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Palbociclib and breast

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https://www.readbyqxmd.com/read/29236940/polyclonal-rb1-mutations-and-acquired-resistance-to-cdk-4-6-inhibitors-in-patients-with-metastatic-breast-cancer
#1
R Condorelli, L Spring, J O'Shaughnessy, L Lacroix, C Bailleux, V Scott, J Dubois, R J Nagy, R B Lanman, A J Iafrate, F Andre, A Bardia
Background: While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known. Patients and methods: We identified patients who had pre and post genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors...
December 11, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29236235/potential-biomarkers-of-cdk4-6-inhibitors-in-hormone-receptor-positive-advanced-breast-cancer
#2
REVIEW
Hehui Fang, Doudou Huang, Fang Yang, Xiaoxiang Guan
PURPOSE: Cyclin D/cyclin-dependent kinase 4/6 (CDK4/6) complex inhibitors have recently been proven effective when combined with endocrine therapy in clinical trials. However, the clinical benefit from CDK4/6 inhibitor varied from different patients. In order to optimize the clinical application of CDK4/6 inhibitors, this review focuses on the potential biomarkers applicable to identify patients who will benefit the most from CDK4/6 inhibition. METHODS: We have summarized the clinical trials about addition of CDK4/6 inhibitors to endocrine therapy and reviewed literature currently available on the potential biomarkers in predicting efficacy of CDK4/6 inhibitors...
December 13, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29234249/mechanisms-of-resistance-to-cdk4-6-inhibitors-in-breast-cancer-and-potential-biomarkers-of-response
#3
REVIEW
Cristina Guarducci, Martina Bonechi, Giulia Boccalini, Matteo Benelli, Emanuela Risi, Angelo Di Leo, Luca Malorni, Ilenia Migliaccio
Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting...
October 2017: Breast Care
https://www.readbyqxmd.com/read/29218462/a-single-institution-experience-with-palbociclib-toxicity-requiring-dose-modifications
#4
Jun Gong, May Cho, Kim Wai Yu, James Waisman, Yuan Yuan, Joanne Mortimer
PURPOSE: Since the widespread implementation of adding palbociclib to endocrine therapy in clinical practice, myelosuppression is becoming increasingly recognized as a toxicity that may lead to dose modification. We aimed to characterize toxicities observed with palbociclib resulting in dose modifications and prescriber preferences in modifying palbociclib dosage in response to treatment-related toxicities outside the context of a clinical trial. METHODS: We conducted a single institution, retrospective study of treatment-related adverse events (AEs) resulting in modifications in dose and schedule and the methods by which dose modifications occurred in patients with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer receiving palbociclib and endocrine therapy...
December 7, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29191840/macrocytosis-and-dysplastic-anemia-is-associated-with-the-cyclin-dependent-kinase-4-6-inhibitor-palbociclib-in-metastatic-breast-cancer
#5
Jesus Anampa, Tamanna Haque, Irina Murakhovskaya, Yanhua Wang, Kimo Bachiashvili, Cristian Papazoglu, Kith Pradhan, Ulrich G Steidl, Joseph A Sparano, Amit Verma
No abstract text is available yet for this article.
November 30, 2017: Haematologica
https://www.readbyqxmd.com/read/29164917/efficacy-and-safety-of-palbociclib-in-heavily-pretreated-patients-with-hr-her2-%C3%A2-metastatic-breast-cancer
#6
Marija Ban, Branka Petrić Miše, Ana Majić, Ivanka Dražić, Eduard Vrdoljak
AIM: CDK4/6 inhibitors in the first and second treatment line in patients with HR+/HER2- metastatic breast cancer (mBC) in combination with hormonal therapy improve progression free survival. Role of CDK4/6 inhibitors in further treatment lines remains unclear. METHODS: Retrospective analysis of 24 HR+/HER2- heavily pretreated mBC patients is presented. RESULTS: A total of 58.3% patients achieved stable disease. No objective response was observed...
