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CDK4/6-Inhibitors Versus Chemotherapy in Advanced HR+/HER2-Negative Breast Cancer: Results and Correlative Biomarker
Francesco Schettini1,2,3, Michela Palleschi4, Francesca Mannozzi5
1Translational Genomics and Targeted Therapies in Solid Tumors Group, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
Background:
The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET.
Materials And Methods:
We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples.
Results:
Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm.
Conclusions:
The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.
Insights
Cyclin-dependent kinase (CDK)4/6 inhibitors plus endocrine therapy (ET) show improved progression-free survival over chemotherapy plus ET for aggressive hormone receptor-positive metastatic breast cancer. Biomarkers like PAM50 intrinsic subtypes can help personalize treatment decisions.
Area of Science:
- Oncology
- Medical Research
- Genomics
Background:
- Optimal treatment for aggressive hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) is debated.
- Lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET.
- Need for personalized therapeutic strategies based on tumor characteristics.
Purpose of the Study:
- To compare the efficacy of chemotherapy + ET versus CDK4/6i + ET in patients with aggressive HR+/HER2-negative MBC.
- To explore the role of PAM50 intrinsic subtypes, genomic, and immunological features in predicting treatment response.
Main Methods:
- An open-label randomized phase II trial (NCT03227328) was conducted.
- Patients with aggressive HR+/HER2-negative MBC were randomized to receive either chemotherapy + ET or CDK4/6i + ET.
- Baseline samples were analyzed for PAM50 intrinsic subtypes, gene expression, and immunological features.
Main Results:
- Median progression-free survival (mPFS) was numerically longer with CDK4/6i + ET (19.9 months) compared to chemotherapy + ET (11.2 months).
- Basal-like tumors showed worse PFS and OS with CDK4/6i + ET, while luminal A tumors had poorer PFS in the chemotherapy arm.
- Genes related to cell survival and proliferation were associated with worse outcomes; immune-related genes and tertiary lymphoid structures showed favorable trends, particularly in the CDK4/6i arm.
Conclusions:
- The KENDO trial provides evidence supporting the use of CDK4/6i + ET over chemotherapy for aggressive HR+/HER2-negative MBC.
- PAM50 intrinsic subtypes, genomic, and immunological features show promise as biomarkers for personalizing treatment selection.
- Further research is warranted to optimize treatment strategies for specific patient subgroups.
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