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Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy
Rosalba Torrisi1, Valentina Vaira2,3, Laura Giordano4
1Medical Oncology and Hematology Unit, Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milano, Italy.
Abstract:
We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (miR-378e, miR-1233, miR-99b-5p, miR-1260b, miR-448, -miR-1252-5p, miR-324-3p, miR-1233-3p) showed a statistically significant negative association with PFS. When we considered PFS < 6 months, miR-378e, miR-99b-5p, miR-877-5p, miR-1297, miR-455-5p, and miR-4536-5p were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27Kip1 and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.
Insights
This study identified specific microRNAs (miRNAs) linked to poor treatment response in metastatic breast cancer patients receiving endocrine therapy and palbociclib. These findings may help predict early progression and understand resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Hormone Receptor-positive/HER2-negative metastatic breast cancer is often treated with endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i).
- Predicting treatment response and understanding resistance mechanisms to CDK4/6i remains a clinical challenge.
Purpose of the Study:
- To identify a panel of microRNAs (miRNAs) in tumor tissues associated with treatment response in metastatic breast cancer patients.
- To explore the potential of these miRNAs in predicting early progression and understanding de novo resistance to ET and palbociclib.
Main Methods:
- Analysis of tumor tissues from 52 patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with ET and palbociclib.
- Statistical analysis to identify miRNAs significantly associated with Progression-Free Survival (PFS), including early progression (<6 months).
- Multivariate analysis to confirm the independent impact of identified miRNAs on PFS.
Main Results:
- Seven miRNAs showed a statistically significant negative association with PFS.
- Specific miRNAs (e.g., miR-378e, miR-99b-5p) were associated with poor outcomes in patients experiencing early progression (<6 months).
- Multivariate analysis confirmed three miRNAs had a significant and independent impact on PFS.
Conclusions:
- A novel panel of miRNAs is associated with an increased likelihood of early progression in patients treated with ET and palbociclib.
- These miRNAs may offer insights into the mechanisms of de novo resistance to CDK4/6 inhibitors.
- Findings are exploratory and require validation in larger patient cohorts.
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