Introduction

Liquid biopsy offers real-time insights into tumor dynamics. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) stand out as promising biomarkers due to their potential to provide comprehensive information about tumor evolution, treatment response, and the emergence of resistance. Concordance between ctDNA, CTCs, and PET-CT scans holds immense promise in cancer management, including identifying treatment resistance and correlating with PET scan outcomes.

Methods

Retrospectively, 18 patients with progressive and/or metastatic disease undergoing treatment were monitored. Paired samples for ctDNA and CTCs were evaluated. NGS libraries were prepared using a hybridization-capture method based on the custom-designed OncoIndx 1080 CGP panel and deep sequenced on the Illumina NextSeq 2000 in paired-end mode (150 × 2). Variant calling was performed using the proprietary bioinformatics pipeline iCare. CTCs were isolated using the OncoDiscover platform possessing an anti-EpCAM antibody-based immunomagnetic system from 1.5 ml of blood. CTCs were confirmed with CK18+, PD-L1+, DAPI+, and CD45– markers.

Results

ctDNA analysis showed that every patient (100%, n = 18) had at least one actionable genomic finding. Among them, 44.44% (n = 8) had concurrent mutations in the BRCA1/2 and TP53 genes, and 87.5% (n = 7) of these patients also possessed detectable CTCs. A smaller subset, 11.11% (n = 2), showed driver mutations in the EGFR gene. The remaining patients exhibited mutations in genes including KRAS, PTEN, STK11, RB1, AR, KIT, MET, and CDKN2A. These molecular profiles correlated with treatment resistance and were consistent with PET scan results showing disease progression in 88.88% (n = 16) of patients. Only 11.11% (n = 2) of the cohort demonstrated therapeutic response in recent PET scans. Notably, the combination of BRCA1/2 and TP53 mutations, along with the presence of CTCs, was primarily observed in patients with advanced or metastatic aggressive disease. These co-occurring mutations were identified in ovarian, biliary duct, and breast cancers.

Conclusions

The concurrent presence of BRCA1/2 and TP53 mutations alongside CTCs suggests aggressive disease progression and metastasis across the patient group. Moreover, the molecular interplay between BRCA1/2 and TP53 mutations has been associated with resistance to PARP inhibitors. These findings emphasize the urgent need for longitudinal monitoring in patients with both BRCA1/2 and TP53 mutations coupled with CTC detection.