November 22, 2017: Future Oncology
https://www.readbyqxmd.com/read/29162134/serum-thymidine-kinase-1-activity-as-a-pharmacodynamic-marker-of-cyclin-dependent-kinase-4-6-inhibition-in-patients-with-early-stage-breast-cancer-receiving-neoadjuvant-palbociclib
#7
Nusayba Bagegni, Shana Thomas, Ning Liu, Jingqin Luo, Jeremy Hoog, Donald W Northfelt, Matthew P Goetz, Andres Forero, Mattias Bergqvist, Jakob Karen, Magnus Neumüller, Edward M Suh, Zhanfang Guo, Kiran Vij, Souzan Sanati, Matthew Ellis, Cynthia X Ma
BACKGROUND: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials...
November 21, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29158285/neoadjuvant-palbociclib-on-er-breast-cancer-n007-clinical-response-and-endopredict-value
#8
Louis Wc Chow, Satoshi Morita, Christopher Yc Chow, Wai Kuen Ng, Masakazu Toi
To test the efficacy of neoadjuvant palbociclib therapy and to evaluate its impact on cell cycle arrest and changes in EndoPredict (EP) scores before and after treatment. Postmenopausal women with histologically proven ER+ve, HER2-ve invasive breast cancer, 2cm or greater, were enrolled in an open-label, single arm study. Twenty eligible patients were given letrozole 2.5mg per day together with palbociclib 125mg per day for 3 out of 4 weeks in repeated cycles for 16 weeks (4 cycles) before surgery. The primary end-points were clinical response rates (cRR) and preoperative endocrine prognostic index (PEPI)...
November 20, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29153774/palbociclib-induced-thrombotic-microangiopathy-in-metastatic-breast-cancer-patient-surviving-for-18-years-case-report-and-review-of-the-literature
#9
Hanan Raiss, Julien Péron, Sophie Tartas, Véronique Trillet-Lenoir, Gilles Freyer, Hassan Errihani
No abstract text is available yet for this article.
October 7, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29137354/erps294-is-a-biomarker-of-ligand-or-mutational-er%C3%AE-activation-and-a-breast-cancer-target-for-cdk2-inhibition
#10
Gary K Scott, David Chu, Ravneet Kaur, Julia Malato, Daniel E Rothschild, Katya Frazier, Serenella Eppenberger-Castori, Byron Hann, Ben Ho Park, Christopher C Benz
ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29119080/metastatic-breast-cancer-endocrine-therapy-landscape-reshaped
#11
REVIEW
Mohamad Adham Salkeni, Samantha June Hall
Endocrine therapy (ET) of hormone receptor (HR)-positive and human epidermal growth factor receptor 2-(HER2)-negative metastatic breast cancer (MBC) historically focused on estrogen deprivation and antagonism. The identification of several intracellular pathways promoting resistance to antiestrogen therapy led to the introduction of novel endocrine drug combinations that reformed treatment schema and expanded therapeutic options. There is no doubt that efforts to overcome or delay resistance to ET are fruiting, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors such as palbociclib and ribociclib, and mechanistic target of rapamycin inhibitors such as everolimus...
October 2017: Avicenna Journal of Medicine
https://www.readbyqxmd.com/read/29103175/efficacy-and-safety-in-older-patient-subsets-in-studies-of-endocrine-monotherapy-versus-combination-therapy-in-patients-with-hr-her2-%C3%A2-advanced-breast-cancer-a-review
#12
REVIEW
Rachel A Freedman, Sara M Tolaney
PURPOSE: Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population. METHODS: We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treated with ET ± targeted agents...
November 4, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29078212/-current-status-of-targeted-treatment-in-breast-cancer
#13
Katharina Seiffert, Barbara Schmalfeldt, Volkmar Müller
Within the last years, significant improvements have been achieved in breast cancer treatment, particularly with the development of targeted therapies. Major progress has been made in identifying the drivers malignant growth in oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of the cyclin-dependent kinases CDK4 and CDK6 like palbociclib and inhibitors of mTOR substantially improve progression-free survival...
November 2017: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/29027483/cdk4-6-blockade-in-breast-cancer-current-experience-and-future-perspectives
#14
Dimitrios Zardavas, Noam Pondé, Konstantinos Tryfonidis
Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer...
