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Updated: Feb 27, 2026
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Characterizing Longitudinal Molecular Changes in ctDNA in Patients with Metastatic Castration-Resistant Prostate
Chinmay T Jani1, Eli Tran2, Nicole Zhang3
1Sylvester Comprehensive Cancer Center , University of Miami/Jackson Health System, Miami, Florida.
Purpose:
Circulating tumor DNA (ctDNA) next-generation sequencing complements tissue-based testing and offers insights into prognosis, treatment selection, and tumor evolution. Despite advances in metastatic castration-resistant prostate cancer (mCRPC) therapies, resistance remains a challenge. This real-world study evaluates longitudinal ctDNA changes following systemic treatments.
Experimental Design:
We analyzed data from Guardant INFORM, a clinical genomic database linking ctDNA profiles with claims data. Patients with prostate cancer who received androgen receptor (AR) pathway inhibitors (ARPi), poly (ADP-ribose) polymerase inhibitors (PARPi), or taxanes and had ctDNA testing within 3 months before and after treatment discontinuation were included. We evaluated pre- and posttreatment mutational differences and survival outcomes (overall survival, time to treatment discontinuation, and time to next treatment), stratifying by treatment type and AR alterations.
Results:
From 36,774 patients with prostate cancer, we identified 678 with paired pre-/post-ARPi, 188 with paired pre-/post-PARPi, and 844 with paired pre-/post-taxane ctDNA samples. After ARPi, the most frequent AR alterations included AR amplification (pre%/post%; 10.8%/25.6%), AR L702H (1.3%/7.9%), and AR T878A (2.9%/7.1%). Following PARPi, the most common homologous recombination repair gene alterations were ATM (25%/23.4%), BRCA2 (22.9%/17%), BRCA1 (4%/2.1%), and CDK12 (5.9%/5.9%). After taxane, frequent alterations included TP53 (47.2%→54%), AR (33.2%/49.9%), PIK3CA (9.4%/15.9%), and EGFR (9.6%/14.6%). All treatment cohorts showed a significant increase in mutation burden after therapy (mean increase 2.0-4.2 alterations; P < 0.001). Across all three treatment groups, the presence of AR alterations was consistently associated with inferior clinical outcomes.
Conclusions:
Our study revealed dynamic shifts in genetic mutations in patients with mCRPC following ARPi, PARPi, and taxanes. Furthermore, our findings highlight associations between AR alterations and clinical outcomes, emphasizing the potential for personalized treatment strategies.
Insights
Longitudinal ctDNA analysis reveals dynamic genetic shifts in metastatic castration-resistant prostate cancer (mCRPC) patients post-treatment. Androgen receptor (AR) alterations correlate with poorer outcomes, guiding personalized mCRPC therapy.
Area of Science:
- Genomics and Precision Medicine
- Oncology
- Molecular Diagnostics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) treatment faces challenges due to therapeutic resistance.
- Circulating tumor DNA (ctDNA) next-generation sequencing (NGS) offers valuable insights into prognosis, treatment selection, and tumor evolution.
- Longitudinal ctDNA analysis can track dynamic genetic changes during systemic therapy in mCRPC.
Purpose of the Study:
- To evaluate longitudinal ctDNA alterations in mCRPC patients undergoing treatment with androgen receptor pathway inhibitors (ARPi), poly (ADP-ribose) polymerase inhibitors (PARPi), or taxanes.
- To assess the association between specific genetic alterations, particularly in AR, and clinical outcomes following these treatments.
- To understand tumor evolution and treatment resistance mechanisms through serial ctDNA profiling.
Main Methods:
- Analysis of the GuardantINFORM clinical-genomic database, linking ctDNA profiles with claims data.
- Inclusion of mCRPC patients with paired ctDNA samples pre- and post-treatment (ARPi, PARPi, taxanes).
- Evaluation of pre- and post-treatment mutational differences and survival outcomes (OS, TTD, TTNT), stratified by treatment type and AR alterations.
Main Results:
- Significant increases in mutation burden observed across all treatment cohorts post-therapy (mean increase 2.0-4.2 alterations; p<0.001).
- Post-ARPi treatment showed increased AR amplification and specific AR mutations (L702H, T878A).
- Post-PARPi treatment revealed alterations in HRR genes like ATM and BRCA2.
- Post-taxane treatment demonstrated increased TP53, AR, PIK3CA, and EGFR alterations.
- The presence of AR alterations consistently correlated with inferior clinical outcomes across all treatment groups.
Conclusions:
- Dynamic genetic shifts occur in mCRPC patients treated with ARPi, PARPi, and taxanes.
- AR alterations are associated with poorer clinical outcomes, underscoring their prognostic significance.
- Longitudinal ctDNA monitoring holds potential for guiding personalized treatment strategies in mCRPC.
