Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations among Patients with Advanced Solid Tumors
Neelima Vidula1, Thereasa A Rich2, Oliver Sartor3
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. nvidula@mgh.harvard.edu.
Purpose:
PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations.
Experimental Design:
Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion-deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy.
Results:
Among 828 patients, one or more deleterious BRCA1/2 mutations were detected in 60 (7.2%) patients, including germline (n = 42) and somatic (n = 18) mutations. Common coexisting mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%), and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline BRCA1/2-mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.
Conclusions:
cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.
Insights
Next-generation sequencing of cell-free DNA (cfDNA) effectively identifies BRCA1/2 mutations, including resistance-causing reversions. This approach aids in guiding precision medicine for advanced cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- PARP inhibitors (PARPi) are effective against cancers with BRCA1/2 mutations.
- Acquired BRCA1/2 reversions can lead to resistance against PARPi and platinum chemotherapy.
- Optimal methods for detecting germline, somatic, and reversion BRCA1/2 mutations are needed.
Purpose of the Study:
- To establish an optimal method for identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2.
- To evaluate the utility of next-generation sequencing (NGS) of cell-free DNA (cfDNA) for detecting these mutations.
Main Methods:
- A clinically validated 73-gene cfDNA assay was used.
- The assay evaluated single-nucleotide variants and insertion-deletion mutations (indels) in BRCA1/2.
- The assay distinguished somatic/reversion from germline mutations with high accuracy in patients with advanced cancers.
Main Results:
- Deleterious BRCA1/2 mutations were detected in 7.2% of 828 patients (42 germline, 18 somatic).
- Polyclonal reversion mutations were found in 21.4% of germline BRCA1/2-mutant patients, often after PARPi exposure.
- Serial cfDNA analysis showed emergent reversion mutations under therapeutic pressure, contributing to treatment resistance.
Conclusions:
- cfDNA NGS accurately identifies therapeutically relevant BRCA1/2 mutations, including somatic and reversion types.
- This method detected mutations missed by germline testing and has treatment implications.
- Further research is needed to confirm the clinical utility of cfDNA NGS in guiding precision medicine for advanced cancers.
