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Association between p16INK4A expression and a treatment response to CDK4/6 inhibitor in advanced breast carcinoma
Xiao Huang1, Shuko Harada2, Shi Wei2
1Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Department of Anatomic Pathology, Division of Pathology-Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Introduction:
Endocrine therapy combined with cyclin-dependent kinase 4 and 6 inhibitors (1) has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinomas. It has been known that the p16-CDK4/6-cyclin D1 axis regulates the S phase of the cell cycle. We investigated the association between p16 expression and the therapeutic response with CDK4/6i in advanced breast carcinoma.
Methods:
Patients diagnosed with invasive breast carcinoma between 2019 and 2024 whose tumors underwent next-generation sequencing (NGS) based analysis were identified. The expression of p16 was assessed in tumor cells and stromal cells within the invasive carcinoma by immunohistochemistry. In tumor cells, p16 expression was subclassified as cytoplasmic (TC), nuclear (TN), or cytoplasmic and nuclear staining (TCN). In stromal cells, p16 expression was assessed in tumor-associated fibroblasts (TAF) and tumor-infiltrating immune cells (TILs) in any cellular compartment.
Results:
Among the 35 cases, p16-TC, -TN, and -TCN were significantly associated with disease progression during CDK4/6i therapy. The positive association between p16-TC and progressive disease remained in the 24 CDK4/6i-treatment naïve tumors. In contrast, the tumors with p16 expression in TAF showed a numerically higher response rate than the p16-TAF-negative ones. We also observed a significant association between p16-TC expression and lymph node metastasis.
Conclusion:
Our study demonstrated a significant association between p16 expression in tumor cells and an unfavorable therapeutic response to CDK4/6i in advanced breast carcinoma. The clinical significance of p16 expression patterns as a predictive biomarker for CDK4/6i deserves further investigation.
Insights
p16 expression in tumor cells correlates with poor response to CDK4/6 inhibitors in advanced breast cancer. Stromal p16 in fibroblasts may indicate a better response, suggesting p16 patterns could predict treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Biomarkers
Background:
- Hormone receptor-positive, HER2-negative breast cancer treatment often involves endocrine therapy plus CDK4/6 inhibitors.
- The p16-CDK4/6-cyclin D1 pathway is crucial for cell cycle regulation.
- Identifying predictive biomarkers for CDK4/6 inhibitor efficacy is essential for personalized treatment.
Purpose of the Study:
- To investigate the association between p16 expression patterns and therapeutic response to CDK4/6 inhibitors in advanced breast carcinoma.
- To explore p16 expression in both tumor and stromal cells as potential predictive biomarkers.
Main Methods:
- Retrospective analysis of 35 advanced breast carcinoma cases diagnosed between 2019-2024.
- Immunohistochemistry used to assess p16 expression in tumor cells (cytoplasmic, nuclear, combined) and stromal cells (tumor-associated fibroblasts, immune cells).
- Correlation of p16 expression patterns with clinical response to CDK4/6 inhibitor therapy.
Main Results:
- p16 expression in tumor cells (cytoplasmic, nuclear, or combined) was significantly associated with disease progression during CDK4/6 inhibitor therapy.
- Cytoplasmic p16 expression in tumor cells showed a positive association with progressive disease, even in treatment-naïve tumors.
- p16 expression in tumor-associated fibroblasts (TAF) was numerically associated with a higher response rate to CDK4/6 inhibitors.
- p16 expression in tumor cells also correlated with lymph node metastasis.
Conclusions:
- p16 expression within tumor cells is linked to an unfavorable response to CDK4/6 inhibitors in advanced breast cancer.
- p16 expression in stromal cells, particularly TAFs, may indicate a potentially better response.
- Further research is warranted to validate p16 expression patterns as predictive biomarkers for CDK4/6 inhibitor therapy in breast cancer.
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