bims-cyhorp 2023-02-05 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2023–02–05
eleven papers selected by
Piotr Okupski,

Adjuvant CDK4/6 inhibitors: can they improve clinical outcomes in hormone receptor-positive (HR+) early breast cancer?
The likelihood of being helped or harmed as a patient-centred tool to assess cyclin dependent kinase 4/6 inhibitors clinical impact and safety in metastatic breast cancer: a systematic review and sensitivity-analysis.
Real-world treatment outcomes in HR+ HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors: Results from a reference center in Brazil.
Development and Validation of a Quantitative LC-MS/MS Method for CDK4/6 Inhibitors Palbociclib, Ribociclib, Abemaciclib, and Abemaciclib-M2 in Human Plasma.
Palbociclib plus endocrine therapy in hormone receptor-positive and HER2 negative metastatic breast cancer: a multicenter real-world study in the northwest of China.
Computational analysis of protein-ligand interaction by targeting a cell cycle restrainer.
Inhibition of the MNK1/2-eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer.
Rhabdomyolysis Induced by the Interaction Between Ribociclib and Statins- Case Report and Literature Review.
[A Case of Recurrent Breast Cancer with Multiple Bone Metastasis Effectively Treated by CDK4/6 Inhibitor in Addition to Aromatase Inhibitor].
A novel ribociclib derivative WXJ-103 exerts anti-breast cancer effect through CDK4/6.
[Eight Cases of Breast Cancer That Relapsed More Than Ten Years after Initial Treatment].

Ann Palliat Med. 2023 Jan 16. pii: apm-22-981. [Epub ahead of print]

Adjuvant CDK4/6 inhibitors: can they improve clinical outcomes in hormone receptor-positive (HR+) early breast cancer?

Stephen R D Johnston.



Keywords:  Adjuvant endocrine therapy; abemaciclib; breast cancer; cyclin-dependent kinase 4/6 inhibitor (CDK4/6 inhibitor); palbociclib

DOI:  https://doi.org/10.21037/apm-22-981
EClinicalMedicine. 2023 Feb;56 101824

The likelihood of being helped or harmed as a patient-centred tool to assess cyclin dependent kinase 4/6 inhibitors clinical impact and safety in metastatic breast cancer: a systematic review and sensitivity-analysis.

Luca Mastrantoni, Armando Orlandi, Antonella Palazzo, Giovanna Garufi, Alessandra Fabi, Gennaro Daniele, Diana Giannarelli, Giampaolo Tortora, Emilio Bria.

   Background: In hormone-receptor positive/HER2-negative metastatic breast cancer (mBC) no randomized comparisons are available between CDK4/6 inhibitors. We undertook this systematic review and meta-analysis to assess the reliability of the likelihood of being helped or harmed (LHH).
Methods: PubMed, CENTRAL, Embase and oncological meetings websites were searched to September 13th, 2022. We included phase III randomized controlled trials (RCTs) investigating palbociclib, ribociclib and abemaciclib in addition to endocrine therapy (ET) compared to placebo in hormone-receptor positive/HER2-negative advanced or mBC. Outcomes were progression-free survival (PFS), overall survival (OS), adverse events (AEs), dose reductions and discontinuations. Hazard ratios (HRs) and risk differences were computed with a random effect model to estimate the number needed to treat/harm (NNT/NNH). LHH was computed as (1/NNT)/(1/NNH). PROSPERO registration number: CRD42022362417.
Findings: 2204 records were screened and seven RCTs (4415 patients) were included. A significant PFS benefit was observed in patients treated with a CDK4/6 inhibitor compared to placebo (HR 0.549; 0.508-0.594, I 2 = 0). Palbociclib, ribociclib and abemaciclib had similar NNTs (4.4, 5.0 and 4.4). Palbociclib and ribociclib showed lower LHHs for grade 3-4 neutropenia (0.33 and 0.35) and febrile neutropenia ([FN], 14.27 and 15.52), while abemaciclib the lowest LHH for any grade diarrhea (0.42). Abemaciclib had a lower LHH for grade 3-4 fatigue (9.92) and the highest LHH for all grade 3-4 AEs (0.62), while ribociclib the lowest LHH (1.75) for grade 3-4 hepatotoxicity. Palbociclib had the highest LHH for dose reductions and discontinuations (0.65 and 6.17). Considering OS, an overall benefit was observed (HR 0.788, 0.727-0.856, I 2 = 0%); ribociclib and abemaciclib had lower NNTs (9.7 and 10.0). Ribociclib showed the highest LHH for diarrhea (1.29), fatigue (7.37), dose reductions (0.28) and discontinuations (2.40), while abemaciclib the highest LHHs for neutropenia (0.40), FN (12.53) and hepatotoxicity (2.23).
Interpretation: Palbociclib and ribociclib showed lower LHHs for haematological toxicities and abemaciclib for diarrhea. Palbociclib confirmed to be a manageable drug. The LHH appears to be a reliable synthesis tool for balancing risks and benefits of experimental drugs when head-to-head comparisons are missing.
Funding: None.

