CDK 4/6 inhibitors combined with radiotherapy: A review of literature

Bosacki, Claire; Bouleftour, Wafa; Sotton, Sandrine; Vallard, Alexis; Daguenet, Élisabeth; Ouaz, Hamza; Cojocaru, Ionel; Moslemi, Dariush; Molekzadehmoghani, Mona; Magné, Nicolas

doi:10.1016/j.ctro.2020.11.010

Cited by 28 publications

(15 citation statements)

References 40 publications

(60 reference statements)

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“…The risk of neutropenia does not appear to be different than with CDK inhibitors alone [72] , and a small retrospective study showed combination treatment to be safe [73] . Alternatively, other studies have raised concern for pulmonary, GI, and skin toxicities [74] , [75] , [76] , [77] . Due to the dosing schedule of palbociclib, RT can be delivered during the week when patients are not receiving the drug.…”

Section: Resultsmentioning

confidence: 99%

Multidisciplinary Treatment of Non-Spine Bone Metastases: Results of a Modified Delphi Consensus Process

Gillespie

Mathis

Vaynrub

et al. 2022

Clinical and Translational Radiation Oncology

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Section: Resultsmentioning

confidence: 99%

Multidisciplinary Treatment of Non-Spine Bone Metastases: Results of a Modified Delphi Consensus Process

Gillespie

Mathis

Vaynrub

et al. 2022

Clinical and Translational Radiation Oncology

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“…However, the clinical effects of combining palbociclib and RT is least well-known. Several small retrospective studies have reported that the combination of RT and CDK inhibitor was generally well tolerated [ 67 ]. The series mainly reported the follow-up of patients irradiated on metastatic lesions.…”

Section: Resultsmentioning

confidence: 99%

Combination of Modern Radiotherapy and New Targeted Treatments for Breast Cancer Management

Beddok

Cottu

Kirova

2021

Cancers

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Background: The objective of the present study was to review the essential knowledge about the combinations of the most commonly used or under development targeted treatments and radiation therapy (RT). Methods: Preclinical and clinical studies investigating this combination were extensively reviewed. Results: Several studies showed that the combination of RT and tamoxifen increased the risk of radiation-induced pulmonary toxicity; therefore, both modalities should not be given concomitantly. The combination of HER2 inhibitors (trastuzumab, pertuzumab) and RT seems to be safe. However, trastuzumab emtansine (T-DM1) should not be administered concurrently with brain RT since this combination could increase the risk of brain radionecrosis. The combination of RT and other new target treatments such as selective estrogen receptor degradants, lapatinib, cell cycle inhibitors, immune checkpoint inhibitors, or molecules acting on DNA damage repair seems feasible but was essentially evaluated on retrospective or prospective studies with a small number of patients. Furthermore, there is considerable heterogeneity among these studies regarding the dose and fractionation of radiation, the dosage of drugs, and the sequence of treatments used. Conclusions: The combination of RT with most targeted therapies for BC appears to be well-tolerated, but these results need to be confirmed in prospective randomized studies.

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“…Taken together, our results suggest that CDK4/6 inhibition + RT is a promising strategy to decrease recurrence and increase local disease control across ER+ and TNBC and that RB may be a potential biomarker for efficacy. Concerns about the safety of concurrent CDK4/6 inhibition and RT remain, and to date, small studies exploring outcomes in patients with MBC receiving palliative radiation and CDK4/6 inhibitor therapy have conflicting results regarding toxicity, depending on the dose/fractionation of radiation and the regions targeted in the metastatic setting (visceral organs) (61)(62)(63)(64). Reassuringly, no studies to date have demonstrated more pronounced side effects of CDK4/6 inhibitors, such as cytopenias and skin desquamation, in women receiving concurrent therapy to the breast or axillary regions.…”

Section: Discussionmentioning

confidence: 99%

RB expression confers sensitivity to CDK4/6 inhibitor–mediated radiosensitization across breast cancer subtypes

Pesch¹,

Hirsh²,

Michmerhuizen³

et al. 2022

JCI Insight

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Standard radiation (RT) therapy does not reliably provide locoregional control for women with multi-node positive and triple-negative (TNBC) breast cancers. We hypothesized that CDK4/6 inhibition (CDK4/6i) would increase the radiosensitivity not only of estrogen receptor positive (ER+) cells, but also TNBC that express retinoblastoma (RB) protein. We found that CDK4/6i radiosensitized RB wild-type TNBC (n=4, rER 1.49 -2.22), but failed to radiosensitize RB-null TNBC (n=3, rER: 0.84 -1.00). RB expression predicted response to CDK4/6i + RT (R 2 =0.84), and radiosensitization was lost in ER+/TNBC cells (rER: 0.88 -1.13) after RB1 knockdown in isogenic and non-isogenic models. CDK4/6i suppressed homologous recombination (HR) in RB wild-type cells, but not in RB-null cells or isogenic models of RB1 loss; HR competency was rescued with RB re-expression. Radiosensitization was independent of non-homologous end joining and the known effects of CDK4/6i on cell cycle arrest. Mechanistically, RB and RAD51 interact in vitro to promote HR repair. CDK4/6i produced RB-dependent radiosensitization in TNBC xenografts, but not in isogenic RB1-null xenografts. Our data provide the preclinical rationale for a clinical trial expanding the use of CDK4/6i + RT to difficult to control RBintact breast cancers (including TNBC) and nominate RB status as a predictive biomarker of therapeutic efficacy.

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CDK 4/6 inhibitors combined with radiotherapy: A review of literature

Cited by 28 publications

References 40 publications

Multidisciplinary Treatment of Non-Spine Bone Metastases: Results of a Modified Delphi Consensus Process

Multidisciplinary Treatment of Non-Spine Bone Metastases: Results of a Modified Delphi Consensus Process

Combination of Modern Radiotherapy and New Targeted Treatments for Breast Cancer Management

RB expression confers sensitivity to CDK4/6 inhibitor–mediated radiosensitization across breast cancer subtypes

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