Abstract：
:Cyclin dependent kinase (CDK) 4/6 inhibitors have advanced the treatment of metastatic breast cancer by targeting the cell cycle machinery, interrupting intracellular and mitogenic hormone signals that stimulate proliferation of malignant cells. Preclinical evidence demonstrated that derangements of cyclin D1, CDK4/6, and retinoblastoma expression are common in breast cancer, and suggested a therapeutic benefit from interrupting this axis required for cell cycle progression. Studies of cell lines and animal models of breast cancer have demonstrated the complex interplay between the cell cycle and estrogen receptor and human epidermal growth receptor 2 signaling, which informs our understanding of synergistic use of CDK4/6 inhibitors with endocrine therapy, as well as mechanisms of resistance to endocrine therapy. Interestingly, estrogen receptor activity leads to upregulation of cyclin D1 expression, but the estrogen receptor is also in turn activated by cyclin D1, independent of estrogen binding. Early CDK inhibitors were nonspecific and limited by systemic toxicities, while the current generation of CDK4/6 inhibitors have shown promise in the treatment of hormone receptor-positive breast cancer. Preclinical investigations of the three CDK4/6 inhibitors approved by the US Food and Drug Administration (palbociclib, ribociclib, and abemaciclib) lend further insight into their mechanism of action, which will hopefully inform the future use and refinement of these therapies. Finally, we summarize evidence for additional novel CDK4/6 inhibitors currently in development.
journal_name
Semin Oncoljournal_title
Seminars in oncologyauthors
Scott SC,Lee SS,Abraham Jdoi
10.1053/j.seminoncol.2018.01.006subject
Has Abstractpub_date
2017-12-01 00:00:00pages
385-394issue
6eissn
0093-7754issn
1532-8708pii
S0093-7754(18)30006-Xjournal_volume
44pub_type
杂志文章,评审abstract：:In a multicenter phase III trial, 267 patients with nonbulky metastatic colorectal cancer who had failed first-line 5-fluorouracil (5-FU) therapy were randomized to receive second-line treatment with either the new topoisomerase agent, irinotecan (Rhône-Poulenc Rorer, Antony, France), or a high-dose infusional 5-FU re...
journal_title：Seminars in oncology
pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
doi：
更新日期：1999-02-01 00:00:00
abstract：:Solid organ tumors associated with neoangiogenesis, as measured by increased microvessel density (MVD), have poorer prognoses. A similar observation of increased MVD has been made in hematologic malignancies; however, its prognostic significance remains unknown. We investigated changes in MVD in 122 newly diagnosed mu...
journal_title：Seminars in oncology
pub_type： 杂志文章
doi：10.1016/s0093-7754(01)90025-9
更新日期：2001-12-01 00:00:00
abstract：:This paper is designed to provide an introduction to music therapy in the continuum of cancer care. The value and use of music therapy during diagnosis and treatment, palliation, hospice, actively dying, and bereavement have been well documented. The music therapy process will be identified, research will be shared, a...
journal_title：Seminars in oncology
pub_type： 杂志文章
doi：10.1053/j.seminoncol.2011.03.010
更新日期：2011-06-01 00:00:00
abstract：:Etoposide has been used in the treatment of a wide variety of neoplasms, including small cell lung cancer. Kaposi's sarcoma, testicular cancer, acute leukemia, and lymphoma. Its current therapeutic use is limited by myelosuppression, particularly neutropenia. Pharmacodynamic studies of etoposide show that this toxicit...
