Characterization of plasma cell-free DNA variants as of tumor- or clonal hematopoiesis-origin in 16,812 advanced cancer patients.

Abstract

Purpose: Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based Comprehensive Genomic Profiling (CGP). However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice.

Experimental design: We assessed the landscape of 16,812 liquid profiles across 49 cancer types using the Caris Assure assay, a whole exome and whole transcriptome NGS workflow that independently sequences both plasma-derived cell-free total nucleic acids (cfTNA) as well as the white blood cell DNA and RNA from the buffy coat. The variant source was identified algorithmically by comparing plasma and buffy coat variant frequency and read quality metrics.

Results: 42.3% of 16,812 patients presented at least one CH variant among reportable clinical genes. We found 39% of BRCA2 variants to be of CH origin, as well as 37.9% of CHEK2, 27.4% of BRCA1, 20.1% of ATM, 7.3% NRAS, 5.8% BRAF, 2.1% EGFR, 2.1% KRAS, and 18.5% TP53. For patients aged 65-69, the median proportion of CH variant classification was 20%, whereas it was 33% for patients aged 70-74, 33% for ages 75-79, and 50% for ages 80+. We found high rates of CH detected in what would be otherwise druggable targets in many cancer types typically treated with PARP inhibitors, including breast, female genital tract, ovarian, pancreatic, prostate, and endometrial cancers.

Conclusion: This large study highlights the need for thorough CH classification during liquid biopsy to appropriately recommend therapies, especially PARP inhibitors.