CDK4/6 inhibitors in breast cancer: differences in toxicity profiles and impact on agent choice. A systematic review and meta-analysis.
TL;DR: The toxicity rate of ribociclib was higher in metastatic patients than non-metastatic patients, with approximately 33% more grade 3–4 toxicities and 21% more neutropenic events.
Abstract: Introduction: CDK4/6 inhibitor approval for hormone-responsive breast tumors has significantly changed therapeutic algorithms, with three drugs currently approved.Areas covered: Here, we analyze th...
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TL;DR: In this paper, the authors explore the preclinical and pharmacological differences between the three approved agents and help understand the benefits seen with these agents in certain subgroups of patients with metastatic HR positive breast cancer.
Abstract: Targeted therapies such as Cyclin Dependent Kinase 4 and 6 (CDK 4/6) inhibitors have improved the prognosis of metastatic hormone receptor (HR) positive breast cancer by combating the resistance seen with traditional endocrine therapy. The three approved agents currently in the market are palbociclib, ribociclib and abemaciclib. Besides the overall similarities associated with CDK4/6 inhibition, there are differences between the three approved agents that may explain the differences noted in unique clinical scenarios- monotherapy, patients with brain metastases or use in the adjuvant setting. This review article will explore the preclinical and pharmacological differences between the three agents and help understand the benefits seen with these agents in certain subgroups of patients with metastatic HR positive breast cancer.
39 citations
TL;DR: In this article, the initial analysis of immune responses after the first dose of vaccination in 21 breast cancer patients receiving cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors was provided.
16 citations
TL;DR: In this article, the authors analyzed thromboembolic events with cyclin-dependent kinase (CDK)4/6 inhibitors, using the Food and Drug Administration adverse event reporting system.
Abstract: We analyzed thromboembolic events, recognized (AESIs), with cyclin-dependent kinase (CDK)4/6 inhibitors, using the Food and Drug Administration adverse event reporting system Methods: Thromboembolic events were characterized in terms of spectrum [venous and arterial thromboembolism (VTE; ATE)] and clinical features by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment Results: A total of 1722 thromboembolic events were retained Increased VTE reporting emerged for CDK4/6 inhibitors in the exploratory analyses (n = 659; ROR = 151; 95% CI = 139–163), with consistent disproportionality in the consolidated analyses (eg, deep vein thrombosis with abemaciclib: 17; 198; 122–319) Higher-than-expected ATE reporting was found for ribociclib, including myocardial infarction (41; 182; 133–248), with rapid onset (median latency 1 vs 6 months for other CDK4/6 inhibitors) Causality was highly probable or probable in 832% of cases, with a negligible proportion of pre-existing drug- and patient-related risk factors except for cardiovascular comorbidities (26%) Conclusions: Although causal association cannot be firmly inferred, oncologists should proactively monitor the occurrence of VTE with CDK4/6 inhibitors The unexpected distinctive increased ATE reporting with ribociclib deserves urgent clarification though large comparative population-based studies We support pharmacovigilance for the post-marketing characterization of AESIs, thus promoting real-time safe prescribing in oncology
14 citations
TL;DR: A review of the history of endocrine treatment for breast cancer is presented in this article, where the authors give an overview of the role in the present standard of care, and discuss the possibilities of improvement.
Abstract: Purpose of review: Due to the findings of current studies and the approval of novel substances for the therapy of hormone-receptor-positive breast cancer patients, the established standards of endocrine treatment are changing. The purpose of this review is to give an overview of the history of endocrine treatment, to clarify its role in the present standard of care, and to discuss the possibilities of improvement. Recent findings: Tamoxifen, aromatase inhibitors, and fulvestrant are the main drugs that have been used for decades in the therapy of hormone-receptor-positive breast cancer patients. However, since a relevant number of women suffer at some point from disease recurrence or progression, several novel substances are being investigated to overcome resistance mechanisms by interfering with certain signaling pathways, such as the PI3K/AKT/mTOR or the CDK4/6 pathways. mTOR and CDK4/6 inhibitors were the first drugs approved for this purpose and many more are in development. Summary: Endocrine treatment is one of the best tolerable cancer therapies available. Continuous investigation serves to improve patients’ outcomes and modernize the current standard of care. Considering the resistance mechanisms and substances analyzed against these, endocrine treatment of hormone-receptor-positive breast cancer is on the brink of a new era.
