bims-cyhorp 2022-06-26 papers

Issue of 2022–06–26
five papers selected by
Piotr Okupski,

Expert Rev Anticancer Ther. 2022 Jun 23.

Efficacy, safety and toxicity management of adjuvant abemaciclib in early stage HR+/HER2- high-risk breast cancer.

Sarah Sammons, Heather Moore, Jaycee Cushman, Erika Hamilton.

INTRODUCTION: The majority of the over 250,000 new cases of invasive breast cancer diagnosed in the United States is driven by hormone receptor signaling (HR+). Since 2015, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard in combination with endocrine therapy (ET) for patients facing metastatic disease.
AREAS COVERED: There are now three approved agents in the metastatic setting; abemaciclib, ribociclib, and palbociclib. Due to the almost doubling of progression free survival (PFS) and improvement in overall survival (OS) in the metastatic setting, studies were conducted to examine the benefit of adding CDK4/6i in the adjuvant setting for those patients at high risk for recurrence. Despite negative results of PALLAS (palbociclib) in this setting, monarchE (abemaciclib) showed an improvement in invasive disease-free survival (IDFS) and distant recurrence free survival (DRFS) at the 3 year time point for patients with high risk tumor characteristics leading to its approval. Herein, we discuss the data, the population studied and the population in which abemaciclib is approved as well as safety, tolerability, and dose reductions for practical management of these patients.
EXPERT OPINION: Abemaciclib is appropriate and beneficial for those patients with high-risk, node-positive, hormonally-driven breast cancer.

Keywords: CDK4/6; HR+ breast cancer; abemaciclib; adjuvant treatment; early breast cancer; endocrine therapy

DOI: https://doi.org/10.1080/14737140.2022.2093719

Cancers (Basel). 2022 Jun 10. pii: 2872. [Epub ahead of print]14(12):

Genomic Aberrations in Circulating Tumor DNAs from Palbociclib-Treated Metastatic Breast Cancer Patients Reveal a Novel Resistance Mechanism.

Maysa Abu-Khalaf, Chun Wang, Zhenchao Zhang, Rui Luo, Weelic Chong, Daniel P Silver, Frederick Fellin, Rebecca Jaslow, AnaMaria Lopez, Terrence Cescon, Wei Jiang, Ronald Myers, Qiang Wei, Bingshan Li, Massimo Cristofanilli, Hushan Yang.

Previously undescribed molecular mechanisms of resistance will emerge with the increased use of cyclin-dependent kinase 4/6 inhibitors in clinical settings. To identify genomic aberrations in circulating tumor DNA associated with treatment resistance in palbociclib-treated metastatic breast cancer (MBC) patients, we collected 35 pre- and post-treatment blood samples from 16 patients with estrogen receptor-positive (ER+) MBC, including 9 with inflammatory breast cancer (IBC). Circulating cell-free DNAs (cfDNAs) were isolated for sequencing using a targeted panel of 91 genes. Our data showed that FBXW7 and CDK6 were more frequently altered in IBC than in non-IBC, whereas conversely, PIK3CA was more frequently altered in non-IBC than in IBC. The cfDNA samples collected at follow-up harbored more mutations than baseline samples. By analyzing paired samples, we observed a higher percentage of patients with mutations in RB1, CCNE1, FBXW7, EZH2, and ARID1A, but a lower proportion of patients with mutated TSC2 at the post-treatment stage when they developed progression. Moreover, acquisition of CCNE1 mutations or loss of TSC2 mutations after treatment initiation conferred an unfavorable prognosis. These data provide insights into the relevance of novel genomic alterations in cfDNA to palbociclib resistance in MBC patients. Future large-scale prospective studies are warranted to confirm our findings.

Keywords: circulating tumor DNA; metastatic breast cancer; palbociclib; somatic mutation; treatment resistance

DOI: https://doi.org/10.3390/cancers14122872

Mol Clin Oncol. 2022 Jul;17(1): 119

Combination of palbociclib with adjuvant endocrine therapy for treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer: An experience at two cancer centers in Saudi Arabia.

Meteb H Al-Foheidi, Asem Mohammed Albeshri, Safwan Noor Moamenkahan, Abdulmajid Mohammed Abdullah, Muhannad Sadaqa Abualola, Muath Hamed Alharbi, Ahmed A Refa, Ali M Bayer, Ahmed Y Shaheen, Syed Sameer Aga, Muhammad Anwar Khan, Mubarak M Al-Mansour, Ezzeldin M Ibrahim.

