Mechanisms of therapeutic CDK4/6 inhibition in breast cancer

Publication date: December 2017
Source:Seminars in Oncology, Volume 44, Issue 6
Author(s): Susan Combs Scott, Sarah S. Lee, Jame Abraham
Cyclin dependent kinase (CDK) 4/6 inhibitors have advanced the treatment of metastatic breast cancer by targeting the cell cycle machinery, interrupting intracellular and mitogenic hormone signals that stimulate proliferation of malignant cells. Preclinical evidence demonstrated that derangements of cyclin D1, CDK4/6, and retinoblastoma expression are common in breast cancer, and suggested a therapeutic benefit from interrupting this axis required for cell cycle progression. Studies of cell lines and animal models of breast cancer have demonstrated the complex interplay between the cell cycle and estrogen receptor and human epidermal growth receptor 2 signaling, which informs our understanding of synergistic use of CDK4/6 inhibitors with endocrine therapy, as well as mechanisms of resistance to endocrine therapy. Interestingly, estrogen receptor activity leads to upregulation of cyclin D1 expression, but the estrogen receptor is also in turn activated by cyclin D1, independent of estrogen binding. Early CDK inhibitors were nonspecific and limited by systemic toxicities, while the current generation of CDK4/6 inhibitors have shown promise in the treatment of hormone receptor-positive breast cancer. Preclinical investigations of the three CDK4/6 inhibitors approved by the US Food and Drug Administration (palbociclib, ribociclib, and abemaciclib) lend further insight into their mechanism of action, which will hopefully inform the future use and refinement of these therapies. Finally, we summarize evidence for additional novel CDK4/6 inhibitors currently in development.



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outside front cover

Publication date: December 2017
Source:Seminars in Oncology, Volume 44, Issue 6





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Masthead

Publication date: December 2017
Source:Seminars in Oncology, Volume 44, Issue 6





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Editorial Board

Publication date: December 2017
Source:Seminars in Oncology, Volume 44, Issue 6





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Table of Contents

Publication date: December 2017
Source:Seminars in Oncology, Volume 44, Issue 6





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Phase II study of S-1 plus oxaliplatin 130 mg/m 2 in Japanese patients with advanced gastric cancer

Abstract

Purpose

Although oxaliplatin 130 mg/m² every 3 weeks was approved for advanced gastric cancer in Japan, data regarding S-1 plus oxaliplatin 130 mg/m² (SOX130) are limited in Japanese patients with advanced gastric cancer. We investigated the feasibility and safety of SOX130 in Japanese patients with advanced gastric cancer.

Methods

Patients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0–1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥ 80% relative dose intensity of oxaliplatin.

Results

Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8–86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1–19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9–8.5) and 13.1 months (95% confidence interval 7.4–19.0), respectively.

Conclusion

Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

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Clinical Significance of Incidental Pituitary TC-99m MIBI Uptake on Parathyroid Spect and Factors Affecting Uptake Intensity

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


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