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Palbociclib and breast

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https://www.readbyqxmd.com/read/27890465/palbociclib-improves-survival-in-advanced-breast-cancer
#1
Talha Khan Burki
No abstract text is available yet for this article.
November 24, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27883943/targeted-therapy-for-breast-cancer-and-molecular-mechanisms-of-resistance-to-treatment
#2
REVIEW
Guowei Gu, Derek Dustin, Suzanne Aw Fuqua
In recent years, clinical trials investigating new drugs and therapeutic combinations have led to promising advances in breast cancer therapy. Subtyping breast cancers into hormone receptor (HR) positive, epidermal growth factor receptor (HER2) positive, and triple negative breast cancer (TNBC) is currently the basis of diagnosing and treating this disease. In addition to endocrine and HER2-targeted therapies in their respective subtypes, evidence from recent preclinical studies have shown several targetable pathways that overcome resistance in the clinical setting...
November 21, 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/27864574/enhancing-endocrine-therapy-combination-strategies-for-the-treatment-of-postmenopausal-hormone-receptor-positive-her2-advanced-breast-cancer
#3
REVIEW
Kathleen I Pritchard, Stephen K Chia, Christine Simmons, Deanna McLeod, Alexander Paterson, Louise Provencher, Daniel Rayson
: : Breast cancer (BC) is the most common malignancy in women worldwide, with approximately two-thirds having hormone receptor (HR)-positive tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3-kinase (PI3K), or cyclin-dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as first-line therapy for HR-positive, HER2-negative advanced BC with special consideration for the former in ET-naïve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as second-line therapy with special consideration in select first-line patients...
November 18, 2016: Oncologist
https://www.readbyqxmd.com/read/27849562/palbociclib-pd-0332991-a-selective-cdk4-6-inhibitor-restricts-tumour-growth-in-preclinical-models-of-hepatocellular-carcinoma
#4
Julien Bollard, Verónica Miguela, Marina Ruiz de Galarreta, Anu Venkatesh, C Billie Bian, Mark P Roberto, Victoria Tovar, Daniela Sia, Pedro Molina-Sánchez, Christie B Nguyen, Shigeki Nakagawa, Josep M Llovet, Yujin Hoshida, Amaia Lujambio
OBJECTIVE: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. DESIGN: The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo...
November 14, 2016: Gut
https://www.readbyqxmd.com/read/27843622/review-of-hormone-based-treatments-in-postmenopausal-patients-with-advanced-breast-cancer-focusing-on-aromatase-inhibitors-and-fulvestrant
#5
REVIEW
Iben Kümler, Ann S Knoop, Christina A R Jessing, Bent Ejlertsen, Dorte L Nielsen
BACKGROUND: Endocrine therapy constitutes a central modality in the treatment of oestrogen receptor (ER)-positive advanced breast cancer. PURPOSE: To evaluate the evidence for endocrine treatment in postmenopausal patients with advanced breast cancer focusing on the aromatase inhibitors, letrozole, anastrozole, exemestane and fulvestrant. METHODS: A review was carried out using PubMed. Randomised phase II and III trials reporting on ≥100 patients were included...
2016: ESMO Open
https://www.readbyqxmd.com/read/27785059/impact-of-palbociclib-combinations-on-treatment-of-advanced-estrogen-receptor-positive-human-epidermal-growth-factor-2-negative-breast-cancer
#6
REVIEW
Katalin Boér
Breast cancer is a heterogeneous disease with multiple subgroups based on clinical and molecular characteristics. For the largest subgroup of breast cancers, hormone receptor-positive/human epidermal growth factor 2 (HER2)-negative tumors, hormone treatment is the mainstay of therapy and is likely to result in significant improvement in disease outcomes. However, some of these cancers demonstrate de novo or acquired resistance to endocrine therapy. Despite intensive research to develop new strategies to enhance the efficacy of currently available treatment options for hormone receptor-positive breast cancer, progress has been slow, and there were few advances for a period of 10 years...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27775259/major-clinical-research-advances-in-gynecologic-cancer-in-2015
#7
REVIEW
Dong Hoon Suh, Miseon Kim, Hak Jae Kim, Kyung Hun Lee, Jae Weon Kim
In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed...
