scholarly journals CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene, and Pathophysiological Conditions

2020 ◽  
Vol 21 (17) ◽  
pp. 6350
Author(s):  
Rossana Roncato ◽  
Jacopo Angelini ◽  
Arianna Pani ◽  
Erika Cecchin ◽  
Andrea Sartore-Bianchi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Response ◽  
Interindividual Variability ◽  
Metastatic Breast ◽  
Cyclin Dependent Kinases ◽  
Therapeutic Class ◽  
Pharmacodynamic Profile ◽  
Altered Pharmacokinetic ◽  
Concomitant Medications ◽  
Potential Interactions

Palbociclib, ribociclib, and abemaciclib belong to the third generation of cyclin-dependent kinases inhibitors (CDKis), an established therapeutic class for advanced and metastatic breast cancer. Interindividual variability in the therapeutic response of CDKis has been reported and some individuals may experience increased and unexpected toxicity. This narrative review aims at identifying the factors potentially concurring at this variability for driving the most appropriate and tailored use of CDKis in the clinic. Specifically, concomitant medications, pharmacogenetic profile, and pathophysiological conditions could influence absorption, distribution, metabolism, and elimination pharmacokinetics. A personalized therapeutic approach taking into consideration all factors potentially contributing to an altered pharmacokinetic/pharmacodynamic profile could better drive safe and effective clinical use.

scholarly journals Development of CDK4/6 Inhibitors: A Five Years Update

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1488
Author(s):  
Alessandra Ammazzalorso ◽  
Mariangela Agamennone ◽  
Barbara De Filippis ◽  
Marialuigia Fantacuzzi
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adverse Effects ◽  
Antiproliferative Activity ◽  
Treatment Efficacy ◽  
Metastatic Breast ◽  
Breast Cancer Treatment ◽  
Survival Outcomes ◽  
Cyclin Dependent Kinases ◽  
Structure Activity

The inhibition of cyclin dependent kinases 4 and 6 plays a role in aromatase inhibitor resistant metastatic breast cancer. Three dual CDK4/6 inhibitors have been approved for the breast cancer treatment that, in combination with the endocrine therapy, dramatically improved the survival outcomes both in first and later line settings. The developments of the last five years in the search for new selective CDK4/6 inhibitors with increased selectivity, treatment efficacy, and reduced adverse effects are reviewed, considering the small-molecule inhibitors and proteolysis-targeting chimeras (PROTACs) approaches, mainly pointing at structure-activity relationships, selectivity against different kinases and antiproliferative activity.

Time to treatment failure of palbociclib and letrozole as second-line therapy or beyond in hormone receptor-positive advanced breast cancer

2018 ◽  
Vol 25 (6) ◽  
pp. 1374-1380 ◽  
Author(s):  
M Alexandra Schickli ◽  
Michael J Berger ◽  
Maryam Lustberg ◽  
Marilly Palettas ◽  
Craig A Vargo
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Treatment Failure ◽  
Endocrine Therapy ◽  
Metastatic Breast ◽  
Second Line ◽  
Time To Treatment ◽  
Cyclin Dependent Kinases ◽  
Hormone Receptor Positive ◽  
Time To Treatment Failure

Purpose The management of endocrine therapy resistance is one of the most challenging facets of advanced breast cancer treatment. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in combination with fulvestrant in postmenopausal women with disease progression following endocrine therapy. However, treatment responsiveness of tumors to palbociclib after multiple lines of endocrine therapy is not clearly established. The purpose of this study was to determine the efficacy of palbociclib and letrozole in patients pretreated with one or more lines of endocrine therapy. Methods This was a single-center, retrospective cohort study of all postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer patients who received palbociclib and letrozole as a second-line endocrine therapy or beyond (and no prior cyclin-dependent kinases 4 and 6 inhibitor therapy) between February 1, 2015, and July 31, 2016. The primary objective was to evaluate time to treatment failure of palbociclib in combination with letrozole as a second-line of therapy or beyond. Results Fifty-three patients meeting eligibility criteria were included in the analysis. For the primary outcome, the median time to treatment failure of palbociclib and letrozole was 6.3 months (95% CI 3.1–7.4 months). Progression-free survival of palbociclib and letrozole therapy was 6.4 months (95% CI 4.9–8.3 months). Conclusions Palbociclib and letrozole therapy is a viable, effective treatment option for metastatic breast cancer patients who were not exposed to cyclin-dependent kinases 4 and 6 inhibitors as a first-line endocrine therapy. The benefits of palbociclib and letrozole therapy were seen without excessive toxicity, and although neutropenia was common, it may be managed with dose reduction.

