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Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib
Zhou Zhu1, Nicholas C Turner2, Sherene Loi3
1Pfizer Inc, La Jolla, CA, USA.
Abstract:
While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor-positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135).
Insights
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors like palbociclib combined with endocrine therapy (ET) show promise for metastatic breast cancer. Adding palbociclib uncovers biomarkers suggesting it may recondition endocrine-resistant tumors to ET.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors plus endocrine therapy (ET) are standard for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.
- Further mechanistic understanding is crucial to optimize treatment benefits.
Purpose of the Study:
- To systematically compare gene expression and progression-free survival relationships from two Phase 3 trials (PALOMA-2 and PALOMA-3).
- To identify biomarkers associated with CDK4/6 inhibitor and ET combination therapy in metastatic breast cancer.
Main Methods:
- Comparative analysis of gene expression and progression-free survival data from PALOMA-2 (first-line) and PALOMA-3 (≥second-line) trials.
- Investigated gene expression patterns in endocrine therapy (ET)-only arms versus combination arms with palbociclib.
Main Results:
- No correlation in gene expression and progression-free survival was observed between therapy lines in the ET-only arm.
- Adding palbociclib to ET yielded concordant biomarkers irrespective of initial ET response.
- Sensitivity genes were enriched in estrogen response pathways, while resistance genes involved mTORC1 signaling and G2/M checkpoint.
Conclusions:
- Palbociclib combined with ET generates consistent biomarkers, suggesting a potential to recondition endocrine-resistant tumors.
- Findings may inform optimal therapeutic sequencing of CDK4/6 inhibitors with different ETs for metastatic breast cancer.
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