Personalized Treatment Selection and Disease Monitoring Using Circulating Tumor DNA Profiling in Real-World Cancer Patient Management

Abstract

Background: Circulating tumor DNA (ctDNA) in the blood plasma of cancer patients is an emerging biomarker used across oncology, facilitating noninvasive disease monitoring and genetic profiling at various disease milestones. Digital droplet PCR (ddPCR) technologies have demonstrated high sensitivity and specificity for robust ctDNA detection at relatively low costs. Yet, their value for ctDNA-based management of a broad population of cancer patients beyond clinical trials remains elusive. Methods: We developed mutation-specific ddPCR assays that were optimized for their use in real-world cancer management, covering 12 genetic aberrations in common cancer genes, such as EGFR, BRAF, KIT, KRAS, and NRAS. We assessed the limit of detection (LOD) and the limit of blank (LOB) for each assay and validated their performance for ctDNA detection using matched tumor sequencing. Results: We applied our custom ddPCR assays to 352 plasma samples from 96 patients with solid tumors. Mutation detection in plasma was highly concordant with tumor sequencing, demonstrating high sensitivity and specificity across all assays. In 20 cases, radiographic cancer progression was mirrored by an increase of ctDNA concentrations or the occurrence of novel mutations in plasma. Moreover, ctDNA profiling at diagnosis and during disease progression reflected personalized treatment selection through the identification of actionable gene targets in 20 cases. Conclusion: Collectively, our work highlights the potential of ctDNA assessment by sensitive ddPCR for accurate disease monitoring, robust identification of resistance mutations, and upfront treatment selection in patients with solid tumors. We envision an increasing future role for ctDNA profiling within personalized cancer management in daily clinical routine.

Circulating tumor DNA in B-cell lymphoma: technical advances, clinical applications, and perspectives for translational research

“…Major advances in polymerase chain reaction- (PCR-) and next-generation sequencing- (NGS-) based technologies have led to improved detection of minimal ctDNA amounts in body fluids, facilitating ultrasensitive detection of minute residual tumor masses during or after therapy (measurable residual disease, MRD) for early identification of treatment failure and prediction of disease relapse in numerous cancer entities including lymphoma. As ctDNA reflects all types of tumor-specific genetic alterations including single nucleotide variants (SNVs), translocations, insertions/deletions (indels), and copy number variations (CNVs), it potentially allows comprehensive assessment of spatial tumor heterogeneity between different tumor lesions, classification of molecular subtypes, and the identification of temporal heterogeneity such as the emergence of resistance mutations over time [ 11 , 15 ]. Both non- or minimal-invasive quantification of tumor burden and the characterization of tumor heterogeneity have potential clinical utility at various lymphoma milestones, with MRD monitoring during and after treatment being the most established application of ctDNA as of yet (Fig.…”

“…'Liquid biopsy' has emerged as an innovative approach to detect and characterize cancers non-or minimal-invasively through profiling of tumor-derived analytes in body fluids, most commonly blood but also cerebrospinal fluid (CSF), urine, ascites, pleural fluid, or saliva [13][14][15][16][17][18][19][20]. Circulating tumor DNA (ctDNA) in the blood plasma or CSF has become the most investigated analyte in B-cell lymphomas, as the majority of lymphoma patients do not present with circulating disease and therefore, circulating tumor cells (CTCs) are usually a less attractive target (Fig.…”

Assessing circulating tumour DNA (ctDNA) as a prognostic biomarker in locally advanced rectal cancer: a systematic review and meta-analysis

“…The consistent association between ctDNA detection and adverse outcomes in LARC suggests its potential as a prognostic biomarker for risk stratification and treatment decision-making. Integrating ctDNA analysis into routine clinical practice could facilitate personalised treatment strategies, including the identification of high-risk patients who may benefit from intensified therapy or closer surveillance [ 55 ]. Furthermore, ongoing research efforts aimed at refining ctDNA-based assays and elucidating the underlying biological mechanisms driving ctDNA release and clearance are crucial for maximising its clinical utility [ 56 ].…”

Liquid profiling of circulating tumor DNA in colorectal cancer: steps needed to achieve its full clinical value as standard care

“…The clinical utility of LP is versatile and has been proven in translational studies, publications on the implementation and diagnostic performance of LP in clinical practice remain limited, leaving its value beyond clinical trials elusive [30,31]. To address this gap, the translation of LP into standard health care, surveillance, and clinical decision making for CRC patients were assessed through a retrospective analysis of realworld, single-center data obtained in the context of clinical care since 2016.…”