Anti-cancer therapy with cyclin-dependent kinase inhibitors: impact and challenges

2021 ◽  
Vol 23 ◽  
Author(s):  
Marika A. V. Reinius ◽  
Elizabeth Smyth
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Kinase Inhibitors ◽  
Metastatic Breast ◽  
Treatment Resistance ◽  
Current Status ◽  
Cyclin Dependent Kinase ◽  
Cancer Management ◽  
Potential Biomarker ◽  
Anti Cancer

Abstract The introduction of cyclin-dependent kinase 4/6 inhibitors (CKIs) has marked a major development in the standard treatment of advanced breast cancer. Extensive preclinical, translational and clinical research efforts into CKI agents are ongoing, and clinical application of this class of systemic anti-cancer therapy is anticipated to expand beyond metastatic breast cancer treatment. Emerging evidence indicates that mechanisms by which CKI agents exert their therapeutic effect transcend their initially expected impacts on cell cycle control into the realms of cancer immunology and metabolism. The recent expansion in our understanding of the multifaceted impact of CKIs on tumour biology has the potential to improve clinical study design, therapeutic strategies and ultimately patient outcomes. This review contextualises the current status of CKI therapy by providing an overview of the original and emerging insights into mechanisms of action and the evidence behind their current routine use in breast cancer management. Recent preclinical and clinical studies into CKIs across tumour types are discussed, including a synthesis of the more than 300 clinical trials of CKI-combination treatments registered as of November 2020. Key challenges and opportunities anticipated in the 2020s are explored, including treatment resistance, combination therapy strategies and potential biomarker development.

A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer

2017 ◽  
Vol 33 (9) ◽  
pp. 1559-1569 ◽  
Author(s):  
Burak Bilgin ◽  
Mehmet A.N. Sendur ◽  
Didem Şener Dede ◽  
Muhammed Bülent Akıncı ◽  
Bülent Yalçın
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitors ◽  
Metastatic Breast ◽  
Cyclin Dependent Kinase ◽  
Comprehensive Review ◽  
A Current

Venous thromboembolism in breast cancer patients receiving cyclin-dependent kinase inhibitors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18184-e18184
Author(s):  
Lorenzo Gervaso ◽  
Alberto J. Montero ◽  
Xuefei Jia ◽  
Alok A. Khorana
Keyword(s):  
Breast Cancer ◽  
Clinical Practice ◽  
Venous Thromboembolism ◽  
Cancer Patients ◽  
Kinase Inhibitors ◽  
Cleveland Clinic ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Cyclin Dependent Kinase ◽  
Breast Cancer Patients

e18184 Background: Venous thromboembolism (VTE) complicates several anti-cancer regimens including chemotherapy and anti-angiogenic agents. Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are a new approach for hormone receptor positive (HR+) metastatic breast cancer (mBC). Reported VTE rates in randomized trials range from 0.6% for ribociclib (MONALEESA-2) to 2% for palbociclib (PALOMA-3) and 5% for abemaciclib (MONARCH-3) but these may underestimate actual rates compared to patients in clinical practice who are generally older and have greater comorbidities. Little is known about real world incidence or prevalence of VTE with CDKIs in mBC. The aim of this study was to evaluate rates of VTE in clinical practice and association with outcomes in mBC patients on CDKIs. Methods: We conducted a retrospective cohort study at Cleveland Clinic Taussig Cancer Institute, approved by the institutional review board. We identified consecutive mBC patients who received any of three FDA-approved CDKIs (palbociclib, ribociclib, abemaciclib) from 1/2015 through 12/2017. VTE including deep venous thrombosis (DVT) and pulmonary embolism (PE) were identified by electronic medical record review. Overall survival (OS), progression free survival (PFS) and time to VTE were estimated by the Kaplan-Meier method and evaluated for association with VTE using Cox proportional hazard regression. Results: The study population included 424 patients, with a median age at diagnosis of 54.76 yrs, (range 27 -85). Palbociclib was the most commonly used CDKI (n = 390, 91.8%); 27 patients (6.3%) received more than one drug. VTE during CDKI therapy occurred in 9% of patients (n = 38), including DVT in 52.6% (n = 20), PE in 18.5% (n = 7) and visceral vein thrombosis (VVT) in 15.8% (n = 6). Median time to VTE was 314 days, and 6-months rate was 4.1%. VTE was associated with numerically worse PFS and OS, but this was not statistically significant (PFS [HR 1.25, 95% CI 0.73 – 2.14, p = 0.42], OS [HR 1.60, 95% CI 0.89 – 2.87, p = 0.12]). Conclusions: VTE affected nearly 10% of breast cancer patients receiving CDKIs, 2- to 5-fold greater than reported in registration trials. Further work is necessary to identify pathophysiology, risk factors and benefit of thromboprophylaxis.