November 2016: Journal of Gynecologic Oncology
https://www.readbyqxmd.com/read/27765908/erps294-is-a-biomarker-of-ligand-or-mutational-er%C3%AE-activation-and-a-breast-cancer-target-for-cdk2-inhibition
#8
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 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27693931/mechanism-of-drug-resistance-in-relation-to-site-of-metastasis-meta-analyses-of-randomized-controlled-trials-in-advanced-breast-cancer-according-to-anticancer-strategy
#9
Saroj Niraula, Alberto Ocana
BACKGROUND: Breast cancer is heterogeneous at different levels: biologic subtypes, intratumoral areas, and sites of metastases. Randomized controlled trials (RCTs) classify metastatic sites as visceral or non-visceral, but this has little influence in treatment decisions, particularly in the absence of clinical urgency. Indeed, it is unclear if response to treatments differs among sites of metastases. PATIENTS AND METHODS: RCTs investigating 3 different anticancer strategies in metastatic breast cancer were identified: (1) new hormonal therapy, (2) new targeted therapies in hormone receptor positive tumours (everolimus or palbociclib), and (3) new anti-HER2 therapies...
September 20, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27648347/palbociclib-a-new-option-for-front-line-treatment-of-metastatic-hormone-receptor-positive-her2-negative-breast-cancer
#10
REVIEW
Harmony J Bowles, Kathryn L Clarke
No abstract text is available yet for this article.
November 2015: Journal of the Advanced Practitioner in Oncology
https://www.readbyqxmd.com/read/27634906/a-gene-expression-signature-of-retinoblastoma-loss-of-function-is-a-predictive-biomarker-of-resistance-to-palbociclib-in-breast-cancer-cell-lines-and-is-prognostic-in-patients-with-er-positive-early-breast-cancer
#11
Luca Malorni, Silvano Piazza, Yari Ciani, Cristina Guarducci, Martina Bonechi, Chiara Biagioni, Christopher D Hart, Roberto Verardo, Angelo Di Leo, Ilenia Migliaccio
Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib...
September 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27571378/chemoproteomic-evaluation-of-target-engagement-by-the-cyclin-dependent-kinase-4-and-6-inhibitor-palbociclib-correlates-with-cancer-cell-response
#12
Tyzoon K Nomanbhoy, Geeta Sharma, Heidi Brown, Jiangyue Wu, Arwin Aban, Subha Vogeti, Senait Alemayehu, Maria Sykes, Jonathan S Rosenblum, John W Kozarich
Palbociclib is a cyclin-dependent kinase (CDK) 4/CDK6 inhibitor approved for breast cancer that is estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative. We profiled palbociclib in cells either sensitive or resistant to the drug using an ATP/ADP probe-based chemoproteomics platform. Palbociclib only engaged CDK4 or CDK6 in sensitive cells. In resistant cells, no inhibition of CDK4 or CDK6 was observed, although the off-target profiles were similar in both cell types. Prolonged incubation of sensitive cells with the compound (24 h) resulted in the downregulation of additional kinases, including kinases critical for cell cycle progression...
September 27, 2016: Biochemistry
https://www.readbyqxmd.com/read/27556863/detection-of-esr1-mutations-in-circulating-cell-free-dna-from-patients-with-metastatic-breast-cancer-treated-with-palbociclib-and-letrozole
#13
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...
August 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27493617/palbociclib-from-bench-to-bedside-and-beyond
#14
REVIEW
Marcus Schmidt
Endocrine therapy is the cornerstone in the treatment of hormone receptor-positive breast cancer. During the last decades, much has been learned about the subtle regulation of the cell cycle. In this tightly regulated network, cyclin-dependent kinases (CDKs) play a pivotal role. Especially CDK4/6 is the key regulator of the G1-S transition. Realizing its importance, specific inhibitors of CDK4/6 were developed. The drug most advanced in clinical development in this class is palbociclib (PD 0332991). This review highlights preclinical data and brings into focus early clinical trials that led to an accelerated approval by the US Food and Drug Administration (FDA) as first-line treatment in combination with letrozole in advanced hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer...