scholarly journals A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer

2018 ◽  
Vol 8 (10) ◽  
pp. 1286-1299 ◽  
Author(s):  
Tanya T. Kwan ◽  
Aditya Bardia ◽  
Laura M. Spring ◽  
Anita Giobbie-Hurder ◽  
Mark Kalinich ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Therapeutic Response ◽  
Metastatic Breast ◽  
Rna Signature

scholarly journals Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer

2019 ◽  
Vol 146 (5) ◽  
pp. 1359-1368 ◽  
Author(s):  
Fei Ma ◽  
Yanfang Guan ◽  
Zongbi Yi ◽  
Lianpeng Chang ◽  
Qiao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Heterogeneity ◽  
Therapeutic Response ◽  
Metastatic Breast

scholarly journals Efficacy and safety of cyclin dependent kinases 4/6 inhibitors in the treatment of metastatic breast cancer: a real-world experience

2020 ◽  
Vol 59 (11) ◽  
pp. 1382-1387
Author(s):  
Luisa Edman Kessler ◽  
Oscar Wiklander ◽  
Eva Hamberg ◽  
Jonas Bergh ◽  
Theodoros Foukakis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Real World ◽  
Metastatic Breast ◽  
Efficacy And Safety ◽  
Cyclin Dependent Kinases

Efficacy of Lower Dose Capecitabine in Patients with Metastatic Breast Cancer and Factors Influencing Therapeutic Response and Outcome

2007 ◽  
Vol 100 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Canfeza Sezgin ◽  
Ender Kurt ◽  
Turkan Evrensel ◽  
Necmettin Ozdemir ◽  
Osman Manavoglu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Therapeutic Response ◽  
Metastatic Breast ◽  
Factors Influencing

scholarly journals Quantitative Evaluation of Therapeutic Response by FDG-PET–CT in Metastatic Breast Cancer

2016 ◽  
Vol 3 ◽  
Author(s):  
Dorothée Goulon ◽  
Hatem Necib ◽  
Brice Henaff ◽  
Caroline Rousseau ◽  
Thomas Carlier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Quantitative Evaluation ◽  
Fdg Pet ◽  
Therapeutic Response ◽  
Metastatic Breast ◽  
Pet Ct ◽  
Fdg Pet Ct

scholarly journals Complete response of Palbociclib in metastatic breast cancer patient: A case report

2018 ◽  
Vol 5 (6) ◽  
pp. 2365-2369
Author(s):  
Mehrdad Payandeh ◽  
Edris Sadeghi ◽  
Mehrnoush Aeinfar ◽  
Saba Yari
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Complete Response ◽  
Oral Drug ◽  
Cyclin Dependent Kinases ◽  
Stage 4 ◽  
Chest X Ray ◽  
Epidermal Growth

Palbociclib, an oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6), has been approved for metastatic breast cancer (mBC) treatment of hormone receptor (HR)-positive/ human epidermal growth factor receptor 2 (HER2)-negative. The study reported the efficacy of Palbociclib as a new oral drug in a patient with mBC. A 40-year-old female with stage 2 right BC change to stage 4 after about two years later referred to oncology clinic. Due to HR-positivity/HER2-negative, she has treated with Palbociclib 125 mg (per one day for twoweek and one-week intervals) with Letrozole. In new assessment and after 8 months of this oral combination therapy, the chest x-ray of lung showed the complete response. Treatment with Palbociclib plus Letrozole had a complete response in the mBC patient after the common chemotherapies and hormone monotherapy.

