Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review
Abstract
:1. Introduction
2. Results
2.1. Overview
2.2. Review of Identified Studies
2.2.1. Breast Cancer
2.2.2. Gynecological Malignancies
2.3. Clinical Trials
3. Discussion
4. Materials and Methods
4.1. Inclusion Criteria
4.2. Search Strategy
4.3. Data Collection Process, Data Items
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BMX | Bone marrow X-linked kinase |
BTK | Bruton’s tyrosine kinase |
cGVHD | Chronic graft versus host disease |
CLL | Chronic lymphocytic leukemia |
CSC | Cancer stem cell |
CTL | Cytotoxic T lymphocytes |
DC | Dendritic cell |
EGFR | Epidermal growth factor receptor |
ER | Estrogene receptor |
i.v. | Intravenously |
IC50 | Half-maximal inhibitory concentration |
IFN | Interferon |
IL | Interleukin |
ITK | interleukin-2-inducible T-cell kinase |
MDSC | Myeloid-derived suppressor cell |
MeSH | Medical Subject Headings |
MZL | Marginal zone lymphoma |
NCI | National cancer institute |
NSCLC | Non-small-cell lung cancer |
ORR | Overall response rate |
PARP | poly-ADP-ribose-polymerase |
PD-1 | Programmed cell death protein 1 |
PD-L1 | Programmed death-ligand 1 |
PR | Progesterone receptor |
q2w | 2-weekly, every 2 weeks |
RLK | Redundant-resting lymphocyte kinase |
SLL | Small lymphocytic lymphoma |
TEC | Tec protein tyrosine kinase |
TFK | TEC family kinase |
TNBC | Triple-negative breast cancer |
WM | Waldenstrom’s macroglobulinemia |
Appendix A
Number | Search Terms | Search Items Medline |
---|---|---|
1 | ibrutinib (Mesh) | 2026 results |
2 | (‘genital neoplasms, female’ [Mesh]) OR ‘breast neoplasms’ [Mesh] | 498.349 results |
3 | 1 AND 2 | 4 results |
Number | Search Terms | Search Items Embase |
---|---|---|
1 | ibrutinib (Emtree) | 6186 results |
2 | ‘female genital tract tumor’/exp OR ‘breast tumor/exp’ | 866.090 results |
3 | 1 AND 2 | 84 results |
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First Author [Ref.] | Year | Study Type | Model | Histology | Outcome Measures | Main Outcomes |
---|---|---|---|---|---|---|
Grabinski | 2014 | Preclinical: in vitro | Cell culture | Breast cancer (HER2+) | Cell viability, phosphorylation of receptor tyrosine kinases | Significant reduction in the viability of HER2+ cell lines due to ibrutinib. IC50 values at nanomolar concentrations. Synergistic cell viability reduction of ibrutinib and PI3K/mTOR inhibitor dactolisib. Reduced MAPK and AKT phosphorylation. |
Sagiv-Barfi | 2015 | Preclinical: in vitro + in vivo (animal) | Cell culture, xenograft mouse model | Breast cancer (TNBC) | Cell viability, tumor size, no. of metastases; Animal survival | Combination of ibrutinib and anti–PD-L1 inhibits growth of TNBC. The combination therapy generates specific antitumor T cells. |
Chen | 2016 | Preclinical: in vitro + in vivo (animal) | Cell culture, xenograft mouse model | Breast cancer (Her2+) | Cell viability, tumor size, drug exposure | Inhibition of growth and suppression of key signaling pathways in HER2+ breast cancer cell lines. Clinically achievable drug levels suppress HER2+ human breast cancer growth in xenograft mouse models. |
Stiff | 2016 | Preclinical: in vitro + in vivo (animal) | Cell culture, xenograft mouse model | Breast cancer (TNBC) | BTK expression, MDSCs frequency in vivo (by IHC), tumor size | Human and murine MDSCs express BTK. Ibrutinib modulates MDSCs’ cell function and generation and diminishes MDSCs in tumor-bearing mice. Ibrutinib potentially enhances immune-based therapies in solid malignancies. |
Wang X | 2016 | Preclinical: in vitro + in vivo (mice) | Cell culture, xenograft mouse model | Breast cancer (Her2+) | Cell viability, tumor size | Ibrutinib is more potent in inhibiting HER2+ cell than lapatinib. Ibrutinib blocks EGFR, HER2, ErbB3, ErbB4 at its downstream effectors. |
Di | 2019 | Preclinical: bioinformatics | Drug functional similarity network | Breast cancer, ovarian cancer | Prior score, false discovery rate | Ibrutinib ranks 3rd in the prioritized list of candidate breast cancer drugs and is considered to have great potential effects. |
