Potential biomarkers of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer

Fang, Hehui; Huang, Doudou; Yang, Fang; Guan, Xiaoxiang

doi:10.1007/s10549-017-4612-y

Cited by 32 publications

(27 citation statements)

References 57 publications

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“…1E and F). Given the role of CCNE1 in inducing E2F transcription factor and cell proliferation, these data support a mechanism of resistance to ET and CDK4/6 inhibitors, as described previously (31)(32)(33).…”

Section: Response By Baseline Clinical Pathologic and Molecular Chasupporting

confidence: 85%

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Hurvitz

Martín

Press

et al. 2020

Clinical Cancer Research

150

124

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Purpose: neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting. Patients and Methods: Postmenopausal women with stage I-IIIB HR þ /HER2 À breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response. Results: Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes. Conclusions: Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR þ /HER2 À early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.

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Section: Response By Baseline Clinical Pathologic and Molecular Chasupporting

confidence: 85%

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Hurvitz

Martín

Press

et al. 2020

Clinical Cancer Research

150

124

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“…While several of these have been reported not to predict differential benefit from the addition of CDK4/6 inhibitor, a recent report from the PALOMA-3 trial demonstrated relatively less benefit in cyclin E overexpressing (CCNE1 mRNA) tumors when palbociclib was added to fulvestrant, supporting the idea that Cyclin E-CDK2 represents a major bypass mechanism for CDK4/6 inhibitors [47]. While current clinical use of CDK4/6 inhibitors is based solely on ER+/HER2-status, investigation of biomarkers predictive of CDK4/6 inhibitor response, beyond ER-positivity, is an ongoing, essential area of research [45].…”

Section: Targeting the Cell Cycle In Er+ Breast Cancer: Cdk4/6 Inhibimentioning

confidence: 94%

“…Other candidate predictive biomarkers that have been considered or included in various studies include Ki67 levels; expression of p16, CDK4, CDK6, Cyclin E, Cdk2 and Rb; hormone-receptor status; as well as specific mutations (e.g. PIK3CA, ESR1, and TP53) [45,46]. While several of these have been reported not to predict differential benefit from the addition of CDK4/6 inhibitor, a recent report from the PALOMA-3 trial demonstrated relatively less benefit in cyclin E overexpressing (CCNE1 mRNA) tumors when palbociclib was added to fulvestrant, supporting the idea that Cyclin E-CDK2 represents a major bypass mechanism for CDK4/6 inhibitors [47].…”

Section: Targeting the Cell Cycle In Er+ Breast Cancer: Cdk4/6 Inhibimentioning

confidence: 99%

Targeting the cell cycle in breast cancer: towards the next phase

et al. 2018

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Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.

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“…ESR1 phosphorylation further increases its affinity for ERE [501]. In the nucleus, it activates estrogen responsive genes including TP53 [502], BRCA1 [503], CDK4/6 [504], as well as many others [505][506][507][508][509]. These genes promote cellular proliferation and survival [506].…”

Section: Classificationmentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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Potential biomarkers of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer

Cited by 32 publications

References 57 publications

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Targeting the cell cycle in breast cancer: towards the next phase

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

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