Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open
Shelly Sorrells1, Kelly E McKinnon1, Ashleigh McBratney1
1Tempus Laboratories, Chicago, IL, USA.
Abstract:
BRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing was performed throughout the course of disease on tumor tissue from multiple sites, circulating tumor DNA from blood plasma, and matched normal tissue. Genomic analyses identified actionable variants for targeted therapies, as well as emerging resistance mutations over time. Two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) were identified upon resistance to PARP inhibitor and platinum treatment, respectively. Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients.
Insights
This case study shows how longitudinal genomic testing can track BRCA-mutant cancer progression and resistance. It identified BRCA2 reversion alterations as a key mechanism of acquired resistance to PARP inhibitors and platinum therapy.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- BRCA-mutant cancers frequently acquire therapeutic resistance.
- Understanding resistance mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To report a case of BRCA2-mutant breast cancer.
- To monitor disease progression and acquired resistance using longitudinal multi-tissue genomic testing.
Main Methods:
- Longitudinal genomic testing on tumor tissue from multiple sites and circulating tumor DNA.
- Analysis of matched normal tissue.
- Identification of actionable variants and resistance mutations.
Main Results:
- Identified two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) upon resistance to PARP inhibitor and platinum treatment.
- These alterations restored the open reading frame of the original germline alteration, suggesting a mechanism for acquired resistance.
- Demonstrated the evolution of multiple subclonal BRCA reversion alterations over time.
Conclusions:
- Longitudinal multi-tissue genomic testing is valuable for monitoring disease progression in oncology patients.
- This approach can predict treatment response and evaluate outcomes.
- BRCA reversion alterations are a significant mechanism of acquired resistance in BRCA-mutant cancers.
