Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER Breast Cancer.

TitleRadiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER Breast Cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsPetroni G, Buqué A, Yamazaki T, Bloy N, Di Liberto M, Chen-Kiang S, Formenti SC, Galluzzi L
JournalClin Cancer Res
Date Published2021 Apr 01

PURPOSE: Recent preclinical data suggest that cyclin-dependent kinase 4/6 (CDK4/6) inhibition may be harnessed to sensitize estrogen receptor-positive (ER) breast cancer to radiotherapy. However, these findings were obtained in human ER breast cancer cell lines exposed to subclinical doses of CDK4/6 inhibitors with limited attention to treatment schedule. We investigated the activity of radiotherapy combined with the prototypic CDK4/6 inhibitor palbociclib placing emphasis on therapeutic schedule.

EXPERIMENTAL DESIGN: We combined radiotherapy and palbociclib in various doses and therapeutic schedules in human and mouse models of ER and ER-negative (ER) breast cancer, including an immunocompetent mouse model that recapitulates key features of human luminal B breast cancer in women. We assessed proliferation, cell death, cell-cycle control, and clonogenic survival , as well as tumor growth, overall survival, and metastatic dissemination .

RESULTS: Radiotherapy and palbociclib employed as standalone agents had partial cytostatic effects , correlating with suboptimal tumor control . However, while palbociclib delivered before focal radiotherapy provided minimal benefits as compared with either treatment alone, delivering focal radiotherapy before palbociclib mediated superior therapeutic effects, even in the absence of p53. Such superiority manifested with enhanced cytostasis and loss of clonogenic potential, as well as with improved local and systemic tumor control.

CONCLUSIONS: Our preclinical findings demonstrate that radiotherapy delivered before CDK4/6 inhibitors mediates superior antineoplastic effects compared with alternative treatment schedules, calling into question the design of clinical trials administering CDK4/6 inhibitors before radiotherapy in women with ER breast cancer.

Alternate JournalClin Cancer Res
PubMed ID33495311
PubMed Central IDPMC8327758
Grant ListP01 CA214274 / CA / NCI NIH HHS / United States
R01 CA188794 / CA / NCI NIH HHS / United States
S10 RR027619 / RR / NCRR NIH HHS / United States
Related Faculty: 
Maurizio DiLiberto, Ph.D. Selina Chen-Kiang, Ph.D.

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