scholarly journals Role of the Combination of Cyclin-Dependent Kinase Inhibitors (CDKI) and Radiotherapy (RT) in the Treatment of Metastatic Breast Cancer (MBC): Advantages and Risks in Clinical Practice

2021 ◽  
Vol 11 ◽  
Author(s):  
Ambrogio Gagliano ◽  
Angela Prestifilippo ◽  
Ornella Cantale ◽  
Gianluca Ferini ◽  
Giacomo Fisichella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Metastatic Breast Cancer ◽  
Gold Standard ◽  
Kinase Inhibitors ◽  
Metastatic Breast ◽  
Cyclin Dependent Kinase ◽  
Safety And Efficacy ◽  
Definite Evidence

Targeting cell cycle has become the gold standard for metastatic breast cancer (MBC), being cyclin-dependent kinase inhibitors (CDKIs) cornerstones of its treatment, alongside radiotherapy (RT). To date, no definite evidence regarding safety and efficacy of the combination of CDKIs plus radiotherapy (RT) is currently available. Purpose of this review is to collect data in favor or against the feasibility of the association of CDKIs + RT, describing its potential adverse events. Our review shows how CDKI + RT allows an overall satisfying disease control, proving to be effective and causing a grade of toxicity mainly influenced by the site of irradiation, leaning to favourable outcomes for sites as liver, spine or brain and to poorer outcomes for thoracic lesions or sites close to viscera; controversial evidence is instead for bone treatment. Toxicity also varies from patient to patient. To sum up, our contribution enriches and enlightens a still indefinite field regarding the feasibility of CDKIs + RT, giving cues for innovative clinical management of hormone-responsive MBC.

scholarly journals Hormone therapy for premenopausal women with metastatic breast cancer: combinations with cyclin-dependent kinase inhibitors

2019 ◽  
Vol 15 (2) ◽  
pp. 30-41
Author(s):  
E. V. Artamonova ◽  
E. I. Kovalenko
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Hormone Therapy ◽  
Randomized Trials ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Metastatic Breast ◽  
Premenopausal Women ◽  
Cyclin Dependent Kinase ◽  
Ovarian Suppression

This article discusses the problems associated with the search of the most effective treatment strategies for HER2-negative metastatic breast cancer in premenopausal women. Until recently, ovarian suppression and hormone therapy had been the main treatments used in this group of patients. The development of palbociclib, called a “breakthrough therapy”, as well as promising results of trials evaluating the efficacy of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors added to hormone therapy in postmenopausal women suggested a need for the assessment of this treatment regimen in combination with ovarian suppression in younger patients.According to the results of randomized trials and subgroup analysis, the addition of a CDK4/6 inhibitor to ovarian suppression and hormonal therapy significantly increases survival. The safety profile is similar to that of older patients. Randomized trials comparing the efficacy of palbociclib + ovarian suppression + aromatase inhibitor vs. chemotherapy in premenopausal women demonstrated significant benefits of a new treatment strategy: a CDK4/6 inhibitor as a part of combination therapy reduced the risk of progression by 36 % compared to capecitabine.

scholarly journals Pertuzumab in Combination with Trastuzumab and Chemotherapy in the Treatment of HER2-Positive Metastatic Breast Cancer: Safety, Efficacy, and Progression Free Survival

2014 ◽  
Vol 8 ◽  
pp. BCBCR.S9032 ◽  
Author(s):  
Joseph J. Maly ◽  
Erin R. Macrae
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitors ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Preclinical Research ◽  
Her2 Positive ◽  
Cancer Management ◽  
Improved Outcomes ◽  
Breast Cancer Management ◽  
Computer Based

Tyrosine kinase inhibitors have revolutionized the oncology community and were pioneered by the use in HER2-targeted therapies. Improved outcomes were seen with the advent of trastuzumab, leading investigators to develop newer agents to target the HER2 pathway such as the novel monoclonal antibody pertuzumab. In this paper, we describe the attributes of pertuzumab including: mechanism of action, pharmacokinetics and metabolism, safety/cardiotoxicity, drug interactions, efficacy, and role in HER2-positive breast cancer management. Newly reviewed here versus previously published reviews on pertuzumab oriented therapy are data of pertuzumab monotherapy as it is used in combination with other anti-HER2 agents derived from preclinical research and ongoing clinical trials. Materials and Methods A computer based literature search was carried out using PubMed data reported at international meetings (ASCO) up to September 2013 were included.

