bims-cyhorp 2022-07-24 papers

Issue of 2022–07–24
three papers selected by
Piotr Okupski,

Front Oncol. 2022 ;12 865292

Real-World Effectiveness of Palbociclib Plus Letrozole vs Letrozole Alone for Metastatic Breast Cancer With Lung or Liver Metastases: Flatiron Database Analysis.

Adam Brufsky, Xianchen Liu, Benjamin Li, Lynn McRoy, Rachel M Layman.

Background: Cyclin-dependent kinase 4/6 inhibitors are a standard treatment for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, real-world data on effectiveness in patients with liver or lung metastatic disease is limited. This study compared outcomes of palbociclib plus letrozole versus letrozole alone in patients with HR+/HER2- MBC with lung or liver metastasis treated in routine clinical practice in the United States.
Methods: This retrospective analysis used Flatiron Health's database of electronic health records. Women with HR+/HER2- MBC and liver or lung metastasis received first-line palbociclib plus letrozole or letrozole alone between February 2015 and February 2019. Real-world progression-free survival (rwPFS) was defined as time from start of treatment to death or disease progression. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics between palbociclib plus letrozole versus letrozole cohorts. Cox proportional-hazards models were used to estimate the effectiveness of palbociclib plus letrozole versus letrozole alone in rwPFS and overall survival (OS).
Results: The study included 353 patients with lung metastasis, 123 with liver metastasis, and 75 with both. After sIPTW, palbociclib plus letrozole versus letrozole alone was significantlly associated with prolonged rwPFS (hazard ratio (HR), 0.56) and OS (HR, 0.58) (both p<0.001) in all patients. Palbociclib plus letrozole compared with letrozole alone demonstrated a median rwPFS of 16.5 versus 10.5 months, respectively (adjusted HR, 0.52; P<0.001), a median OS of not reached versus 40.3 months (adjusted HR, 0.60; P<0.01) in patients with lung metastasis, and median OS of 30.1 versus 16.8 months (adjusted HR, 0.56; P<0.03 in patients with liver metastasis. In patients with liver metastasis, palbociclib plus letrozole had a median rwPFS of 10.7 months versus 8.0 months in the letrozole alone cohort (adjusted HR, 0.70; P=0.12).
Conclusions: In this real-world population, palbociclib in combination with letrozole is associated with improved outcomes compared with letrozole alone for patients with HR+/HER2- MBC and liver or lung metastasis in the first-line setting. The findings support first-line palbociclib in combination with an aromatase inhibitor as standard of care for HR+/HER2- MBC regardless of visceral disease.
Clinical Trial Registration: NCT04176354.

Keywords: HR+/HER2−; metastatic breast cancer; palbociclib; real-world data; visceral metastasis

DOI: https://doi.org/10.3389/fonc.2022.865292

Med Oncol. 2022 Jul 23. 39(10): 158

Expression patterns and therapeutic implications of CDK4 across multiple carcinomas: a molecular docking and MD simulation study.

Hina Qayoom, Umar Mehraj, Shazia Sofi, Shariqa Aisha, Abdullah Almilaibary, Mustfa Alkhanani, Manzoor Ahmad Mir.

The CDKs are known to play a critical role in cell cycle regulation process. Among the different groups of CDKs, CDK4 overexpression/hyperactivation is found to be present in many cancers and a specific CDK4 inhibitor, palbociclib has been recently approved by the FDA against breast cancer. However, the treatment with palbociclib has shown many associated toxicities such as-anemia, thrombocytopenia, neutropenia, and febrile neutropenia and more. Despite the fact being FDA approved for only breast cancer and no other cancers and CDK4 being overexpressed in multiple cancers. Therefore, we in our study intend to screen two novel CDK4 inhibitors that show considerably less associated toxicities and greater therapeutic implications than palbociclib. We screened the compounds using Lipinski's rule, ADMET analysis and further analyzed the selected compounds using a virtual screening method called molecular docking and validated our results by MD simulation. We studied the expression patterns and prognostic significance of CDK4 across multiple carcinomas by using some database like UALCAN, cBioportal, and KM-Plotter.

Keywords: ADMET; CDK4; MD simulation; Molecular docking; Palbociclib; Pan-cancer

DOI: https://doi.org/10.1007/s12032-022-01779-9

BMC Complement Med Ther. 2022 Jul 20. 22(1): 193

Metformin and Gegen Qinlian Decoction boost islet α-cell proliferation of the STZ induced diabetic rats.

Li Xu, Shreyas Jois, Hongliang Cui.

BACKGROUND: The traditional Chinese medicine Gegen Qinlian Decoction (GQD), as well as metformin, had been reported with anti-diabetic effects in clinical practice.
OBJECTIVE: To verify whether these two medicines effectively ameliorate hyperglycemia caused by deficiency of islet β-cell mass which occurs in both type 1 and type 2 diabetes.
METHODS: SD rats were injected with a single dose of STZ (55 mg/kg) to induce β-cell destruction. The rats were then divided into control, diabetes, GQD and metformin group. GQD and metformin groups were administered with GQD extract or metformin for 6 weeks. The islet α-cell or β-cell mass changes were tested by immunohistochemical and immunofluorescent staining. The potential targets and mechanisms of GQD and metformin on cell proliferation were tested using in silico network pharmacology. Real-time PCR was performed to test the expression of islet cells related genes and targets related genes.
RESULTS: Both GQD and metformin did not significantly reduce the FBG level caused by β-cell mass reduction, but alleviated liver and pancreas histopathology. Both GQD and metformin did not change the insulin positive cell mass but increased α-cell proliferation of the diabetic rats. Gene expression analysis showed that GQD and metformin significantly increased the targets gene cyclin-dependent kinase 4 (Cdk4) and insulin receptor substrate (Irs1) level.
CONCLUSION: This research indicates that GQD and metformin significantly increased the α-cell proliferation of β-cell deficiency induced diabetic rats by restoring Cdk4 and Irs1 gene expression.

Keywords: Diabetes; Gegen Qinlian Decoction; Islet α-cells; Islet β-cells; Metformin

DOI: https://doi.org/10.1186/s12906-022-03674-2