Inhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences

Drugs, Год журнала: 2020, Номер 81(3), С. 317 - 331

Опубликована: Дек. 28, 2020

The cyclin-dependent kinase (CDK) 4/6 inhibitors belong to a new class of drugs that interrupt proliferation malignant cells by inhibiting progression through the cell cycle. Three such inhibitors, palbociclib, ribociclib, and abemaciclib were recently approved for breast cancer treatment in various settings combination regimens. On basis their impressive efficacy, all three CDK4/6 now play an important role patients with HR+, HER2- cancer; however, optimal use still needs be established. have many similarities both pharmacokinetics pharmacodynamics. However, there are some differences on which choice particular inhibitor individual patient can important. In this article, clinical pharmacokinetic pharmacodynamic profiles reviewed future directions applicability will discussed.

Язык: Английский

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How liquid biopsies can change clinical practice in oncology

Annals of Oncology, Год журнала: 2019, Номер 30(10), С. 1580 - 1590

Опубликована: Июль 31, 2019

Cell-free DNA fragments are shed into the bloodstream by tumor cells. The analysis of circulating (ctDNA), commonly known as liquid biopsy, can be exploited for a variety clinical applications. ctDNA is being used to genotype solid cancers non-invasively, track dynamics and detect emergence drug resistance. In few settings, biopsies have already entered practice. For example, guide treatment in subset lung cancers. this review, we discuss how recent improvements sensitivity accuracy analyses led unprecedented advances research field. We further consider what required routine deployment diagnostic space. pinpoint technical hurdles that yet overcome, including preanalytical analytical challenges. foresee will transform practice: complementing (or replacing) imaging monitor response detecting minimal residual disease after surgery with curative intent.

Язык: Английский

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Liquid biopsy in breast cancer: A comprehensive review

Clinical Genetics, Год журнала: 2019, Номер 95(6), С. 643 - 660

Опубликована: Янв. 24, 2019

Breast cancer is the most common among women worldwide. Due to its complexity in nature, effective breast treatment can encounter many challenges. Traditional methods of detection such as tissue biopsy are not comprehensive enough capture entire genomic landscape tumors. However, with introduction novel techniques, application liquid has been enhanced, enabling improvement various aspects management including early diagnosis and screening, prediction prognosis, relapse, serial sampling efficient longitudinal monitoring disease progress response treatment. Various components tumor cells released into blood circulation be analyzed sampling, some which include circulating (CTCs), DNA (ctDNA), cell‐free RNA, tumor‐educated platelets exosomes. These utilized for different purposes. As an example, ctDNA sequenced genetic profiling tumors enhance individualized screening. CTC plasma count analysis or after curative resection surgery could facilitate minimal residual disease, aiding initiation adjuvant therapy prevent recurrence. Furthermore, assessed determine stage prognosis cancer. In this review, we discuss advantages limitations used will expand on that require further focus future research.

Язык: Английский

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ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

Breast Cancer Research, Год журнала: 2021, Номер 23(1)

Опубликована: Авг. 15, 2021

In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone therapy, estrogen deprivation by aromatase inhibition. How these affect tumor sensitivity established and novel therapies active areas research. These include receptor-targeting agents, such as selective receptor modulators, covalent antagonists, degraders (including tamoxifen, fulvestrant, agents), combination therapies, endocrine therapy plus CDK4/6, PI3K, or mTORC1 this review, we summarize existing knowledge surrounding mechanisms action roles in We then analyze recent literature on how outcomes therapies. For tamoxifen relative vitro but do not clearly lead patients, making agents category promising. Regarding nullify any inhibitor component combination. Thus, combinations using alternatives inhibition, where non-endocrine is efficacious monotherapy, still effective against mutations. results emphasize importance investigating combinatorial resistance, challenging efforts are. also discuss future directions open questions, studying differences among distinct mutations, asking adjust clinical decisions based molecular surveillance testing, developing that

Язык: Английский

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Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Май 29, 2020

Abstract Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity PARP inhibitors in 43 patients untreated TNBC. The primary end point, decreased Ki67, occured 12% In secondary point analyses, HR deficiency was identified 69% TNBC mutational-signature-based HRDetect assay. Cancers mutational signatures had functional defect HR, assessed by impaired RAD51 foci formation on treatment biopsy. Following rucaparib there no association Ki67 change deficiency. contrast, early circulating tumor dynamics rucaparib, ctDNA levels suppressed mutation-signature HR-deficient cancers. ad hoc analysis, induced expression interferon response genes majority TNBCs have repair, identifiable signature that may be targetable inhibitors.