scholarly journals Cyclin-dependent kinase inhibitors: efficacy and safety

2019 ◽  
pp. 42-55 ◽  
Author(s):  
I. B. Kononenko ◽  
A. V. Snegovoi ◽  
V. Yu. Selchuk
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Hormone Receptor ◽  
Randomized Clinical Trials ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Endocrine Treatment ◽  
Cyclin Dependent Kinase

Breast Cancer is the most common type of cancer worldwide. Scientific advances and new ways of treating have significantly improved the prognosis of breast cancer in recent decades. The emergence of modern cyclin-dependent kinase (CDK) inhibitors has changed the treatment paradigm for metastatic hormone receptor (HR)-positive breast cancer. In the past four years, the CDK4/6 inhibitors, ribociclib, palbociclib and abemaciclib, received their first FDA approval for the treatment of Hormone Receptor (HR)- positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA, MONALEESA and the MONARCH randomized clinical trials, respectively. In the Russian standards for the treatment of metastatic HR positive and HER2-negative breast cancer are included two inhibitors of CDK4/6 – ribociclib, palbociclib. This review summarizes the background of clinical efficacy and potential toxicities seen with the use CDK4/6 inhibitors with endocrine treatment in pre- or postmenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer. Despite the similar toxicities, inhibitors of cyclin-dependent kinases differ in their severity and some types of adverse events. Most hematologic abnormalities seen with CDK4/6 inhibitors are not complicated and are adequately managed with standard supportive care and dose adjustments when indicated. This review focuses on the practical management of adverse events associated with CDK4/6 inhibitors.

scholarly journals 4CPS-293 Efficacy and safety of cyclin dependent kinase inhibitors in metastatic breast cancer

2021 ◽  
Author(s):  
L Cantarelli ◽  
JA Morales Barrios ◽  
S Garcia Gil ◽  
B Del Rosario Garcia ◽  
GJ Nazco Casariego ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitors ◽  
Metastatic Breast ◽  
Cyclin Dependent Kinase ◽  
Efficacy And Safety

Phytochemicals for Breast Cancer Therapy: Current Status and Future Implications

2015 ◽  
Vol 15 (2) ◽  
pp. 116-135 ◽  
Author(s):  
Jawed Siddiqui ◽  
Aru Singh ◽  
Megha Chagtoo ◽  
Nidhi Singh ◽  
Madan Godbole ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Current Status ◽  
Breast Cancer Therapy

Serum Carboxypeptidase N1 Serves as a Potential Biomarker Complementing CA15-3 for Breast Cancer

2020 ◽  
Vol 20 (17) ◽  
pp. 2053-2065
Author(s):  
Ranliang Cui ◽  
Chaomin Wang ◽  
Qi Zhao ◽  
Yichao Wang ◽  
Yueguo Li
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Critical Concentration ◽  
Tumour Size ◽  
Clinical Stage ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Potential Biomarker ◽  
Incidence And Mortality ◽  
Combined Detection

Background: The incidence and mortality of breast cancer are increasing annually. Breast cancer seriously threatens women's health and quality of life. We aimed to measure the clinical value of CPN1, a new serum marker of breast cancer and to evaluate the efficacy of CPN1 in combination with CA15-3. Methods: Seventy samples of breast cancer with lymph node metastasis, seventy-three samples of nonmetastatic breast cancer and twenty-five samples of healthy human serum were collected. Serum CA15-3 concentration was determined by Roche Elecsys, and serum CPN1 concentration was determined by ELISA. Results: In breast cancer patients, serum CPN1 concentration was positively correlated with tumour size, clinical stage and CA15-3 concentration (r = 0.376, P<0.0001). ROC curve analysis showed that the optimal critical concentration of CPN1 for breast cancer diagnosis was 32.8pg/ml. The optimal critical concentration of CPN1 in the diagnosis of metastatic breast cancer was 66.121pg/ml. CPN1 has a greater diagnostic ability for breast cancer (AUCCA15-3=0.702 vs. AUCCPN1=0.886, P<0.0001) and metastatic breast cancer (AUCCA15-3=0.629 vs. AUCCPN1=0.887, P<0.0001) than CA15-3, and the combined detection of CA15-3 and CPN1 can improve the diagnostic efficiency for breast cancer (AUCCA15-3+CPN1=0.916) and for distinguishing between metastatic and non-metastatic breast cancer (AUCCA15-3+CPN1=0.895). Conclusion: CPN1 can be used as a new tumour marker to diagnose and evaluate the invasion and metastasis of breast cancer. The combined detection of CPN1 and CA15-3 is more accurate and has a certain value in clinical application.

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