October 23, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28994315/first-line-treatment-disruption-among-post-menopausal-women-with-hr-her2-metastatic-breast-cancer-a-retrospective-us-claims-study
#15
Derek H Tang, Nanxin Li, Ella X Du, Miranda Peeples, Lihao Chu, Jipan Xie, Victoria Barghout
OBJECTIVE: This study assessed disruption of first-line treatments initiated after the approval of the first CDK 4/6 inhibitor, palbociclib, among post-menopausal women with HR+/HER2- metastatic breast cancer (mBC) in the US. METHODS: Post-menopausal women with HR+/HER2- mBC who initiated first-line endocrine therapy or chemotherapy (index therapy) between February 3, 2015 (palbociclib approval date) and February 29, 2016 (end of data) were identified from the Symphony Source Lx database...
October 27, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28978004/detection-of-esr1-mutations-in-circulating-cell-free-dna-from-patients-with-metastatic-breast-cancer-treated-with-palbociclib-and-letrozole
#16
Rekha Gyanchandani, Karthik J Kota, Amruth R Jonnalagadda, Tanya Minteer, Beth A Knapick, Steffi Oesterreich, Adam M Brufsky, Adrian V Lee, Shannon L Puhalla
ESR1 mutations are frequently acquired in hormone-resistant metastatic breast cancer (MBC). CDK4/6 inhibition along with endocrine therapy is a promising strategy in hormone receptor-positive MBC. However, the incidence and impact of ESR1 mutations on clinical outcome in patients treated with CDK4/6 inhibitors have not been defined. In this study, we evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with MBC undergoing palbociclib and letrozole therapy. Four common ESR1 mutations (D538G, Y537C, Y537N, and Y537S) were analyzed in serial blood draws using ddPCR...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28974548/selective-androgen-receptor-modulator-rad140-inhibits-the-growth-of-androgen-estrogen-receptor-positive-breast-cancer-models-with-a-distinct-mechanism-of-action
#17
Ziyang Yu, Suqin He, Dannie Wang, Hitisha K Patel, Chris P Miller, Jeff Brown, Gary Hattersley, Jamal C Saeh
PURPOSE: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer eliciting favorable response. The present study evaluates the activity and efficacy of the oral selective AR modulator (SARM) RAD140 in in vivo and in vitro models of AR/ER+ breast cancer. EXPERIMENTAL DESIGN: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity...
October 3, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28961554/cdk4-6-inhibition-in-early-and-metastatic-breast-cancer-a-review
#18
REVIEW
A F de Groot, C J Kuijpers, J R Kroep
Breast cancer (BC) is responsible for 14% of cancer-related deaths in women [1]. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of selective drugs, offering an effective and tolerable treatment. CDK4/6 inhibitors induce cell cycle arrest in the G1 phase, and may thereby prevent tumour progression. Three CDK4/6 inhibitors have been tested in clinical BC trials: palbociclib, ribociclib, and abemaciclib. The Food and Drug Administration (FDA) and European Commission (EMA) have approved palbociclib for the treatment of patients HR+ HER2- locally advanced or metastatic BC (aBC) in combination with an aromatase inhibitor as initial therapy in postmenopausal women or in combination with fulvestrant in women who have received prior endocrine therapy...
November 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28947566/cytoplasmic-cyclin-e-mediates-resistance-to-aromatase-inhibitors-in-breast-cancer
#19
Iman Doostan, Cansu Karakas, Mehrnooh Kohansal, Kwang Hui Low, Matthew J Ellis, John A Olson, Vera Suman, Kelly Hunt, Stacy Moulder-Thompson, Khandan Keyomarsi
PURPOSE: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect...
September 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28947133/palbociclib-induced-autophagy-and-senescence-in-gastric-cancer-cells
#20
Claudio A Valenzuela, Leandro Vargas, Valentina Martinez, Sindy Bravo, Nelson E Brown
Targeting cyclin D-CDK4/6 kinase complexes has recently been shown to increase the survival of breast cancer patients with estrogen receptor positive breast tumors. Based on these outcomes, CDK4/6 inhibitors are currently being tested, alone o in combination with other drugs, in the treatment of other malignancies characterized by hyper-activation of cyclin D-CDK4/6 complexes. Nonetheless, a better understanding of the cellular processes that are implemented in response to CDK4/6 inhibition is necessary to expand the therapeutic window and confront the development of drug resistance...
November 15, 2017: Experimental Cell Research
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