Язык: Английский

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ESR1 mutations in breast cancer

Cancer, Год журнала: 2019, Номер 125(21), С. 3714 - 3728

Опубликована: Июль 18, 2019

The acquisition of ligand‐independent ESR1 mutations during aromatase inhibitor therapy in metastatic estrogen receptor (ER)‐positive breast cancer is a common mechanism hormonal resistance. Preclinical and clinical studies have demonstrated that can preexist primary tumors be enriched metastasis. Furthermore, express unique transcriptional profile favors tumor progression, suggesting selected may influence Several groups used sensitive detection methods using patient liquid biopsies to track or truncal somatic predict treatment outcome some these techniques eventually guide sequential options patients. Further development standardization mutation tracking circulating DNA ongoing. Clinically, patients with derive benefit when treated fulvestrant CDK4/6‐targeted therapies, but the more potent selective ER degraders and/or new targeted biotherapies are needed overcome endocrine‐resistant phenotype mutant–bearing tumors. In this review, we discuss mechanisms resistance dissemination as well for tracking, newly discovered potential therapeutic targets, implications treating

Язык: Английский

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Cell-Free DNA and Apoptosis: How Dead Cells Inform About the Living

Trends in Molecular Medicine, Год журнала: 2020, Номер 26(5), С. 519 - 528

Опубликована: Фев. 17, 2020

Язык: Английский

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Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples

Journal of Experimental & Clinical Cancer Research, Год журнала: 2020, Номер 39(1)

Опубликована: Май 27, 2020

Abstract In a large number of cancer types, treatment selection depends on the presence specific tumor biomarkers. Due to dynamic nature cancer, very often these predictive biomarkers are not uniformly present in all cells. Tumor heterogeneity represents indeed one main causes therapeutic failure, and its decoding remains major ongoing challenge field. Liquid biopsy is sampling analysis non-solid biological tissue through rapid non-invasive methods, which allows assessment real-time evolving landscape cancer. Samples can be obtained from blood most other bodily fluids. A blood-based liquid capture circulating cells leukocytes, as well tumor-derived nucleic acids. this review, we discuss current possibly future applications oncology, advantages limitations clinical practice. We specifically focused role tool metastatic patients.

Язык: Английский

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Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin

Genome Research, Год журнала: 2019, Номер 29(3), С. 418 - 427

Опубликована: Фев. 26, 2019

Cell-free DNA (cfDNA) in human plasma is a class of biomarkers with many current and potential future diagnostic applications. Recent studies have shown that cfDNA molecules are not randomly fragmented possess information related to their tissues origin. Pathologies causing death cells from particular result perturbations the relative distribution affected tissues. Such tissue-of-origin analysis particularly useful development liquid biopsies for cancer. It therefore value accurately determine contributions pool simultaneous manner. In this work, we report open chromatin regions, show characteristic fragmentation patterns reflected by sequencing coverage imbalance differentially phased fragment end signals. The latter refers differences read densities sequences corresponding orientation upstream downstream ends relation reference genome. preferentially occur tissue-specific regions where contributed into plasma. Quantitative analyses such signals allow measurement various toward pool. These findings were validated data obtained pregnant women, organ transplantation recipients, cancer patients. Orientation-aware has applications noninvasive prenatal testing, monitoring, biopsy.

Язык: Английский

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Liquid biopsies: Potential and challenges

International Journal of Cancer, Год журнала: 2020, Номер 148(3), С. 528 - 545

Опубликована: Июль 19, 2020

The analysis of tumor cells or cell products obtained from blood other body fluids ("liquid biopsy" [LB]) provides a broad range opportunities in the field oncology. Clinical application areas include early detection cancer recurrence, individual risk assessment and therapy monitoring. LB allows to portray entire disease as are released all metastatic primary sites, providing comprehensive real-time information on evolution, therapeutic targets mechanisms resistance therapy. Here, we focus most prominent markers, circulating (CTCs) tumor-derived DNA (ctDNA), patients with breast, prostate, lung colorectal cancer, four frequent types Europe. After brief introduction key technologies used detect CTCs ctDNA, discuss recent clinical studies these biomarkers for prognostication well prediction monitoring therapies. We also point out current methodological biological limitations that still hamper implementation into practice.

Язык: Английский

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