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Elie El Rassy, Ziad Bakouny, Tarek Assi, Joseph Kattan
AIM: To determine which of the CDK4/6 inhibitors is the optimal treatment in metastatic luminal breast cancer. MATERIALS & METHODS: A network meta-analysis using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The associations of aromatase inhibitor with ribociclib, palbociclib and abemaciclib were similar in efficacy. Palbociclib-based regimen was associated with significantly lower treatment discontinuation rates compared with the other approved drugs in this indication...
March 12, 2018: Future Oncology
Jasmine L Gowarty, Jon D Herrington
A promising drug, palbociclib, received accelerated approval as a first line treatment when used with the aromatase inhibitor, letrozole, for postmenopausal women with hormone receptor positive advanced or metastatic breast cancer. We report a case of a patient who presented with febrile neutropenia, grade 3 stomatitis with lip swelling, periorbital edema, and transaminitis while on palbociclib and verapamil. Labs normalized upon discontinuation of verapamil and our patient was able to continue treatment with palbociclib and letrozole...
January 1, 2018: Journal of Oncology Pharmacy Practice
Songlin Liu, Yunhong Tang, Xianrui Yuan, Dun Yuan, Junyu Liu, Buyan Li, Yifeng Li
Genomic studies have established a set of three core-signaling pathways, receptor tyrosine kinase (RTK), p53 and retinoblastoma (Rb) signaling pathways, contributing glioblastoma (GBM) and revealed that dysregulation of at least two pathways is required for GBM progression. In the present study, we investigate efficacy of combination of palbociclib, cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, and erlotinib, epidermal growth factor receptor (EGFR) inhibitor in GBM cell systems with different p53 status. Cell proliferation and colony formation assays showed that the combination treatment synergistically suppressed GBM cell proliferation...
March 6, 2018: Investigational New Drugs
Ben O'Leary, Sarah Hrebien, James P Morden, Matthew Beaney, Charlotte Fribbens, Xin Huang, Yuan Liu, Cynthia Huang Bartlett, Maria Koehler, Massimo Cristofanilli, Isaac Garcia-Murillas, Judith M Bliss, Nicholas C Turner
CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3...
March 1, 2018: Nature Communications
Sadakatsu Ikeda, Igor F Tsigelny, Åge A Skjevik, Yuko Kono, Michel Mendler, Alexander Kuo, Jason K Sicklick, Gregory Heestand, Kimberly C Banks, AmirAli Talasaz, Richard B Lanman, Scott Lippman, Razelle Kurzrock
BACKGROUND: Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. MATERIALS AND METHODS: We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated...
February 27, 2018: Oncologist
Christian Maurer, Arlindo R Ferreira, Samuel Martel, Matteo Lambertini, Noam Pondé, Philippe Aftimos, Evandro de Azambuja, Martine Piccart
This is a single center retrospective analysis of patients with hormone receptor-positive, HER2-negative metastatic breast cancer progressing after ≥ 4 treatment lines treated with palbociclib in combination with endocrine therapy within a compassionate use program. Thirty-four patients were included between 10/2015 and 02/2017, the majority (82.4%) being previously treated with mTOR inhibitors. Disease control rate was 52.9% and 24.4% at week 12 and 24. Overall progression-free survival was 3.1 months with no difference between mTOR inhibitor-pretreated (3...
February 20, 2018: Breast: Official Journal of the European Society of Mastology
Allan Ramos-Esquivel, Hellen Hernández-Steller, Marie-France Savard, Denis Ulises Landaverde
BACKGROUND: To compare the efficacy and toxicity of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and nonsteroidal aromatase inhibitors (AI) versus AI alone as first-line therapy for patients with advanced hormone receptor-positive breast cancer. MATERIALS AND METHODS: Phase III randomized clinical trials (RCT) were identified after a systematic review of electronic databases. A random-effect model was used to determine the pooled hazard ratio (HR) for progression-free survival (PFS) using the inverse-variance method...