10 citations
TL;DR: Abemaciclib was well tolerated in Japanese patients in MONARCH 2 and MONARCH 3, with common, clinically relevant TEAEs manageable with appropriate interventions.
Abstract: Purpose Our objective was to gain a better understanding of the safety of abemaciclib in Japanese patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Patients and Methods Treatment-emergent adverse events (TEAEs) were assessed in pooled Japanese subpopulation data from two phase 3 studies assessing abemaciclib/placebo in combination with fulvestrant (MONARCH 2; M2) or non-steroidal aromatase inhibitors (MONARCH 3; M3). For common, clinically relevant TEAEs, event characteristics and management were summarized by study. Results In the Japanese safety subpopulation (abemaciclib: N=101; placebo: N=46), all patients experienced ≥1 TEAE (Grade ≥ 3: abemaciclib, 71.3%; placebo, 23.9%; no Grade 5). Clinically relevant TEAEs that were more frequent in abemaciclib-treated Japanese patients compared to the overall safety populations included diarrhea (any grade, 95.0%; Grade ≥ 3, 12.9%), neutropenia (any grade, 75.2%; Grade 3–4, 35.6%), increased alanine aminotransferase (ALT; any grade, 39.6%; Grade 3–4, 14.9%), and increased aspartate aminotransferase (AST; any grade, 37.6%; Grade 3–4, 8.9%). Diarrhea was Grade ≤3 and successfully managed with medications (≥87%) and dose reductions (≤25%) and/or omissions (≤23.3%). Most Grade ≥2 diarrhea occurred in the first treatment cycle, declining thereafter. Neutropenia, the most common Grade ≥3 TEAE in abemaciclib-treated Japanese patients, was generally manageable with dose omissions (M2: 42.0%; M3: 23.1%) and/or reductions (M2: 16%; M3: 15.4%). Neutrophil counts plateaued after Cycle 2, recovering to pretreatment levels after discontinuation of abemaciclib. Hepatic events were managed with medication (≤21%) and dose adjustments (≤33.3%), with most Grade ≥2 events occurring in early treatment cycles. Discontinuation of any study treatment in Japanese patients occurred more frequently due to increased ALT/AST (M2: 9.1%/10.5%; M3: 16.7%/10.5%) compared with diarrhea (M2: 0%; M3: 2.8%) or neutropenia (M2: 0%; M3: 3.8%). Conclusion Abemaciclib was well tolerated in Japanese patients in MONARCH 2 and MONARCH 3, with common, clinically relevant TEAEs manageable with appropriate interventions.
5 citations
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TL;DR: Moher et al. as mentioned in this paper introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses, which is used in this paper.
Abstract: David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
62,157 citations
TL;DR: A status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions.
Abstract: This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions There will be an estimated 181 million new cancer cases (170 million excluding nonmelanoma skin cancer) and 96 million cancer deaths (95 million excluding nonmelanoma skin cancer) in 2018 In both sexes combined, lung cancer is the most commonly diagnosed cancer (116% of the total cases) and the leading cause of cancer death (184% of the total cancer deaths), closely followed by female breast cancer (116%), prostate cancer (71%), and colorectal cancer (61%) for incidence and colorectal cancer (92%), stomach cancer (82%), and liver cancer (82%) for mortality Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality) Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts CA: A Cancer Journal for Clinicians 2018;0:1-31 © 2018 American Cancer Society
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Journal Article•
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Daniel C. Koboldt1, Robert S. Fulton1, Michael D. McLellan1, Heather Schmidt1 +352 more•Institutions (35)
TL;DR: The ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity.
Abstract: We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.
9,355 citations
University of Bristol1, University Hospitals Bristol NHS Foundation Trust2, Monash University3, French Institute of Health and Medical Research4, Cochrane Collaboration5, Paris Descartes University6, St George's, University of London7, University of York8, Queen Mary University of London9, Clinical Trial Service Unit10, Harvard University11, University of Oxford12, Odense University Hospital13, University of Southern Denmark14, University of Alberta15, University of Toronto16, University of Manchester17, Johns Hopkins University18, McGill University19, University College London20
TL;DR: The Cochrane risk-of-bias tool has been updated to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
Abstract: Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
9,228 citations