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CDk4/6 and Breast

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https://www.readbyqxmd.com/read/28741274/cyclin-dependent-kinase-4-6-inhibitors-in-breast-cancer-palbociclib-ribociclib-and-abemaciclib
#1
REVIEW
Dorota Kwapisz
PURPOSE: The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression and its dysregulation is an important contributor to endocrine therapy resistance. CDK4/6 inhibitors trigger cell cycle arrest in Rb protein (pRb)-competent cells. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising results of efficacy and manageable safety profiles. The main objective of this review is to discuss preclinical and clinical data to date, and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in breast cancer...
July 24, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28706010/clinical-management-of-potential-toxicities-and-drug-interactions-related-to-cyclin-dependent-kinase-4-6-inhibitors-in-breast-cancer-practical-considerations-and-recommendations
#2
REVIEW
Laura M Spring, Mark L Zangardi, Beverly Moy, Aditya Bardia
Aberrations of the cell cycle are pervasive in cancer, and selective cell cycle inhibition of cancer cells is a target of choice for a number of novel cancer therapeutics. Cyclin-dependent kinases (CDKs) are key regulatory enzymes that control cell cycle transitions and the commitment to cell division. Palbociclib and ribociclib are both orally active, highly selective reversible inhibitors of CDK4 and CDK6 that are approved by the U.S. Food and Drug Administration (FDA) for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies...
July 13, 2017: Oncologist
https://www.readbyqxmd.com/read/28699811/fatigue-alopecia-and-stomatitis-among-patients-with-breast-cancer-receiving-cyclin-dependent-kinase-4-and-6-inhibitors-a-systematic-review-and-meta-analysis
#3
Shaimaa Lasheen, Kyrillus S Shohdy, Loay Kassem, Omar Abdel-Rahman
BACKGROUND: Cyclin-dependent kinase (CDK) inhibitors emerge as efficacious agents in hormone positive metastatic breast cancer with more acceptable toxicity profiles than cytotoxic chemotherapy. However, some adverse effects such as fatigue, alopecia and stomatitis, vastly concern patients. METHODS: The search was conducted in PubMed, American Society of Clinical Oncology meeting library, European Society for Medical Oncology meeting abstract, and the San Antonio meeting abstract databases...
July 12, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28697311/breast-cancer-treatment-induced-cardiotoxicity
#4
Samuel Martel, Christian Maurer, Matteo Lambertini, Noam Pondé, Evandro de Azambuja
Breast cancer is the most frequent cancer affecting women worlwide. In every setting, the majority of women are treated with an evergrowing arsenal of therapeutic agents that have greatly improved their outcomes. However, these therapies can also be associated with significant adverse events. Areas covered: This review aims to thoroughly describe the current state of the evidence regarding the potential cardiotoxicity of agents commonly used in the treatment of breast cancer. These include chemotherapeutic agents, anti-HER2 therapies and CDK4/6 and mTOR inhibitors...
July 11, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28685610/circumvent-hesitancy-between-cdk4-6-and-mtor-inhibitors-in-second-line-treatment-of-hr-erb2-metastatic-breast-cancer
#5
Elie El Rassy, Pamela Abdayem, Joseph Kattan
No abstract text is available yet for this article.
July 7, 2017: Future Oncology
https://www.readbyqxmd.com/read/28680952/a-review-of-fulvestrant-in-breast-cancer
#6
REVIEW
Mark R Nathan, Peter Schmid
Fulvestrant is a selective estrogen receptor degrader that binds, blocks and degrades the estrogen receptor (ER), leading to complete inhibition of estrogen signaling through the ER. This review article further explains the mechanism of action of the drug and goes on to review the trials carried out to optimize its dosing. Multiple trials have been undertaken to compare fulvestrant with other endocrine treatments, and results have shown it to have similar efficacy to anastrozole, tamoxifen and exemestane at 250 mg every 28 days...
