CDK4/6 inhibitors in advanced breast cancer, what is beyond?

Mohammed, Amrallah A.; Rashied, Hanaa; Elsayed, Fifi Mostafa

doi:10.4081/oncol.2019.416

Cited by 7 publications

(8 citation statements)

References 51 publications

(40 reference statements)

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“… 10 The addition of a second antibody targeting Her2 to trastuzumab, pertuzumab, has further increased disease-free survival in this population, 11 as has the addition of trastuzumab-emtansine (TDM-1) for patients not reaching pathological complete response prior to surgery. 12 13 Similar trends can be seen in metastatic BCa, where the approval of CDK4/6 inhibitors in the strictly hormone-dependent or luminal setting, 14 15 again use of trastuzumab and pertuzumab 16 17 as well as TDM-1 18 in Her2-positive BCa and most recently the addition of the immune checkpoint-inhibitor atezolizumab to chemotherapy in triple-negative breast cancer led to higher survival rates in cancer patient populations. 19 …”

Section: Introductionmentioning

confidence: 68%

“…We were not able to register these contacts for this study. Examples for such phenomena could be the replacement of intravenous chemotherapy by CDK4/6 inhibitors for HR-positive/Her2-negative advanced breast cancer, 14 regorafenib or TAS-102 for metastatic colorectal cancer, 27 28 second generation antiandrogens for prostate cancer, 29 30 tyrosine kinase inhibitors for advanced renal 31 32 and EGFR- (Epidermal Growth Factor Receptor)mutated lung cancer 33 or antihormonal agents given through injections—such as somatostatin analogues for neuroendocrine tumours. 34 In some instances, sharp increases and declines of patient contacts were caused by experimental testing of compounds in clinical trials (eg, increase in renal cancer patient contacts through the use of bevacizumab; figure 2C , years 2007–2009).…”

Section: Discussionmentioning

confidence: 99%

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Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field

et al. 2020

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BackgroundNovel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology.MethodsNumbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system.ResultsA patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported.ConclusionsWe present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity.

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field

et al. 2020

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“…Abemaciclib and Palbociclib are a class of small molecule inhibitors of both CDK4 and CDK6 that are FDA approved for the treatment of hormone receptor positive (HR+) breast cancer in post-menopausal women (15) . We treated MCF7 and T47D breast cancer cell lines with abemaciclib and palbociclib, respectively.…”

Section: Immunologic Activity Of Cdk4/6i On Breast Cancer Cell Linesmentioning

confidence: 99%

“…In order to better understand the mechanism underlying the induction of so many HLA ligands derived from the inhibited pathway we focused on CCND1 as an important target as it is important for carcinogenesis in many cancer types (15,16) and proven to lead to immunogenic HLA ligands. Furthermore, CCND1 is the direct interacting partner of CDK4/6 (16) and we exclusively identified in both cell lines, peptides derived from CCND1 after CDK4/6i treatment (ALLESSLRQA in complex with HLA-A*02:01 on MCF7 cells and DRVLRAML in complex with B*14:02 on T47D cells).…”

Section: Increased Degradation Of Pathway Specific Source Proteins Asmentioning

confidence: 99%

Low-Dose CDK4/6 Inhibitors Induce Presentation of Pathway Specific MHC ligands as Targets for Cancer Immunotherapy

Charles

Bourne

Mun

et al. 2020

Preprint

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Purpose: Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) lead to cell-cycle arrest but also demonstrate antineoplastic activity through triggering T cell-mediated immunity. One of the potential mechanisms responsible for this immunological effect might be qualitative and quantitative changes in human leukocyte antigen (HLA) ligands on the cell surface after treatment with CDK4/6i. These changes may increase the immunogenicity of breast cancer cells offering potential synergies for combinations with cancer immunotherapies. Experimental Design:We investigated the ability of two CDK4/6 inhibitors (CDK4/6i), Abemaciclib and Palbociclib, to alter the immunopeptidome at subclinical, non-toxic, levels in different breast cancer cell lines. Biochemical isolation of HLA ligands, identification by mass spectrometry and subsequent network analysis after drug treatment were used to characterize the changes in the immunopeptidome. The mechanisms for altered CDK4/6 presentation were explored.Results: Low-dose treatment with 100nM of Abemaciclib and Palbociclib led to upregulation of cell surface HLA levels and induced hundreds of HLA ligands in breast cancer cell lines. These new ligands were significantly and most strongly enriched for peptides derived from proteins involved in the "G1/S phase transition of cell cycle" pathway and included among others, HLA ligands from CDK4, CDK6, Cyclin D1 and Cyclin E1. An increase in transcript, protein, and subsequent ubiquitination for Cyclin D1, which could lead to enhanced degradation of the target protein, was identified as a potential mechanism for the altered presentation of peptides.Conclusions: CDK4/6i treatment gave rise to drug-induced antigens through cell cycle disruption and increased antigen presentation. Interestingly, these induced HLA ligands are often sourced from the proteins of the CDK4/CDK6/CCND1 complex or more downstream interaction partners, providing evidence that inhibition of a distinct cellular pathway leads to increased presentation of the proteins involved. These findings suggested CDK4/6i provided a tool for highly selective induction of HLA ligands that may be targeted by T cell-based immunotherapeutics. Translational RelevanceThese data demonstrated that low-dose treatment of breast cancer cells with CDK4/6 inhibitors, Abemaciclib and Palbociclib, induced marked changes in presentation of HLA ligands, especially from proteins involved in the G1/S phase transition, the phase in which these drugs arrest the cells. Enhanced ubiquitination and degradation was identified as a mechanism for the altered presentation for one of the relevant proteins. The induced HLA ligands may provide ideal specific targets for combination immunotherapies. The data show for the first time that selective inhibition of a distinct pathway can lead to specific presentation of HLA ligands in breast cancer cells. This work supports the rationale for testing the combination of low-dose CDK4/6i with immunotherapeutic agents, such as immune checkpoint blockade antibodies or T-cell-based...

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“…Although there are no head to head trials between the three, given the nature of each drug, patients are able to try another one if the one they have been or had been receiving resulted in intolerance [62]. Although currently, loss of the RB tumor suppressor function is the only indication that the drug is taking clinical effect, further research will look to expand the possible biomarkers for CDK4/6 inhibition [63].…”

Section: Nacs000594 4(4)2020mentioning

confidence: 99%