February 22, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
Yubing Zhou, Jacson K Shen, Zujiang Yu, Francis J Hornicek, Quancheng Kan, Zhenfeng Duan
Overexpression and/or hyperactivation of cyclin-dependent kinase 4 (CDK4) has been found in many types of human cancers, and a CDK4 specific inhibitor, palbociclib, has been recently approved by the FDA for the treatment of breast cancer. However, the expression and the therapeutic potential of CDK4 in osteosarcoma remain unclear. In the present study, CDK4 was found to be highly expressed in human osteosarcoma tissues and cell lines as compared with normal human osteoblasts. Elevated CDK4 expression correlated with metastasis potential and poor prognosis in osteosarcoma patients as determined by immunohistochemical analysis in a human osteosarcoma tissue microarray (TMA)...
February 13, 2018: Biochimica et Biophysica Acta
Se Jin Oh, Hanbyoul Cho, Suhyun Kim, Kyung Hee Noh, Kwon-Ho Song, Hyo-Jung Lee, Seon Rang Woo, Suyeon Kim, Chel Hun Choi, Joon-Yong Chung, Stephen M Hewitt, Jae-Hoon Kim, Seungki Baek, Kyung-Mi Lee, Cassian Yee, Hae-Chul Park, Tae Woo Kim
Immune editing caused by anti-tumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOGhigh cancer stem cell-like (CSC-like) cells. In the current study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immune-edited cells and upregulates NANOG by hyperactivating the Cyclin D1-CDK4/6 axis. The SCP3-Cyclin D1-CDK4/6 axis was preserved across various types of human cancer, and correlated negatively with progression-free survival of cervical cancer patients...
February 6, 2018: Cancer Research
Daguang Wang, Yabin Sun, Wei Li, Fei Ye, Yang Zhang, Yuchen Guo, David Y Zhang, Jian Suo
PD0332991 (palbociclib/Ibrance®) is a cyclin-dependent kinase (CDK)4/6 inhibitor that has recently been approved for the treatment of estrogen receptor‑positive advanced breast cancer. The present study investigated the antiproliferative effects of PD0332991 on gastric cancer (GC) cells and the underlying molecular mechanisms. The activity of PD0332991 was tested in several GC cell lines, including AGS, KATO‑Ⅲ, NCI‑N87 and HS746T. Growth inhibitory activity of PD0332991, alone or in combination with fluorouracil (5‑FU), was measured by MTT assay...
February 6, 2018: International Journal of Molecular Medicine
Brian Smith, Yi-Hsin Hsu, Rene Flores, Mihai Gagea, Suzanne Craig, Mien-Chie Hung
c-MET inhibitor, crizotinib, and CDK 4/6 inhibitor, palbociclib, have been evaluated in combination as cancer treatment in vitro. Because the toxicological data for the combination of these drugs is limited, we investigated the toxicity of the crizotinib and palbociclib combination in 80 ICR (CD-1) mice (average age = ~20 weeks). Treatments were arranged as a 2 × 2 × 2 factorial and included sex (female vs. male), crizotinib (0 or 4 mg), and palbociclib (0 or 1 mg). Drugs were administered to mice by oral gavage 24 hours (n = 40) and 7 days (n = 40) prior to the collection of blood and tissue samples to determine serum chemistry, hematology, and histopathology...
2018: American Journal of Cancer Research
Minghui Liu, Hongyu Liu, Jun Chen
An uncontrolled cell cycle is an obvious marker of tumor cells. The G1‑S phase is an important restriction point in the normal cell cycle, but in cancer cells the restriction function is reduced, leading to uncontrolled cell proliferation. Two cyclin‑dependent kinases (CDKs), CDK4 and CDK6, play a crucial role in the G1‑S phase transition. Inhibitors of CDK4/6 are presently the subjects of numerous studies, and PD 0332991, an inhibitor of CDK4/6, has been used to treat hormone receptor (HR)‑positive, advanced‑stage breast cancer...
January 19, 2018: Oncology Reports
Sri Lakshmi Hyndavi Yeruva, Mehrbod Som Javadi, Vered Stearns
No abstract text is available yet for this article.