2017: Oncology and Therapy
https://www.readbyqxmd.com/read/28669712/lessons-in-precision-oncology-from-neoadjuvant-endocrine-therapy-trials-in-er-breast-cancer
#7
Matthew J Ellis
For post-menopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer neoadjuvant endocrine therapy (NET) is an under-utilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates. Individual responses to endocrine therapy can also be used to tailor systemic treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify patients at low risk of relapse after NET so that adjuvant chemotherapy can safely be avoided. In a recent validation study, patients with pathological stage 1 or 2A breast cancers with a Ki67 value of 2...
June 29, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/28657360/a-current-and-comprehensive-review-of-cyclin-dependent-kinase-%C3%A4-nhibitors-for-the-treatment-of-metastatic-breast-cancer
#8
Burak Bilgin, Mehmet An Sendur, Didem Şener Dede, Muhammed Bülent Akıncı, Bülent Yalçın
BACKGROUND: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinases (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates. SCOPE: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC)...
June 28, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28653662/cdk4-6-and-autophagy-inhibitors-synergistically-induce-senescence-in-rb-positive-cytoplasmic-cyclin-e-negative-cancers
#9
Smruthi Vijayaraghavan, Cansu Karakas, Iman Doostan, Xian Chen, Tuyen Bui, Min Yi, Akshara S Raghavendra, Yang Zhao, Sami I Bashour, Nuhad K Ibrahim, Meghan Karuturi, Jing Wang, Jeffrey D Winkler, Ravi K Amaravadi, Kelly K Hunt, Debu Tripathy, Khandan Keyomarsi
Deregulation of the cell cycle machinery is a hallmark of cancer. While CDK4/6 inhibitors are FDA approved (palbociclib) for treating advanced estrogen receptor-positive breast cancer, two major clinical challenges remain: (i) adverse events leading to therapy discontinuation and (ii) lack of reliable biomarkers. Here we report that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumours in vivo...
June 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28652278/palbociclib-combined-with-fulvestrant-in-premenopausal-women-with-advanced-breast-cancer-and-prior-progression-on-endocrine-therapy-paloma-3-results
#10
Sibylle Loibl, Nicholas C Turner, Jungsil Ro, Massimo Cristofanilli, Hiroji Iwata, Seock-Ah Im, Norikazu Masuda, Sherene Loi, Fabrice André, Nadia Harbeck, Sunil Verma, Elizabeth Folkerd, Kathy Puyana Theall, Justin Hoffman, Ke Zhang, Cynthia Huang Bartlett, Mitchell Dowsett
BACKGROUND: The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET). PATIENTS AND METHODS: One hundred eight premenopausal endocrine-refractory women ≥18 years with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) ± goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo...
June 26, 2017: Oncologist
https://www.readbyqxmd.com/read/28649895/the-safety-and-efficacy-of-palbociclib-in-the-treatment-of-metastatic-breast-cancer
#11
Johannes Ettl, Nadia Harbeck
Palbociclib (Ibrance®) is the first-in-class CDK4/6 inhibitor which has been introduced into clinical practice for the treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). It is an orally administered drug, which acts by selectively inhibiting cyclin-dependant kinases CDK4 and CDK6. Given together with anti-estrogens like letrozole and fulvestrant it enhances the antiproliferative effect of these drugs without compromising the favorable toxicity profile of endocrine therapy...
July 12, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28626036/treating-er-breast-cancer-with-cdk4-6-inhibitors
#12
(no author information available yet)
Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment.