Keywords:  CDK4/6 inhibitors; LHH; Metastatic breast cancer; NNH; NNT

DOI:  https://doi.org/10.1016/j.eclinm.2023.101824
Cancer Treat Res Commun. 2023 Jan 19. pii: S2468-2942(23)00004-7. [Epub ahead of print]35 100683

Real-world treatment outcomes in HR+ HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors: Results from a reference center in Brazil.

Marcello Moro Queiroz, Karina Perez Sacardo, Mauricio Fernando Ribeiro, Luiza Lara Gadotti, Rodrigo Saddi, Leandro Jonata de Carvalho Oliveira, Rudinei Diogo Marques Linck, Marcelo Rocha de Souza Cruz, Romualdo Barroso-Sousa, Marina Sahade, Tatiana Strava Correa, Max Senna Mano, Daniele Assad Suzuki, Andrea Kazumi Shimada, Artur Katz.

   BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been recently developed and introduced into clinical practice.
METHODS: We retrospectively analyzed data from patients with confirmed HR+/HER2 metastatic breast cancer treated with hormonal therapy in combination with ribociclib (R), palbociclib (P), or abemaciclib (A).
OUTCOMES: median progression-free survival (mPFS), time to treatment discontinuation (mTTD), and objective response rate (ORR).
RESULTS: Between January 2016 - June 2021, 142 patients were treated with an CDK4/6i (79 P, 42 R, 21 A). The median age was 59 years and 67.6% had recurrent disease. Roughly 35.2%, 36.6%, 28.2% of the patients had 1, 2 or 3+ metastatic sites, respectively, and 55.6% of the patients received CDK4/6i as a first-line treatment. The mPFS was 28m(R) vs. 14m(P) vs. 6m(A) (P = 0.002), with a higher proportion of patients receiving R in the first-line setting. However, no difference was seen when the analysis was restricted to the first-line scenario (P = 0.193). Sixty-four patients required one dose reduction, and 19 patients required two. ORR was 76.2% (R) vs 62% (P) vs 42.9% (A). More patients achieved a complete response with R and P, with no difference in the incidence of partial response and stable disease. Adverse events occurred in 94.4% of the population, with the most common grade 3-4 AE being neutropenia (59.1%).
CONCLUSIONS: Our results confirm the efficacy and tolerability of CDK4/6i in routine clinical practice. This is the first real-world data describing and comparing the efficacy and toxicity of CDK4/6i in the Brazilian population.

Keywords:  Breast cancer; Cyclin-dependent kinase 4/6 inhibitors; Endocrine therapy; Real-world

DOI:  https://doi.org/10.1016/j.ctarc.2023.100683
Ther Drug Monit. 2023 Jan 10.

Development and Validation of a Quantitative LC-MS/MS Method for CDK4/6 Inhibitors Palbociclib, Ribociclib, Abemaciclib, and Abemaciclib-M2 in Human Plasma.

Sarah M Burke, Mustafa Kamal, Andrew K L Goey.

BACKGROUND: The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, palbociclib, ribociclib, and abemaciclib, are standard-of-care agents for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative metastatic breast cancer. In support of therapeutic drug monitoring and clinical pharmacokinetic studies, a liquid chromatography coupled with tandem mass spectrometry assay for the simultaneous quantitation of CDK4/6 inhibitors and the major active metabolite M2 of abemaciclib in human plasma has been developed.
METHODS: Analytes were extracted from 50 μL of human plasma by precipitating proteins with methanol and then collecting the supernatant. Reversed-phase high-performance liquid chromatography was performed for analyte separation using a biphasic gradient at a flow rate of 0.25-0.5 mL/min. The total run time was 9.5 minutes. The analytes were detected using MS/MS with electrospray ionization operating in positive ion mode.
RESULTS: Validation according to the US Food and Drug Administration's guidance showed that the new assay produced accurate (94.7%-107%) and precise (within-run: 1.2%-8.2%; between-run: 0.6%-7.5%) measurements of all analytes over a concentration range of 5-2000 ng/mL. Overall, analyte recoveries were consistent (mean values: 110%-129%). The analytes were also stable in human plasma and the final extract under various storage conditions. Finally, the clinical applicability of the assay was confirmed by quantitation of all analytes in plasma samples obtained from patients treated with CDK4/6 inhibitors. Reproducibility of the measured analyte concentrations in study samples was confirmed successfully by incurred sample reanalysis.
CONCLUSIONS: A sensitive liquid chromatography coupled with tandem mass spectrometry method to measure CDK4/6 inhibitors was developed and validated according to the Food and Drug Administration criteria. Quantitation of all analytes in clinical plasma samples confirmed that the assay is suitable for therapeutic drug monitoring and clinical pharmacokinetic studies of CDK4/6 inhibitors.

