Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib.
Zhou ZhuNicholas C TurnerSherene LoiFabrice AndréMiguel MartinVéronique DiérasKaren A GelmonNadia HarbeckCathy ZhangJoan Q CaoZhengming YanDongrui R LuPing WeiTodd L VanArsdalePaul A RejtoXin HuangHope S RugoSibylle LoiblMassimo CristofanilliRichard S FinnYuan LiuPublished in: NPJ precision oncology (2022)
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).
Keyphrases
- metastatic breast cancer
- gene expression
- epidermal growth factor receptor
- end stage renal disease
- cell cycle
- ejection fraction
- newly diagnosed
- chronic kidney disease
- healthcare
- free survival
- tyrosine kinase
- prognostic factors
- genome wide
- dna methylation
- stem cells
- transcription factor
- palliative care
- dna damage
- hiv infected
- bone marrow
- combination therapy
- oxidative stress
- patient reported
- chronic pain
- estrogen receptor
- replacement therapy
- signaling pathway
- pain management
- cancer therapy
- quality improvement
- health insurance
- bioinformatics analysis