June 16, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28620137/biological-specificity-of-cdk4-6-inhibitors-dose-response-relationship-in-vivo-signaling-and-composite-response-signature
#13
Erik S Knudsen, Jack Hutcheson, Paris Vail, Agnieszka K Witkiewicz
Recently developed potent and selective CDK4/6 inhibitors fall into two classes based on structure and toxicity profiles in clinical studies. One class, exemplified by palbociclib and ribociclib, exhibits neutropenia as a dose-limiting toxicity and requires discontinuous dosing. In contrast, the structurally distinct CDK4/6 inhibitor abemaciclib is dosed continuously, and has diarrhea and fatigue as dose-limiting toxicities. In preclinical models, palbociclib has been extensively studied and induces cell cycle inhibition in an RB-dependent manner...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28606920/single-cell-dynamics-determines-response-to-cdk4-6-inhibition-in-triple-negative-breast-cancer
#14
Uzma Asghar, Alexis R Barr, Ros Cutts, Matthew Beaney, Irina S Babina, Deepak Sampath, Jennifer Giltnane, Jennifer A Lacap, Lisa Crocker, Amy Young, Alex Pearson, Maria Teresa Herrera-Abreu, Chris Bakal, Nicholas C Turner
Purpose: Triple negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes, and investigated mechanisms of sensitivity. <p>Experimental design: A panel of cell lines representative of TNBC were tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single cell analysis in conjunction with time-lapse imaging.</p> <p>Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro [p<0...
June 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28585619/-palbociclib-combinations-as-new-therapeutic-strategies-in-the-treatment-of-hr-her2-advanced-breast-cancer
#15
Katalin Boér
Until recently, the only endocrine agents used to treat HR+/HER2- advanced breast cancers were tamoxifen, aromatase inhibitors and fulvestrant, although a substantial proportion of patients relapse on these standard therapies. Intensive research has been conducted to develop new strategies to overcome endocrine resistance and to enhance the efficacy of endocrine treatments by combining hormone therapy with other targeted treatment approaches. The development of selective CDK4/6 inhibitors and the introduction of palbociclib, the first molecule in this class in clinical practice, represent an important step in the treatment of HR+ advanced breast cancer...
June 6, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28580868/cell-cycle-therapeutics-come-of-age
#16
Matthew Ingham, Gary K Schwartz
The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy...
June 3, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28566333/cdk4-phosphorylation-status-and-a-linked-gene-expression-profile-predict-sensitivity-to-palbociclib
#17
Eric Raspé, Katia Coulonval, Jaime M Pita, Sabine Paternot, Françoise Rothé, Laure Twyffels, Sylvain Brohée, Ligia Craciun, Denis Larsimont, Véronique Kruys, Flavienne Sandras, Isabelle Salmon, Steven Van Laere, Martine Piccart, Michail Ignatiadis, Christos Sotiriou, Pierre P Roger
Cyclin D-CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER-positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4...
May 31, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28560460/synthetic-lethal-interaction-of-cdk-inhibition-and-autophagy-inhibition-in-human-solid-cancer-cell-lines
#18
Yoshinari Okada, Shunsuke Kato, Yasuhiro Sakamoto, Takayuki Oishi, Chikashi Ishioka
Cell cycle control is a promising target in cancer treatments, and some small-molecule cyclin-dependent kinase (CDK) inhibitors have exhibited clinical effectiveness. However, no biomarkers predictive of efficacy have been developed. Recent studies have revealed that CDK inhibitor (CKI) proteins, such as p27 and p16, also induced cytoprotective autophagy in cancer cells. However, it is unclear whether small-molecule CKIs also induce autophagy in solid tumors, as induced autophagy promotes cancer cell survival...
July 2017: Oncology Reports
https://www.readbyqxmd.com/read/28559771/cdk4-6-inhibitors-in-the-treatment-of-metastatic-breast-cancer
#19
Johannes Ettl, Jens Huober, Diana Lüftner, Frederik Marmé, Rachel Würstlein
No abstract text is available yet for this article.
May 2017: Breast Care
https://www.readbyqxmd.com/read/28533223/monarch-1-a-phase-2-study-of-abemaciclib-a-cdk4-and-cdk6-inhibitor-as-a-single-agent-in-patients-with-refractory-hr-her2-metastatic-breast-cancer
#20
Maura N Dickler, Sara Tolaney, Hope S Rugo, Javier Cortés, Veronique Dieras, Debra A Patt, Hans Wildiers, Clifford A Hudis, Joyce A O'Shaughnessy, Esther Zamora, Denise Yardley, Martin Frenzel, Andrew G Koustenis, José Baselga
<br />The phase 2 MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC). <br /><br />Experimental Design: <br />MONARCH 1 was a phase 2 single arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible...
May 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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