Inhibitors of cyclin-dependent kinases as new class of drugs in oncology. Achievements and development prospects in treatment of ER+ /HER 2- breast cancer

2019 ◽  
Vol 1 (10) ◽  
pp. 6-14
Author(s):  
A. A. Vakhitova ◽  
R. V. Orlova
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Metastatic Breast ◽  
Cyclin Dependent Kinases ◽  
New Class ◽  
Hormone Sensitive ◽  
Her 2 ◽  
Cycle Regulation ◽  
Development Prospects

The review is devoted to a new class of drugs - inhibitors of cy-clin-dependent kinases. The discovery of the genetic and molecular mechanisms of cell cycle regulation, and as a result, the emergence of CDK4 / 6 inhibitors was a breakthrough in the treatment of ER+ HER2- metastatic breast cancer and changed the paradigm of hormone therapy in this group of patients. We consider the current role of CDK4 / 6 inhibitors in treating patients with hormone-sensitive breast cancer, as well as the prospects for the future use of this class of drugs. The article presents the results of the main registration studies of the FDA-approved inhibitors of CDK4 / 6: palbocyclyb, ribocyclyb, abemocyclib; a comparative analysis of their efficacy and toxicity profile was carried out.

Assessing tumor heterogeneity using circulating tumor DNA to predict and monitor therapeutic response in metastatic breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11543-11543
Author(s):  
Fei Ma ◽  
Yanfang Guan ◽  
Zongbi Yi ◽  
Lianpeng Chang ◽  
Xuefeng Xia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Heterogeneity ◽  
Therapeutic Response ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Response To Treatment ◽  
Clonal Population ◽  
Tumor Dna

11543 Background: Within metastatic breast cancer (mBC), tumor heterogeneity limited efficacy and duration of response to treatment. In this study, circulating tumor DNA (ctDNA) was used to evaluate tumor heterogeneity as a prognostic factor and monitor therapeutic response in patients with mBC. Methods: We collected plasma samples from 37 HER2-positive mBC patients treated with pyrotinib. Target-capture deep sequencing was performed to detect somatic mutations in plasma ctDNA. Clonal population structures were identified based on variations from ctDNA using Bayesian cluster with PyClone. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population. Results: Mutations in TP53 and genes of PI3K/Akt/mTOR pathway were associated with drug resistance for pyrotinib. The result showed that patients with resistant mutations occurring as a truncal event, who receiving monotherapy of pyrotinib, presented worse therapeutic effect (HR, 4.52; P = 0.03). The median PFS of patients with versus without resistant mutations in trunk clonal population was 7.8 weeks (95% CI 7.4 to 26.8 weeks) versus 31.6 weeks (95% CI 15.7 to 60 weeks), respectively. Patients with high heterogeneity (clonal population ≥3) had a significantly worse PFS (HR, 2.79; 95% CI 1.23 to 6.34; P = 0.014). The median PFS among patients with high versus low heterogeneity was 30.0 weeks (95% CI 13.9 to 53.5 weeks) versus 60.0 weeks (95% CI 31.4 to 84 weeks), respectively. Longitudinal monitoring of 21 patients during treatment showed positive correlation between mTBI in ctDNA and tumor size evaluated by CT imaging (P < 0.0001). Monitoring the mTBI in serial ctDNA increased sensitivity for prediction of progressive disease in 6 of 21 patients, with a mean time of 12.7 weeks earlier than using CT scan. ROC curve analysis showed an area under the curve value was 0.97 (p < 0.0001). Conclusions: Assessing tumor heterogeneity in ctDNA provides genetic predictors of treatment outcome. Molecular tumor burden in ctDNA is a potential indicator of therapeutic response. These observations might be supplements for the current therapeutic response evaluation.

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