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MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer.

ABSTRACT: With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for novel therapeutic options to manage the disease after the inevitable development of resistance to CDK4/6i. In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of these molecules, the current preclinical evidence for the efficacy of MDM2 inhibitors in ER+ breast cancer, and discuss the possibility of targeting the p53/MDM2 via inhibition of MDM2 in the CDK4/6i resistance setting.

SUBMITTER: Portman N

PROVIDER: S-EPMC8596371 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer.

Portman Neil N Chen Julia J Lim Elgene E

Frontiers in oncology 20211103

With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for novel therapeutic options to manage the disease after the inevitable development of resistance to CDK4/6i. In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of t ...[more]

PMID: 34804982

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Project description:ImportanceEndocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) agents is the standard first-line treatment for patients with hormone receptor-positive, ERBB2 (formerly HER2 or HER2/neu)-negative metastatic breast cancer. However, optimal therapy after tumor progression to ET plus CDK4/6i remains unclear.ObjectiveTo evaluate progression-free survival (PFS) and overall survival (OS) in the clinical practice setting in patients with hormone receptor-positive, ERBB2-negative metastatic breast cancer following progression with ET plus CDK4/6i.Design, setting, and participantsThe multicenter retrospective cohort study included 506 patients diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer between April 22, 2015, and January 31, 2023, and who received ET-based or chemotherapy (CT)-based treatment following progression during ET plus CDK4/6i. Outcomes were analyzed based on treatment type, clinicopathologic features, and the duration of prior CDK4/6i therapy.Main outcomes and measuresThe primary end point was PFS in the clinical practice setting, defined as the time between the initiation of the first systemic treatment on tumor progression to ET plus CDK4/6i treatment and the detection of disease progression or patient death from any cause. The secondary end point was OS in the clinical practice setting, defined as the time interval between tumor progression during ET plus CDK4/6i treatment and patient death from any cause.ResultsIn 506 women (median age at diagnosis, 52.4 [IQR, 44.6-62.8] years) diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer progressing during ET plus CDK4/6i, independent factors associated with poorer PFS outcomes were visceral metastases (hazard ratio [HR], 1.45; 95% CI, 1.17-1.80; P = .008) and de novo metastatic disease (HR, 1.25; 95% CI, 1.01-1.54; P = .04). A longer duration of CDK4/6i therapy (OS HR, 0.55; 95% CI, 0.41-0.73; P < .001) and an older age (PFS HR, 0.99; 95% CI 0.98-1.00; P = .03) were associated with better outcomes. Compared with oral CT, both intravenous CT- and ET-based treatments were associated with shorter PFS (intravenous CT: hazard ratio [HR], 1.45; 95% CI, 1.11-1.89; P = .006; everolimus plus exemestane: HR, 1.38; 95% CI, 1.06-1.78; P = .02; ET only: HR, 1.38; 95% CI, 1.05-1.89; P = .02). A duration of CDK4/6i treatment exceeding 12 months was associated with longer OS (HR, 0.55; 95% CI, 0.41-0.73; P < .001). Among patients with visceral metastases, intravenous CT was associated with shorter OS compared with oral CT (HR, 1.52; 95% CI, 1.03-2.24; P = .04).Conclusions and relevanceIn this cohort study, the duration of tumor control achieved with CDK4/6i-based therapy and the presence of visceral metastases emerged as key factors that may affect treatment decision. Oral CT may offer potential benefits for specific patient subgroups.

Project description:BackgroundCDK4/6 inhibitors combined with endocrine therapy are standard first- or second-line treatment for patients with HR-positive and HER2-negative advanced breast cancer, however, there is currently no optimal recommendation for therapeutic strategies after progression on CDK4/6i. The aim of this study is to analyze the efficacy and safety of HDAC inhibitor Tucidinostat combined with endocrine therapy in patients after prior CDK4/6 inhibitor progression.MethodsThe pathological and clinical data of 44 HR-positive and HER2-negative breast cancer patients treated with tucidinostat after progression on CDK4/6i at the Breast Oncology Department of the Fifth Medical Center of the PLA General Hospital from July 2019 to October 2021 were retrospectively analyzed. Observation indexes included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR) and adverse events. At the same time, we attempted to identify potential genomic predictors using available next-generation sequencing (NGS).ResultsA total of 44 patients were enrolled in this study. Median follow-up was 10 months (1-26 months) by the data cutoff date (February 2022). The CBR was 6.8% (3/44), the median PFS was 2.0 months (95% CI 1.9-2.1), and the median OS was 14 months (95% CI 6.3-21.7). The mPFS was 4.1 months (95%CI: 0-8.2) in patients with 1 metastatic site, and the mPFS was 4.5 months (95%CI: 4.2-4.8) in patients who received sequential tucidinostat after CDK4/6i failure. Multivariate analysis showed that patients with 1 metastatic site or sequential tucidinostat treatment after failure of CDK4/6i were more likely to benefit from tucidinostat combined with endocrine therapy. Preliminary data showed PIK3CA mutation may be associated with resistance of tucidinostat therapy. No grade 4 adverse events and no treatment-related deaths were recorded in the study. Dose reductions because of adverse events occurred in 4 (9.1%) patients.ConclusionsThis study preliminarily shows that tucidinostat combined with endocrine therapy may be an optional sequential strategy for patients with HR+/HER2-advanced breast cancer that has progressed on CDK4/6 inhibitor, especially for these with lower tumor burden and fewer prior palliative treatment.

Dataset Information

MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer.

Publications

MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer.

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