Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA
G Gremel1, R J Lee1, M R Girotti1
1Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester.
Background:
The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment.
Patients And Methods:
We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy.
Results:
Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel.
Conclusion:
We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.
Insights
Liquid biopsies using cell-free DNA (cfDNA) reveal tumor evolution and distinct subclone responses to targeted therapy, immunotherapy, and chemotherapy in metastatic melanoma, even without tissue biopsies.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Precision medicine in oncology necessitates detailed tumor characterization and response monitoring.
- Understanding tumor heterogeneity is crucial for effective cancer treatment.
Purpose of the Study:
- To monitor treatment response in metastatic vaginal mucosal melanoma using circulating cell-free DNA (cfDNA).
- To investigate the mechanisms behind mixed clinical responses to targeted therapy.
Main Methods:
- Next-generation sequencing of cfDNA for longitudinal analysis.
- Whole-exome sequencing to identify tumor subclones.
- Monitoring response to targeted therapy (imatinib), immunotherapy, and chemotherapy (carboplatin/paclitaxel).
Main Results:
- Identified two tumor subclones: one KIT-mutant (responded to imatinib) and one KIT-wild-type (did not respond).
- Subclones exhibited differential responses to immunotherapy.
- Both subclones responded to carboplatin/paclitaxel, with the KIT-wild-type subclone showing progression after chemotherapy.
Conclusions:
- cfDNA analysis can reveal tumor evolution and subclonal treatment responses.
- This approach is valuable when tumor biopsies are inaccessible.
- Liquid biopsies offer insights into dynamic treatment effects in metastatic melanoma.