June 2016: Breast Care
https://www.readbyqxmd.com/read/27493616/palbociclib-first-cdk4-6-inhibitor-in-clinical-practice-for-the-treatment-of-advanced-hr-positive-breast-cancer
#15
REVIEW
Johannes Ettl
Palbociclib is the first inhibitor of the cyclin-dependent kinases (CDK) 4 and 6 to be introduced into clinical practice. Preclinical investigations led to its clinical development in advanced hormone receptor (HR)-positive breast cancer. To date, 2 significant clinical trials have been fully published. In this article, the results of these trials and their clinical relevance for the management of HR-positive advanced breast cancer are discussed.
June 2016: Breast Care
https://www.readbyqxmd.com/read/27493615/clinical-development-of-the-cdk4-6-inhibitors-ribociclib-and-abemaciclib-in-breast-cancer
#16
REVIEW
Romualdo Barroso-Sousa, Geoffrey I Shapiro, Sara M Tolaney
Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development...
June 2016: Breast Care
https://www.readbyqxmd.com/read/27488531/an-in-vivo-reporter-to-quantitatively-and-temporally-analyze-the-effects-of-cdk4-6-inhibitor-based-therapies-in-melanoma
#17
Jessica L F Teh, Timothy J Purwin, Evan J Greenawalt, Inna Chervoneva, Allison Goldberg, Michael A Davies, Andrew E Aplin
Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved...
September 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27472462/effective-combination-therapies-in-preclinical-endocrine-resistant-breast-cancer-models-harboring-er-mutations
#18
Brendon Ladd, Anne Marie Mazzola, Teeru Bihani, Zhongwu Lai, James Bradford, Michael Collins, Evan Barry, Anne U Goeppert, Hazel M Weir, Kelly Hearne, Jonathan G Renshaw, Morvarid Mohseni, Elaine Hurt, Sanjoo Jalla, Haifeng Bao, Robert Hollingsworth, Corinne Reimer, Michael Zinda, Stephen Fawell, Celina M D'Cruz
Although endocrine therapy is successfully used to treat patients with estrogen receptor (ER) positive breast cancer, a substantial proportion of this population will relapse. Several mechanisms of acquired resistance have been described including activation of the mTOR pathway, increased activity of CDK4 and activating mutations in ER. Using a patient derived xenograft model harboring a common activating ER ligand binding domain mutation (D538G), we evaluated several combinatorial strategies using the selective estrogen receptor degrader (SERD) fulvestrant in combination with chromatin modifying agents, and CDK4/6 and mTOR inhibitors...
July 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27447842/the-mammary-ducts-create-a-favourable-microenvironment-for-xenografting-of-luminal-and-molecular-apocrine-breast-tumours
#19
Elodie Richard, Thomas Grellety, Valerie Velasco, Gaetan MacGrogan, Hervé Bonnefoi, Richard Iggo
There is a paucity of models for hormone receptor positive (HR+) breast cancer because of the difficulty of establishing xenografts from these tumours. We show that this obstacle can be overcome by injecting human tumour cells directly into the mammary ducts of immunodeficient mice. Tumours from 31 patients were infected overnight with a lentiviral vector expressing tdTomato and injected through the nipple into the mammary ducts of NOD-SCID-ILR2RG-/- mice. Tumours formed in the mice in 77% of cases after the first injection (6/8 luminal A; 15/20 luminal B and 3/3 molecular apocrine)...
July 22, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27429659/cdk4-6-inhibition-in-luminal-breast-cancer
#20
Simon Peter Gampenrieder, Gabriel Rinnerthaler, Richard Greil
Endocrine therapy represents the basis for the treatment of estrogen receptor-positive breast cancer, but several tumors harbor intrinsic resistance and acquired resistance to endocrine therapy is inevitable in metastatic disease. Combination strategies of endocrine therapy with targeted agents are aimed to overcome endocrine resistance. The selective CDK4/6 inhibitor palbociclib has shown promising results in metastatic luminal breast cancer when used in combination with endocrine therapy both in the first-line setting as in pretreated women...
2016: Memo
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