The addition of palbociclib (a cyclin-dependent kinase 4/6 inhibitor) to endocrine therapy (ET) has been shown to significantly improve progression-free survival (PFS) and overall survival (OS) among patients with hormone receptor-positive (HR+) advanced breast cancer. The current study presents the local experience of using palbociclib at two cancer centers in Saudi Arabia. Electronic data of patients with metastatic HR+ and human epidermal growth factor receptor 2-negative breast cancer who progressed after prior ET and received at least one cycle of palbociclib plus ET, were retrospectively reviewed. A total of 97 patients were identified, and their data were included in the analysis. The median age of the patients was 55 years. Patients were heavily pretreated in the metastatic setting (55% received systemic chemotherapy and 49% received two or more lines of prior ET). In total, 29 (30%) and 50 (52%) patients achieved an objective response and clinical benefit, respectively. The median follow-up time was 31.0 months [95% confidence interval (CI), 16.9-44.9] and the median PFS time was 16.3 months (95% CI, 11.4-21.2), with 58% of patients remaining progression-free at 12 months. Upon multivariate regression analysis, liver involvement was the only significant independent variable that predicted a greater risk of progression or death (hazard ratio, 2.32; 95% CI, 1.22-4.40; P=0.010). The median OS time was 19.6 months (95% CI, 18.1-20.9), with 12- and 24-month OS rates of 75 and 30%, respectively. Overall, real-world data showed that administration of palbociclib in combination with ET in patients with advanced HR+ breast cancer achieved a favorable outcome that was comparable to that reported in clinical trials.

Keywords: breast cancer; cyclin-dependent kinase 4/6 inhibitor; estrogen receptor; human epidermal growth factor receptor 2; palbociclib; therapy

DOI: https://doi.org/10.3892/mco.2022.2552

Int J Mol Sci. 2022 Jun 11. pii: 6547. [Epub ahead of print]23(12):

Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity.

Nischal Koirala, Nandini Dey, Jennifer Aske, Pradip De.

The development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer patient population. Due to the activation of compensatory pathways, patients eventually suffer from resistance to HER2-directed therapies and develop a more aggressive disease phenotype. One of these mechanisms is the crosstalk between ER and HER2 signaling, especially the CDK4/6-Cyclin D-Rb signaling axis that is commonly active and has received attention for its potential role in regulating tumor progression. CDK 4/6 inhibitors interfere with the binding of cell-cycle-dependent kinases (CDKs) with their cognate partner cyclins, and forestall the progression of the cell cycle by preventing Rb phosphorylation and E2F release that consequentially leads to cancer cell senescence. CDK 4/6 inhibitors, namely, palbociclib, ribociclib, and abemaciclib, in combination with anti-estrogen therapies, have shown impressive outcomes in hormonal receptor-positive (HR+) disease and have received approval for this disease context. As an extension of this concept, preclinical/clinical studies incorporating CDK 4/6 inhibitors with HER2-targeted drugs have been evaluated and have shown potency in limiting tumor progression, restoring therapeutic sensitivity, and may improving the management of the disease. Currently, several clinical trials are examining the synergistic effects of CDK 4/6 inhibitors with optimized HER2-directed therapies for the (ER+/-) HER2+ population in the metastatic setting. In this review, we aim to interrogate the burden of HER2+ disease in light of recent treatment progress in the field and examine the clinical benefit of CDK 4/6 inhibitors as a replacement for traditional chemotherapy to improve outcomes in HER2+ breast cancer.

Keywords: ERBB2; HER2+ breast cancer; HER2-targeted drug delivery; brain metastasis; cell cycle inhibitors; cell cycle pathway

DOI: https://doi.org/10.3390/ijms23126547

Front Oncol. 2022 ;12 865454

Investigating the Mechanism of Inhibition of Cyclin-Dependent Kinase 6 Inhibitory Potential by Selonsertib: Newer Insights Into Drug Repurposing.

Mohammad Hassan Baig, Mohd Yousuf, Mohd Imran Khan, Imran Khan, Irfan Ahmad, Mohammad Y Alshahrani, Md Imtaiyaz Hassan, Jae-June Dong.

Cyclin-dependent kinases (CDKs) play significant roles in numerous physiological, and are considered an attractive drug target for cancer, neurodegenerative, and inflammatory diseases. In the present study, we have aimed to investigate the binding affinity and inhibitory potential of selonsertib toward CDK6. Using the drug repurposing approach, we performed molecular docking of selonsertib with CDK6 and observed a significant binding affinity. To ascertain, we further performed essential dynamics analysis and free energy calculation, which suggested the formation of a stable selonsertib-CDK6 complex. The in-silico findings were further experimentally validated. The recombinant CDK6 was expressed, purified, and treated with selonsertib. The binding affinity of selonsertib to CDK6 was estimated by fluorescence binding studies and enzyme inhibition assay. The results indicated an appreciable binding of selonsertib against CDK6, which subsequently inhibits its activity with a commendable IC50 value (9.8 μM). We concluded that targeting CDK6 by selonsertib can be an efficient therapeutic approach to cancer and other CDK6-related diseases. These observations provide a promising opportunity to utilize selonsertib to address CDK6-related human pathologies.

Keywords: MD simulation; anticancer therapy; cyclin-dependent kinases; drug design and development; drug repurposing; molecular docking

DOI: https://doi.org/10.3389/fonc.2022.865454