journal_title：Seminars in oncology
pub_type： 杂志文章
doi：
更新日期：1992-12-01 00:00:00
abstract：:The treatment of locally advanced carcinoma of the cervix with radiation therapy as a single modality is inadequate, specifically for stage III and IVA disease. While chemotherapy as single-modality therapy is ineffective in advanced cervical cancer, there is some evidence of efficacy when used in combination with rad...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：
更新日期：1996-08-01 00:00:00
abstract：:One of the most known oncogenes is the epidermal growth factor receptor (EGFR) family. It activates multiple signaling cascades that promote carcinogenesis and immune evasion. Therefore, these molecules have been extensively targeted in cancer immunotherapy. Beyond EGFR signaling cascade inhibition, some of these agen...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/j.seminoncol.2018.04.008
更新日期：2018-01-01 00:00:00
abstract：:The role of radiation therapy in the management of breast cancer continues to evolve. For patients with early stage breast cancer, hypofractionated whole breast irradiation following breast conserving surgery now represents the standard of care based on randomized data with long-term efficacy and toxicity outcomes. Pa...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/j.seminoncol.2020.05.003
更新日期：2020-08-01 00:00:00
abstract：:Platelet-derived microparticles (PMPs) represent the most abundant microparticle (MP) subtype. Their presence reflects platelet activity, physiopathology, and the thrombotic state of cancer patients. The quantity and composition of PMPs strictly depends on the way MPs were generated. Because platelets play a key role ...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/j.seminoncol.2014.04.010
更新日期：2014-06-01 00:00:00
abstract：:The ability of dexrazoxane (DEX) to protect against doxorubicin (DOX)-induced cardiomyopathy has been demonstrated in mice, normotensive and hypertensive rats, rabbits, dogs, swine, and humans. These animal models of DOX-induced cardiomyopathy were found to be highly predictive of DEX activity clinically. In mice admi...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：
更新日期：1998-08-01 00:00:00
abstract：:Eighteen percent of incident malignancies in the United States are a second (or subsequent) cancer. Second primary neoplasms (SPNs), particularly solid tumors, are a major cause of mortality and serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer ...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/j.seminoncol.2013.09.012
更新日期：2013-12-01 00:00:00
abstract：:Most important is the physician's attitude, energy, and skill focused toward helping the patient through the difficulties in the last weeks of life. Many causes of nausea, dyspnea, and other troublesome symptoms can be effectively treated, and pharmacologic palliation is nearly always possible. A multidisciplinary tea...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：
更新日期：1994-12-01 00:00:00
abstract：:The clinical development of the recombinant alpha interferons has provided a prototype for the clinical development of biological compounds. With over 5,000 patients now treated with these compounds, some general principles have emerged that have wider implications for phase I-II strategies for testing other biologica...
journal_title：Seminars in oncology
pub_type： 临床试验,杂志文章,评审
doi：
更新日期：1987-06-01 00:00:00
abstract：:Hepatic metastases are a major cause of morbidity and mortality for patients with colorectal cancer (CRC). The rationale for hepatic arterial chemotherapy has both an anatomical and pharmacological basis. Several randomized clinical studies of fluoropyrimidine showed higher response rates in all trials when the drug w...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：
更新日期：1999-10-01 00:00:00
abstract：:The development of targeted agents has brought new opportunities and extraordinary therapeutic challenges to cancer therapy. Several agents that inhibit epidermal growth factor receptor (HER1/EGFR) tyrosine kinase have been developed and are advanced in their clinical development. Preclinical and clinical data show th...
journal_title：Seminars in oncology
pub_type： 杂志文章
doi：
更新日期：2003-06-01 00:00:00
abstract：:Lymphomas of the head and neck arise in Waldeyer's ring, the salivary glands, nasal cavity, paranasal sinuses, thyroid gland, and orbit. Though anatomically in close proximity, lymphomas arising in these sites have distinct clinical characteristics. Factors that appear to influence the pattern of disease include concu...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：
更新日期：1999-06-01 00:00:00
abstract：:The humanized anti-p185(HER2) monoclonal antibody trastuzumab has been shown to effectively inhibit the growth of HER2-overexpressing breast cancer cells in vivo and in vitro. The treatment of cancer cells with trastuzumab results in downregulation of the HER2 receptor. Further downstream cellular events include the a...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1016/s0093-7754(01)90276-3
更新日期：2001-10-01 00:00:00
abstract：:Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown in vitro and clinical activity against non-small cell lung cancer and astrocytic brain tumors, tumors traditionally thought of as relatively resistant to chemotherapy and radiotherapy. Because of its ability to block dividing cells in the G2/M p...
journal_title：Seminars in oncology
pub_type： 临床试验,杂志文章
doi：
更新日期：1996-12-01 00:00:00
abstract：:Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane used in routine clinical practice, has aroused considerable interest for its high single-agent activity against breast cancer and for its novel mechanism of action. Epirubicin, the 4' epimer of doxorubicin, is another agent with a high a...
