Dynamic changes in gene alterations during chemotherapy in metastatic castrate resistant prostate cancer

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Docetaxel chemotherapy is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC).
• Genomic alterations in AR, TP53, RB1, and PTEN are common in mCRPC, with TP53, RB1, and PTEN linked to poor outcomes.
• The clonal dynamics of these key driver genes during chemotherapy in mCRPC remain poorly understood.

Purpose of the Study:

• To characterize the clonal dynamics of cell-free DNA (cfDNA) alterations in key driver genes during docetaxel chemotherapy in mCRPC patients.
• To investigate the association between changes in cfDNA alterations and clinical response to chemotherapy.
• To explore the potential role of these dynamics in treatment resistance and lineage plasticity.

Main Methods:

• Retrospective analysis of serially collected blood samples from mCRPC patients undergoing chemotherapy.
• Profiling of cell-free DNA (cfDNA) alterations, including AR, TP53, RB1, and PTEN.
• Correlation of cfDNA alteration dynamics with Prostate-Specific Antigen (PSA) levels and clinical outcomes.

Main Results:

• Androgen Receptor (AR) alterations and overall mutational load significantly decreased in patients with stable or reduced PSA after 3 chemotherapy cycles.
• Reductions in RB1, TP53, and PTEN alterations were less pronounced, suggesting persistence.
• Modest reductions in RB1, TP53, and PTEN alterations may indicate a clonal signature associated with treatment-induced lineage plasticity (TILP) and resistance.

Conclusions:

• Clonal dynamics of driver genes like RB1, TP53, and PTEN during chemotherapy may reflect mechanisms of resistance in mCRPC.
• Persistent alterations in these genes could be linked to treatment-induced lineage plasticity (TILP).
• Monitoring cfDNA driver gene clonal dynamics during chemotherapy may offer clinical utility for assessing treatment response and resistance in mCRPC.