December 21, 2017: Clinical Breast Cancer
Tomasz Sarosiek
Cyclin-dependent kinases (CDKs) are a family of enzyme proteins present in cell nuclei that regulate the various stages of the cell cycle. They act as proto-oncogens, and increased expression of some of these proteins (CDK4 and CDK6) is observed in breast cancer cells and associated with decreased sensitivity to anti-estrogen therapy. CDK inhibitors are chemicals that inhibit the enzymatic activity of specific CDKs. Currently three drugs in this group are available on the market and are registered for the treatment of advanced HR-positive, HER2-negative breast cancer...
January 23, 2018: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
H S Rugo, V Diéras, K A Gelmon, R S Finn, D J Slamon, M Martin, P Neven, Y Shparyk, A Mori, D R Lu, H Bhattacharyya, C Huang Bartlett, S Iyer, S Johnston, J Ettl, N Harbeck
Background: Patient-reported outcomes are integral in benefit-risk assessments of new treatment regimens. The PALOMA-2 study provides the largest body of evidence for patient-reported health-related quality of life (HRQOL) for patients with metastatic breast cancer receiving first-line endocrine-based therapy (palbociclib plus letrozole and letrozole alone). Patients and Methods: Treatment-naïve postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer were randomized 2:1 to palbociclib plus letrozole (n=444) or placebo plus letrozole (n=222)...
January 19, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Chandrasekar Durairaj, Ana Ruiz-Garcia, Eric R Gauthier, Xin Huang, Dongrui R Lu, Justin T Hoffman, Richard S Finn, Anil A Joy, Johannes Ettl, Hope S Rugo, Jenny Zheng, Keith D Wilner, Diane D Wang
The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14...
January 22, 2018: Anti-cancer Drugs
Norikazu Masuda, Reiki Nishimura, Masato Takahashi, Kenichi Inoue, Shinji Ohno, Hiroji Iwata, Yuko Mori, Satoshi Hashigaki, Yasuaki Muramatsu, Takashi Nagasawa, Yoshiko Umeyama, Masakazu Toi
This single-arm, open-label, phase II study in 42 Japanese postmenopausal patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer evaluated the efficacy, safety, and pharmacokinetics of first-line palbociclib (125 mg once daily, 3 weeks on/1 week off) coadministered with letrozole (2.5 mg once daily). Primary endpoint of investigator-assessed 1-year progression-free survival (PFS) probability was 75.0% (90% CI, 61.3%-84.4%), far surpassing the 40% lower limit of the 90% CI supporting efficacy...
January 18, 2018: Cancer Science
Tomás Reinert, Carlos H Barrios
We reviewed randomized phase II/III trials comparing first- or second-line endocrine therapy as monotherapy or in combination with targeted therapies for treatment of postmenopausal patients with hormone receptor-positive advanced breast cancer. First-line was defined as treatment for endocrine therapy-naïve advanced breast cancer or advanced disease treated with endocrine therapy in the adjuvant/neoadjuvant setting. Second-line was defined as endocrine therapy for advanced breast cancer following disease progression on endocrine therapy for advanced disease...
November 2017: Therapeutic Advances in Medical Oncology
N C Turner, R S Finn, M Martin, S-A Im, A DeMichele, J Ettl, V Diéras, S Moulder, O Lipatov, M Colleoni, M Cristofanilli, D R Lu, A Mori, C Giorgetti, S Iyer, C Huang Bartlett, K A Gelmon
Background: This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methods: Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N=521) and postmenopausal women untreated for ABC (PALOMA-2; N=666) were randomized 2:1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo...
January 11, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Tom Degenhardt, Rachel Wuerstlein, Tanja Eggersmann, Nadia Harbeck
Despite improvements in the diagnosis and management of early stage breast cancer, about one third of the patients still progress to metastatic disease. Most of the patients with metastatic breast cancer have a hormone receptor positive and human epidermal growth factor receptor 2 negative subtype with a median survival of more than 3 years. For these patients, endocrine therapy with its favorable toxicity profile is the current standard of care. However, patients with metastatic breast cancer have an incurable disease...
January 17, 2018: Expert Opinion on Drug Safety
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