journal_title：Seminars in oncology
pub_type： 临床试验,杂志文章
doi：
更新日期：1997-10-01 00:00:00
abstract：:MicroRNAs (miRNAs) are aiding our understanding of cancer biology, and are now coming close to therapeutic use as well. Here, we focus specifically on the interaction between miRNAs and genomic instability. MiRNA regulation is essential to many cellular processes, and escape from this regulatory network seems to be a ...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/j.seminoncol.2011.08.003
更新日期：2011-12-01 00:00:00
abstract：:Inflammatory breast cancer (IBC) is an extremely aggressive disease that progresses rapidly and carries a very grim prognosis. It is characterized by erythema, rapid enlargement of the breast, skin ridging, and a characteristic peau d'orange appearance of the skin secondary to dermal lymphatic tumor involvement. Altho...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/j.seminoncol.2007.11.010
更新日期：2008-02-01 00:00:00
abstract：:Epigenetic alterations play a pivotal role in cancer development and progression. Pharmacologic reversion of such alterations is feasible, and second generation "epigenetic drugs" are in development and have been demonstrated to possess significant immunomodulatory properties. This knowledge, together with the availab...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/j.seminoncol.2015.02.003
更新日期：2015-06-01 00:00:00
abstract：:Hepatic metastases are a major cause of mortality in patients with colorectal carcinoma. The rationale for regional therapy is presented. The randomized studies are reviewed and they demonstrated a significantly higher response rate with hepatic arterial therapy versus systemic therapy. Survival information is difficu...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：
更新日期：1992-04-01 00:00:00
abstract：:Current therapies for the treatment of malignancies are associated with significant toxicity, as chemotherapy and radiation therapy do not discriminate between normal and malignant cells. One approach to ameliorating the toxicity associated with therapy is through the use of chemoprotective agents. This article review...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：
更新日期：1992-12-01 00:00:00
abstract：:The use of adjuvant radiation therapy and chemotherapy diminishes the likelihood of local-regional and distant recurrences and appears to prolong survival in patients who have undergone a complete surgical resection of a Dukes-Kirklin stage B2 or C rectal cancer. Patients with this malignant condition rarely develop p...
journal_title：Seminars in oncology
pub_type： 杂志文章
doi：
更新日期：1985-09-01 00:00:00
abstract：:The majority of patients with advanced prostatic cancer respond either to castration or estrogen therapy. In an attempt to identify an alternative hormonal therapy, 25 symptomatic stage D prostate cancer patients were treated with megestrol acetate as initial hormonal therapy. Thirty-three patients were evaluable for ...
journal_title：Seminars in oncology
pub_type： 杂志文章
doi：
更新日期：1985-03-01 00:00:00
abstract：:Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) displays nonlinear pharmacokinetics in humans. Both peak plasma paclitaxel concentrations and areas under the curve (AUCs) of the concentration versus time profiles will change disproportionately to changes in dose. Models that accurately describe the pla...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：
更新日期：1995-06-01 00:00:00
abstract：:Complementary and alternative therapies are used with increasing frequency in men with prostate cancer. However, little is known about the efficacy of such therapies for this cancer. While epidemiological data support the association between intake of certain micronutrients with development of prostate cancer, there e...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/sonc.2002.50007
更新日期：2002-12-01 00:00:00
abstract：:A dose-finding study was set up to identify the optimal dose of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin for phase II studies in patients with advanced chemotherapy-naive non-small cell lung cancer (NSCLC). The influence of drug sequence on the toxicity and pha...
journal_title：Seminars in oncology
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：1995-08-01 00:00:00
abstract：:Studies in vitro and in animal models have helped define the mechanism of action of antiestrogens and the differences in the physical properties of the various antiestrogens. Tamoxifen is the most widely studied antiestrogen. A review of 45 separate studies has shown a response rate to tamoxifen in advanced breast can...
journal_title：Seminars in oncology
pub_type： 临床试验,杂志文章
doi：
更新日期：1983-12-01 00:00:00
abstract：:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options and exceedingly high mortality rates. Currently, cure can only be achieved through resection, however the vast majority of patients present with advanced disease for which upfront surgery is not an option. In...
journal_title：Seminars in oncology
pub_type： 杂志文章,评审
doi：10.1053/j.seminoncol.2018.12.002
更新日期：2019-02-01 00:00:00