Hong | 2019 | Phase Ib/II | Human | Breast cancer (TNBC, HER2+), pancreatic cancer, NSCLC | Overall response rate, progression-free survival, overall survival | Recommended phase 2 dose: 560 mg ibrutinib daily, durvalumab 10 mg/kg i.v. q2w. ORR: 3% for breast cancer; 2% for pancreatic cancer; 0% for NSCLC. Limited antitumor activity; acceptable safety profile. |
Varikuti | 2020 | Preclinical: in vivo (animal) | Cell culture, xenograft mouse model | Breast cancer (Luminal B) | Cell viability, tumor size, metastasis count, cell maturation analysis, T-cell proliferation and effector function | Ibrutinib inhibits tumor growth in vitro. Treated mice suffer lower tumor burden and less metastases. MDSCs switch phenotype to mature dendritic cells in vitro and less MDSCs and more DCs in vivo. Ibrutinib induces antitumor Th1 and CTL response. |
First Author [Ref.] | Year | Study Type | Model | Histology | Outcome Measures | Main Outcomes |
---|---|---|---|---|---|---|
Zucha | 2015 | Pre-clinical: in vitro | Human tissue samples, cell culture, spheroids | Ovarian cancer | Cell viability, BTK expression | BTK is a histological biomarker and a prognostic predictor of ovarian cancer. Ovarian CSCs express BTK and contribute to cisplatin resistance. BTK inhibition targets CSCs and reduces their survival against cisplatin. Cisplatin–ibrutinib combination has synergistic effects in eliminating ovarian cancer cells. |
Tamura | 2018 | Preclinical: in vitro | Cell culture, patient-derived tumor organoids | Endometrial cancer | Tumor size, inhibitory concentration | Ibrutinib inhibits the growth of carboplatin/paclitaxel-resistant cells at lower concentrations than carboplatin, paclitaxel, methotrexate, and vindesine. Less efficacy in clear-cell adenocarcinoma cell lines. |
Di | 2019 | Preclinical: bioinformatics | Drug functional similarity network | Ovarian cancer, breast cancer | Prior score, false discovery rate | Low rank in ovarian cancer drug candidates. |
Lohse | 2019 | Preclinical: in vitro | Drug sensitivity testing in patient-derived cell lines | Ovarian cancer | Modified drug sensitivity scoring | Weak effect on endometrioid and papillary-serous cell line. No effect on clear-cell cancer lines. |
Ref. | Title | Phase/ Status | Brief Summary | Primary Outcomes |
---|---|---|---|---|
NCT02403271 [15] | A Multi-Center Study of Ibrutinib in Combination with MEDI4736 [Durvalumab] in Subjects With Relapsed or Refractory Solid Tumors | Phase Ib/II; completed 1 (Ref.: Results section, Hong et al., 2019 [41]) | A phase 1b/2, multi-center study to assess the safety and efficacy of ibrutinib in combination with durvalumab (MEDI4736) in participants with relapsed or refractory solid tumors. | Safety and tolerability, dosage, overall response rate per RECIST 1.1 |
NCT03379428 [16] | Trial of Ibrutinib Plus Trastuzumab in HER2-Amplified Metastatic Breast Cancer | Phase I/II; recruiting 1 | Open-label dose-escalation study to evaluate the maximum-tolerated dose and dose-limiting side effects of daily oral ibrutinib in combination with trastuzumab i.v. q3w, in patients with HER2-amplified metastatic breast cancer with progress after prior therapy with T-DM1. | Maximum-tolerated dose, clinical benefit rate |
NCT03525925 [17] | Ibrutinib and Nivolumab in Treating Participants with Metastatic Solid Tumors | Phase I; active, not recruiting 1 | A phase I trial investigating the effect of ibrutinib and nivolumab on circulating levels of MDSCs in patients with metastatic solid tumors and assessing the safety of the study combination. | Circulating levels of myeloid-derived suppressor cells |
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Metzler, J.M.; Burla, L.; Fink, D.; Imesch, P. Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review. Int. J. Mol. Sci. 2020, 21, 4154. https://doi.org/10.3390/ijms21114154
Metzler JM, Burla L, Fink D, Imesch P. Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review. International Journal of Molecular Sciences. 2020; 21(11):4154. https://doi.org/10.3390/ijms21114154
Chicago/Turabian StyleMetzler, Julian Matthias, Laurin Burla, Daniel Fink, and Patrick Imesch. 2020. "Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review" International Journal of Molecular Sciences 21, no. 11: 4154. https://doi.org/10.3390/ijms21114154