DOI: https://doi.org/10.1097/FTD.0000000000001063
BMC Cancer. 2023 Jan 30. 23(1): 103

Palbociclib plus endocrine therapy in hormone receptor-positive and HER2 negative metastatic breast cancer: a multicenter real-world study in the northwest of China.

Jiao Yang, Bing Zhao, Xiaoling Ling, Donghui Li, Jiuda Zhao, Yonggang Lv, Guangxi Wang, Xinlan Liu, Nanlin Li, Jin Yang.

   BACKGROUND: Real-world data of Palbociclib are insufficient in China. This study aimed to investigate the treatment pattern and real-world outcomes in hormone receptor positive and human epidermal growth factor 2 receptor negative (HR+/HER2-) metastatic breast cancer (MBC) patients treated with Palbociclib in the northwest of China.
METHODS: HR+/HER2- MBC patients who received Palbociclib in 8 centers from July 2017 to September 2019 were retrospectively included in this study. Real-world objective response rate (ORR), progression-free survival (PFS) and safety profiles were analyzed. The survival curves were plotted by the Kaplan-Meier method to analyze PFS, which was verified by the log-rank test.
RESULTS: In total, 211 women were eligible for the analysis. A total of 85 patients (40.3%), 78 (37.0%), and 48 (22.7%) received Palbociclib in the first-, second-, third- or later-line setting, respectively. 46 patients achieved partial response and 145 patients experienced stable disease, with an ORR of 21.8% and a disease control rate of 90.5%. Following a median follow-up period of 14.2 months, the median PFS was 12.2 months (95% confidence interval, 10.1-14.3 m), and the median overall survival was not reached. Early Palbociclib initiation, sensitivity or acquired resistance to endocrine therapy, estrogen receptor and progesterone receptor double positivity, less than 3 metastatic sites, without visceral metastasis, bone metastasis only, without prior chemotherapy or endocrine therapy were associated with a prolonged PFS in MBC (All P < 0.05). The most common grade 3 or 4 adverse events (AE) was neutropenia (36.5%), and the most common nonhematologic AE was fatigue (10.9%). No patient experienced AE leading to treatment discontinuation.
CONCLUSION: Palbociclib plus endocrine therapy exhibited favorable effectiveness and manageable toxicities in the real-world setting, supporting their use in Chinese patients with HR+/HER2 - MBC.

Keywords:  CDK4/6 inhibitor; Endocrine therapy; Metastatic breast cancer; Real-world

DOI:  https://doi.org/10.1186/s12885-023-10568-0
Comput Methods Programs Biomed. 2023 Jan 24. pii: S0169-2607(23)00034-2. [Epub ahead of print]231 107367

Computational analysis of protein-ligand interaction by targeting a cell cycle restrainer.

Rahul Singh, Rituraj Purohit.

   BACKGROUND AND OBJECTIVE: The cyclin-dependent kinases 4/6 (CDK4/6) are among the most crucial controllers of the cell cycle, and their abnormal activity may induce uncontrolled cell multiplication, leading to cancers. The FDA currently approved three CDK4/6 inhibitors, however, they are associated with a variety of side effects. Thus it is required to design/develop novel potent and safe CDK4/6 inhibitors.
METHODS: In the present work, we furnished an integrated in-silico approach followed by steered molecular dynamics (SMD) simulations to identify molecules that can be developed into novel CDK4/6 inhibitors.
RESULTS: Out of thirty-two 3-methyleneisoindolin-1-one molecules we selected top three M18, M24, and M32 molecules as potential drug candidates based on their respective interaction energies. According to the robust 250 ns MD simulations and thermodynamic free energy, M24 was the best molecule in comparison to palbociclib. In SMD, M24 required ∼205.587 kJ/mol/nm external pulling force, while palbociclib needed ∼160.97 kJ/mol/nm to dissociate from the binding pocket of the CDK4.
CONCLUSIONS: The high pulling force required for M24 dissociation from the binding site denotes stronger binding with CDK4. Therefore, M24 offers the possibility of a critical starting structure in developing effective CDK4 inhibitors.

