens ◽  
Aleksander S Popel
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Predictive Biomarkers ◽  
Virtual Patient ◽  
Systems Pharmacology ◽  
Quantitative Systems Pharmacology ◽  
Patient Cohort ◽  
Model Predictions

BackgroundImmune checkpoint blockade therapy has clearly shown clinical activity in patients with triple-negative breast cancer, but less than half of the patients benefit from the treatments. While a number of ongoing clinical trials are investigating different combinations of checkpoint inhibitors and chemotherapeutic agents, predictive biomarkers that identify patients most likely to benefit remains one of the major challenges. Here we present a modular quantitative systems pharmacology (QSP) platform for immuno-oncology that incorporates detailed mechanisms of immune–cancer cell interactions to make efficacy predictions and identify predictive biomarkers for treatments using atezolizumab and nab-paclitaxel.MethodsA QSP model was developed based on published data of triple-negative breast cancer. With the model, we generated a virtual patient cohort to conduct in silico virtual clinical trials and make retrospective analyses of the pivotal IMpassion130 trial that led to the accelerated approval of atezolizumab and nab-paclitaxel for patients with programmed death-ligand 1 (PD-L1) positive triple-negative breast cancer. Available data from clinical trials were used for model calibration and validation.ResultsWith the calibrated virtual patient cohort based on clinical data from the placebo comparator arm of the IMpassion130 trial, we made efficacy predictions and identified potential predictive biomarkers for the experimental arm of the trial using the proposed QSP model. The model predictions are consistent with clinically reported efficacy endpoints and correlated immune biomarkers. We further performed a series of virtual clinical trials to compare different doses and schedules of the two drugs for simulated therapeutic optimization.ConclusionsThis study provides a QSP platform, which can be used to generate virtual patient cohorts and conduct virtual clinical trials. Our findings demonstrate its potential for making efficacy predictions for immunotherapies and chemotherapies, identifying predictive biomarkers, and guiding future clinical trial designs.

scholarly journals Granulocyte Colony Stimulating Factor Expression in Breast Cancer and Its Association with Carbonic Anhydrase IX and Immune Checkpoints

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1022
Author(s):  
Shawn C. Chafe ◽  
Nazia Riaz ◽  
Samantha Burugu ◽  
Dongxia Gao ◽  
Samuel C. Y. Leung ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Carbonic Anhydrase ◽  
Immune Checkpoint ◽  
Positive Association ◽  
Carcinoma Cells ◽  
Carbonic Anhydrase Ix ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Significant Positive Association ◽  
Stimulating Factor

Purpose: Granulocyte colony-stimulating factor (G-CSF) and hypoxia modulate the tumour immune microenvironment. In model systems, hypoxia-induced carbonic anhydrase IX (CAIX) has been associated with G-CSF and immune responses, including M2 polarization of macrophages. We investigated whether these associations exist in human breast cancer specimens, their relation to breast cancer subtypes, and clinical outcome. Methods: Using validated protocols and prespecified scoring methodology, G-CSF expression on carcinoma cells and CD163 expression on tumour-associated macrophages were assayed by immunohistochemistry and applied to a tissue microarray series of 2960 primary excision specimens linked to clinicopathologic, biomarker, and outcome data. Results: G-CSFhigh expression showed a significant positive association with ER negativity, HER2 positivity, presence of CD163+ M2 macrophages, and CAIX expression. In univariate analysis, G-CSFhigh phenotype was associated with improved survival in non-luminal cases, although the CAIX+ subset had a significantly adverse prognosis. A significant positive association was observed between immune checkpoint biomarkers on tumour-infiltrating lymphocytes and both G-CSF- and CAIX-expressing carcinoma cells. Immune checkpoint biomarkers correlated significantly with favourable prognosis in G-CSFhigh/non-luminal cases independent of standard clinicopathological features. Conclusions: The prognostic associations linking G-CSF to immune biomarkers and CAIX strongly support their immunomodulatory roles in the tumour microenvironment.

Sign in / Sign up

Export Citation Format

Share Document