Liquid biopsy and its role in an advanced clinical trial for lung cancer

Abstract

Liquid biopsy methodologies, for the purpose of plasma genotyping of cell-free DNA (cfDNA) of solid tumors, are a new class of novel molecular assays. Such assays are rapidly entering the clinical sphere of research-based monitoring in translational oncology, especially for thoracic malignancies. Potential applications for these blood-based cfDNA assays include: (i) initial diagnosis, (ii) response to therapy and follow-up, (iii) tumor evolution, and (iv) minimal residual disease evaluation. Precision medicine will benefit from cutting-edge molecular diagnostics, especially regarding treatment decisions in the adjuvant setting, where avoiding over-treatment and unnecessary toxicity are paramount. The use of innovative genetic analysis techniques on individual patient tumor samples is being pursued in several advanced clinical trials. Rather than using a categorical treatment plan, the next critical step of therapeutic decision making is providing the "right" cancer therapy for an individual patient, including correct dose and timeframe based on the molecular analysis of the tumor in question. Per the 21st Century Cures Act, innovative clinical trials are integral for biomarker and drug development. This will include advanced clinical trials utilizing: (i) innovative assays, (ii) molecular profiling with cutting-edge bioinformatics, and (iii) clinically relevant animal or tissue models. In this paper, a mini-review addresses state-of-the-art liquid biopsy approaches. Additionally, an on-going advanced clinical trial for lung cancer with novelty through synergizing liquid biopsies, co-clinical trials, and advanced bioinformatics is also presented. Impact statement Liquid biopsy technology is providing a new source for cancer biomarkers, and adds new dimensions in advanced clinical trials. Utilizing a non-invasive routine blood draw, the liquid biopsy provides abilities to address perplexing issues of tumor tissue heterogeneity by identifying mutations in both primary and metastatic lesions. Regarding the assessment of response to cancer therapy, the liquid biopsy is not ready to replace medical imaging, but adds critical new information; for instance, through a temporal assessment of quantitative circulating tumor DNA (ctDNA) assay results, and importantly, the ability to monitor for signs of resistance, via emerging clones. Adjuvant therapy may soon be considered based on a quantitative cfDNA assay. As sensitivity and specificity of the technology continue to progress, cancer screening and prevention will improve and save countless lives by finding the cancer early, so that a routine surgery may be all that is required for a definitive cure.

RETRACTED ARTICLE: Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

“…Therefore, we did not rely on the commercial kit and followed a new strategy. This strategy relies on the fact that contaminating cellular DNA liberated during preparation from blood cells is larger in size, whereas cfDNA is known to consist of a major fraction with an average length of ~ 170 bp corresponding to the length of DNA wrapped around one nucleosome plus a linker sequence 7 and further fractions of multiple length of ~ 340 bp, ~ 510 bp and ~ 680 bp in decreasing quantities 3 . These sizes are thought to be generated by the action of caspase-activated endonucleases that cleave DNA between nucleosomes during apoptosis, a major source of cfDNA release 26 .…”

“…to 50-fold compared to healthy persons, depending on the type of cancer and the burden of disease 3 . Noteworthy, total cfDNA levels were observed to decrease after therapy or surgery 8 .…”

“…Importantly, certain aberrant DNA methylation patterns are found across different cancer types making them suitable for a "PANCancer" diagnosis, i.e., simultaneous screening for several cancer types in one approach 11 . Since tumors shed cfDNA 3 , cancer cell-specific DNA methylation signatures in cfDNA allow identification of breast, colon and lung cancer, e.g. 5 .…”

Current Achievements and Applications of Transcriptomics in Personalized Cancer Medicine

“…The first approach is limited by the uncommonness of cancer cells in the bloodstream (around one CTC per billion blood cells) [ 162 ], which significantly reduce the clinical application of this method. Alternatively, analysis of nucleic components of tumor cells—cell free DNA (cfDNA) and circulating RNA (circRNA, including miRNA)—is gaining an increasing interest, demonstrated in numerous studies and clinical trials [ 159 , 163 , 164 , 165 ]. Rapid advancement of novel technologies, enables to detect cancerous DNA/RNA with high accuracy for diagnosis, prognosis and therapeutic monitoring [ 166 ].…”

Extracellular vesicle molecular signatures characterize metastatic dynamicity in ovarian cancer

“…Cell-free DNA-based tests such as Guardant360 CDx, for non-small cell lung cancer , Signatera, for minimal residual disease detection, FoundationOne ® Liquid CDx, for pan-tumor screen are amongst of the recently approved liquid biopsy platforms (20,21). One of the most important improvements liquid biopsies offer over traditional tissue biopsies, is the potential to monitor tumor changes longitudinally (22,23). Extracellular vesicles (EVs) in particular hold significant promise in the successful application of liquid biopsies to the clinic.…”