Keywords:  CDK4; Docking; MD-simulations; MM-PBSA; Steered molecular dynamics

DOI:  https://doi.org/10.1016/j.cmpb.2023.107367
Mol Cancer Ther. 2023 Feb 01. 22(2): 192-204

Inhibition of the MNK1/2-eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer.

Sathyen A Prabhu, Omar Moussa, Christophe Gonçalves, Judith H LaPierre, Hsiang Chou, Fan Huang, Vincent R Richard, Pault Y M Ferruzo, Elizabeth M Guettler, Isabel Soria-Bretones, Laura Kirby, Natascha Gagnon, Jie Su, Jennifer Silvester, Sai Sakktee Krisna, April A N Rose, Karen E Sheppard, David W Cescon, Frédérick A Mallette, Rene P Zahedi, Christoph H Borchers, Sonia V Del Rincon, Wilson H Miller.

Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders the translation of mRNAs that code for proteins involved in cell survival. We hypothesized that cancer cells treated with palbociclib use upregulated phosphorylated eIF4E (phospho-eIF4E) to escape the antitumor benefits of this drug. Indeed, we found that pharmacologic or genetic disruption of MNK1/2 activity, the only known kinases for eIF4E, enhanced the ability of palbociclib to decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis of melanoma cells treated with combined MNK1/2 and CDK4/6 inhibitors showed downregulation of proteins with critical roles in cell-cycle progression and mitosis, including AURKB, TPX2, and survivin. We also observed that palbociclib-resistant breast cancer cells have higher basal levels of phospho-eIF4E, and that treatment with MNK1/2 inhibitors sensitized these palbociclib-resistant cells to CDK4/6 inhibition. In vivo we demonstrate that the combination of MNK1/2 and CDK4/6 inhibition significantly increases the overall survival of mice compared with either monotherapy. Overall, our data support MNK1/2 inhibitors as promising drugs to potentiate the antineoplastic effects of palbociclib and overcome therapy-resistant disease.

DOI: https://doi.org/10.1158/1535-7163.MCT-22-0092
Breast Cancer (Dove Med Press). 2023 ;15 47-50

Rhabdomyolysis Induced by the Interaction Between Ribociclib and Statins- Case Report and Literature Review.

Omar Badran, Mahmoud Abu Amna, Ilit Turgeman, Gil Bar-Sela.

  Cyclin-dependent kinase (CDK) 4/6 inhibitors given with endocrine therapy are standard of care for the treatment of women with advanced hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER-2) negative breast cancer. Ribociclib is a CDK 4/6 inhibitor with moderate to solid inhibition of CYP3A4, a member of the cytochrome P450 family oxidase system, which may lead to interactions with medicinal substrates that are metabolized via CYP3A4. Statins are among the most widely prescribed medications worldwide, predominantly metabolized by the CYP3A4 isoenzyme. Rhabdomyolysis is a known rare side effect of statins, commonly triggered by drug interactions. We report a case of a 73-year-old woman with metastatic HR-positive and HER-2 negative breast cancer who developed rhabdomyolysis and acute kidney injury due to interaction between simvastatin and ribociclib with a literature review.

Keywords:  CYP3A4; creatine kinase, CK. acute kidney injury; drug interaction

DOI:  https://doi.org/10.2147/BCTT.S380485
Gan To Kagaku Ryoho. 2022 Dec;49(13): 1491-1493

[A Case of Recurrent Breast Cancer with Multiple Bone Metastasis Effectively Treated by CDK4/6 Inhibitor in Addition to Aromatase Inhibitor].

Eigo Satoh, Masatake Hara, Daisuke Uehira, Koji Yonekura, Ayano Murakata, Ryoki Ohinata, Yasuhiro Toyofuku, Hideaki Tanami, Takayuki Osanai, Norihide Sugano, Takaaki Sakoma.

