Clinical Management of Potential Toxicities and Drug Interactions Related to Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Practical Considerations and Recommendations

Spring, Laura; Zangardi, Mark; Moy, Beverly; Bardia, Aditya

doi:10.1634/theoncologist.2017-0142

Cited by 136 publications

(134 citation statements)

References 60 publications

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“…All three inhibitors are associated with toxicities resulting in loss of haematocytes (Kassem et al 2018), consistent with a role for CDK6 in the activation of haematopoetic stem cells (Scheicher et al 2015). Toxicities associated with all three drugs are, however, considered to be manageable and reversible (Spring et al 2017).…”

Section: Cdk4/6 Inhibitorsmentioning

confidence: 75%

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Portman

Alexandrou

Carson

et al. 2019

Endocrine-Related Cancer

116

121

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Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.

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Section: Cdk4/6 Inhibitorsmentioning

confidence: 75%

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Portman

Alexandrou

Carson

et al. 2019

Endocrine-Related Cancer

116

121

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“…ER+ BC is relatively genomically stable with a primary dependency on estrogen signaling, and it typically has normal function of RB and p53 tumor suppressor pathways compared to other BC subtypes, such as HER2+ and TNBC. Similarly, HER2-induced cell growth is also mediated by the CDK4/6-RB axis [103]. The mouse models of human BC also indicate that the stimulation of the cyclin D1-CDK4/6 axis leads to a tumorigenic phenotype and contributes toward the initiation and maintenance of tumorigenesis in HER2+ BC [101].…”

Section: Dysregulation Of Cdks In Bcmentioning

confidence: 97%

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

338

216

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Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

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“…A greater reduction in absolute neutrophil count appears to be associated with increased PALBO exposure, while no definitive exposure-response relationship was found in 81 patients treated at 125 mg fixed dose [6]. Some adverse events, as neutropenia or QT prolongation, have shown to be proportional to RIBO exposure [7]. Finally, an exposure-efficacy analysis in patients treated with LETRO showed a longer time to tumour progression for those patients achieving LETRO plasma concentrations � 85.6 ng/mL [5].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous quantification of palbociclib, ribociclib and letrozole in human plasma by a new LC-MS/MS method for clinical application

et al. 2020

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A novel LC-MS/MS method was developed for the quantification of the new cyclin dependent kinase inhibitors (CDKIs) palbociclib and ribociclib and the aromatase inhibitor letrozole used in combinatory regimen. The proposed method is appropriate to be applied in clinical practice due to the simple and fast sample preparation based on protein precipitation, the low amount of patient sample necessary for the analysis (10 μL) and the total run time of 6.5 min. It was fully validated according to FDA and EMA guidelines on bioanalytical method validation. The linearity was assessed (R 2 within 0.9992-0.9983) over the concentration ranges of 0.3-250 ng/mL for palbociclib, 10-10000 ng/mL for ribociclib and 0.5-500 ng/mL for letrozole that properly cover the therapeutic plasma concentrations. A specific strategy was implemented to reduce the carryover phenomenon, formerly known for these CDKIs. This method was applied to quantify the C min of palbociclib, ribociclib and letrozole in plasma samples from patients enrolled in a clinical study. The same set of study samples was analysed twice in separate runs to assess the reproducibility of the method by means of the incurred samples reanalysis. The results corroborated the reliability of the analyte concentrations obtained with the bioanalytical method, already proved by the validation process. The percentage differences were always within ±10% for all the analytes and the R 2 of the correlation graph between the two quantifications was equal to 0.9994. OPEN ACCESS Citation: Posocco B, Buzzo M, Poetto AS, Orleni M, Gagno S, Zanchetta M, et al. (2020) Simultaneous quantification of palbociclib, ribociclib and letrozole in human plasma by a new LC-MS/MS method for clinical application. PLoS ONE 15(2): e0228822.

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Clinical Management of Potential Toxicities and Drug Interactions Related to Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Practical Considerations and Recommendations

Abstract: This review article reports the clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors in breast cancer, with a focus on palbociclib and ribociclib, and summarizes practical management strategies for the oncologist.

Cited by 136 publications

References 60 publications

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Simultaneous quantification of palbociclib, ribociclib and letrozole in human plasma by a new LC-MS/MS method for clinical application

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