bims-cyhorp 2022-07-03 papers

Issue of 2022–07–03
four papers selected by
Piotr Okupski,

Recenti Prog Med. 2022 Jun;113(6): 376-379

Palbociclib plus letrozole induces a complete metabolic response in metastatic breast cancer patient with idiopathic thrombocytopenia.

Vittoria Barberi, Davide Renna, Alessio Annovazzi, Gianluigi Ferretti, Michelangelo Russillo, Francesco Cognetti.

Breast cancer is still the leading cause of cancer-related deaths among women aged 20-59 and metastatic breast cancer remains an incurable disease. The therapeutic paradigm of patients with HR-positive HER2-negative metastatic breast cancer has been expanded by the introduction of the inhibitors of cyclin-dependent kinases 4/6. Three compounds, palbociclib, ribociclib, and abemaciclib, have already been approved by the Food and Drug Administration (FDA) for use together with endocrine therapy; abemaciclib is also approved as a single agent. In the first-line setting, all three agents - together with an aromatase inhibitor (AI) - substantially prolonged progression-free survival. Hematologic toxicities are the most common adverse events associated with CDK4/6i, mainly with palbociclib and ribociclib. Due to the hematologic toxicity, the prescribing information of palbociclib (P) recommends monitoring complete blood counts before starting therapy and at the beginning of each cycle, as well as on day 15 of the first 2 cycles. However, there are no guidelines regarding the management of patients candidate to CDK4/6i who have bone marrow impairment. Neutropenia frequently occurs during the treatment with P, whereas thrombocytopenia represents a rare event. We here report a case of a 60-year-old woman with idiopathic thrombocytopenia treated with P plus letrozole, who presented a metabolic complete response.

DOI: https://doi.org/10.1701/3827.38111

Cancer. 2022 Jun 29.

Venous and arterial thrombosis associated with abemaciclib therapy for metastatic breast cancer.

Nathan W Watson, Seth A Wander, Joseph J Shatzel, Hanny Al-Samkari.

BACKGROUND: The CDK4/6 inhibitor abemaciclib is a mainstay of treatment for hormone receptor-positive breast cancer. However, increased venous thromboembolism (VTE) rates in multiple clinical trials resulted in a black-box warning for this agent. Thrombosis rates in unselected real-world populations receiving abemaciclib remain ill defined.
METHODS: A multicenter observational cohort study was conducted of patients with metastatic breast cancer receiving abemaciclib. The primary end point was thrombosis during treatment or within 30 days of discontinuation. Multivariable logistic models assessed predictors of VTE, and a multivariable Cox proportional hazards model assessed mortality.
RESULTS: A total of 364 patients were included, with a median treatment duration of 5.5 months. Twenty-six patients developed 27 (7.4%) thrombotic events (17 VTE, nine arterial thrombosis, and one with both events). No baseline characteristics were associated with increased VTE risk in multivariable modeling. Patients developing VTE during therapy had a higher risk of death than those who did not (hazard ratio, 2.09; 95% CI, 1.07-4.13). Median survival in patients who developed VTE compared with those who did not was 9.6 vs 25.8 months, respectively. The rate of VTE and any thrombosis during abemaciclib therapy was 9.1 and 13.7 events per 100 person-years, respectively, which is notably higher than rates observed in clinical trials.
CONCLUSIONS: In a real-world setting, abemaciclib was associated with a VTE rate approximately two-fold greater than the already elevated rates reported in the MONARCH trials. Patients developing thrombosis on abemaciclib had a significantly higher risk of death. Given these findings, studies evaluating the role of thromboprophylaxis in patients receiving abemaciclib are needed.

Keywords: CDK 4/6 inhibitors; abemaciclib; arterial thrombosis; breast cancer; venous thromboembolism

DOI: https://doi.org/10.1002/cncr.34367

Phytother Res. 2022 Jul 02.

Molecular dynamics simulation and in vitro evaluation of herb-drug interactions involving dietary polyphenols and CDK inhibitors in breast cancer chemotherapy.

Prajakta H Patil, Sumit Birangal, G Gautham Shenoy, Mahadev Rao, Sandeep Kadari, Amit Wankhede, Himanshu Rastogi, Tarun Sharma, Jakir Pinjari, Jagadish Puralae Channabasavaiah.

Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC50 values of curcumin and quercetin were 16.10 and 0.05 μM, respectively, for CYP3A4-mediated 1'-hydroxylation of midazolam. The dietary polyphenols prolonged the in vitro half-life of palbociclib and ribociclib by 6.4-fold and decreased their intrinsic microsomal clearance by approximately 4.6 times. Our findings indicate that curcumin and quercetin effectively cause herb-drug interactions and should be cautiously used to avoid therapeutic failure.

Keywords: CDK inhibitors; CYP3A4 inhibition; dietary polyphenols; herb-drug interactions; molecular docking

DOI: https://doi.org/10.1002/ptr.7547

Front Oncol. 2022 ;12 820696

Cyclin-Dependent Kinase Inhibitors Function as Potential Immune Regulators via Inducing Pyroptosis in Triple Negative Breast Cancer.

Tao Xu, Zhen Wang, Jiahao Liu, Ge Wang, Dongchen Zhou, Yaying Du, Xingrui Li, Yu Xia, Qinglei Gao.

Background: Immunotherapy is the most promising treatment in triple-negative breast cancer (TNBC), and its efficiency is largely dependent on the intra-tumoral immune cells infiltrations. Thus, novel ways to assist immunotherapy by increasing immune cell infiltrations were highly desirable.
Methods: To find key immune-related genes and discover novel immune-evoking molecules, gene expression profiles of TNBC were downloaded from Gene Expression Omnibus (GEO). Single-sample gene set enrichment analysis (ssGSEA) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identified hub genes. The CMap database was used subsequently to predicate potential drugs that can modulate the overall hub gene expression network. In vitro experiments were conducted to assess the anti-tumor activity and the pyroptosis phenotypes induced by GW-8510.
Results: Gene expression profiles of 198 TNBC patients were downloaded from GEO dataset GSE76124, and ssGSEA was used to divide them into Immune Cell Proficiency (ICP) group and Immune Cell Deficiency (ICD) group. Hub differential expressed gene modules between two groups were identified by WGCNA and then annotated by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A cyclin-dependent kinase (CDK) 2 inhibitor, GW-8510 was then identified by the CMap database and further investigated. Treatment with GW-8510 resulted in potent inhibition of TNBC cell lines. More importantly, in vitro and in vivo studies confirmed that GW-8510 and other CDK inhibitors (Dinaciclib, and Palbociclib) can induce pyroptosis by activating caspase-3 and GSDME, which might be the mechanism for their immune regulation potentials.
Conclusion: GW-8510, as well as other CDK inhibitors, might serve as potential immune regulators and pyroptosis promotors in TNBC.

Keywords: CDK inhibitor; GW-8510; connectivity map database; pyroptosis; triple negative breast cancer

DOI: https://doi.org/10.3389/fonc.2022.820696