We report a case of recurrent breast cancer with multiple bone metastasis in a 62-year-old woman. Her breast cancer (invasive ductal carcinoma, T2N0M0, Stage ⅡA)was resected in 2001(partial mastectomy plus axillary lymph node dissection) with adjuvant chemotherapy(UFT)and irradiation to her left remnant breast. In February 2018, she complained of severe pain in right femoral joint and hip. CT scan showed a left cystic breast tumor(17 cm)and multiple bone metastasis. The core needle biopsy of the costal bone lesion and left mastectomy were performed. These pathological findings were recurrence of the breast cancer(ER+). The endocrine therapy(exemestane, aromatase inhibitor), the administration of denosumab and irradiation to painful bone lesions were performed, but it did not suppress tumor progression. The treatment of letrozole plus palbociclib(CDK4/6 inhibitor)were continued for 3 months from May 2018, and this therapy made her bone lesions smaller, but palbociclib were stopped due to its severe neutropenia. After that, the single administration of letrozole was continued, but the tumor marker did not become normal. In February 2019, abemaciclib was administered in addition to letrozole. One year later, her symptoms improved and her bone metastases have showed partial response.
Anticancer Drugs. 2022 Dec 19.

A novel ribociclib derivative WXJ-103 exerts anti-breast cancer effect through CDK4/6.

Jing Ji, Zhen Zhang, Xingbei He, Gang Pan, Guanchu Li, Jinyu Lv, Yuxin Xu, Mengru Xie, Jing Feng, Weiling Wang, Bin Liu, Jinming Ma, Xiujun Wang.

The triple-negative breast cancer (TNBC) subtype is the most aggressive type of breast cancer with a low survival prognosis and high recurrence rate. There is currently no effective treatment to improve it. In this work, we explored the effect of a synthetic compound named WXJ-103 on several aspects of TNBC biology. The human breast cancer cell lines MDA-MB-231 and MCF-7 were used in the experiments, and the cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and the cell migration and invasion abilities were detected by wound healing assay and Transwell invasion assay. Cell cycle and apoptosis experiments were analyzed by flow cytometry, and protein levels related to cyclin-dependent kinase (CDK) 4/6-cyclin D-Rb-E2F pathway were analyzed by western blotting. Then, in-vivo experiments were performed to determine the clinical significance and functional role of WXJ-103. The results show that WXJ-103 can inhibit the adhesion, proliferation, migration, and invasion of TNBC cells, and can arrest the cell cycle in G1 phase. The levels of CDK4/6-cyclin D-Rb-E2F pathway-related proteins such as CDK6 and pRb decreased in a dose-dependent manner. Therefore, the antitumor activity of WXJ-103 may depend on the inhibition of CDK4/6-cyclin D1-Rb-E2F pathway. This research shows that WXJ-103 may be a new promising antitumor drug, which can play an antitumor effect on TNBC and provide new ideas for the treatment of TNBC.

DOI: https://doi.org/10.1097/CAD.0000000000001475
Gan To Kagaku Ryoho. 2022 Dec;49(13): 1935-1937

[Eight Cases of Breast Cancer That Relapsed More Than Ten Years after Initial Treatment].

Atsushi Yoshimura, Takeshi Ueda, Tetsuya Tanaka, Yuuki Kirihataya, Masahiro Soga, Tomoyo Yokotani.

Recurrence is more common for breast cancer than other solid tumors. In the last 5 years, we experienced 8 cases that relapsed more than 10 years after initial treatment. All cases were hormone-sensitive and HER2-negative. The Ki-67 percentage score was less than 15% in 7 cases. The age range at recurrence was 56-93 years(mean, 74.6 years), and the time to recurrence was 10-14 years and 20 or more years in 6 and 2 cases(mean, 14.6 years), respectively. The triggers for diagnosis were subjective symptoms, follow-up, and examination for other diseases in 3, 3, and 2 cases, respectively. The recurrence sites included the axilla, pleura/lung, liver/lung, skin, and chest wall in 3, 2, 1, 1, and 1 case, respectively. Treatment included an aromatase inhibitor(AI)and AI plus CDK4/6 inhibitor in 5 and 3 cases, respectively. The post-recurrence treatment period was 6-31 months(mean, 21.6 months), with 4 cases of PR, 3 cases of SD, and 1 case of death from other disease. There were 3 cases of axillary recurrence and 1 case each of neuropathic pain, upper limb edema, and local pain; all were alleviated by the treatment. In 2 cases, the pleural effusion decreased without chest tube drainage. Hormone receptor- positive late-relapse cases are generally highly therapeutically sensitive with favorable prognosis. In many cases, AI alone was selected considering patient age, side effects, treatment costs, and other factors.