Tailoring treatment to the tumor genomic landscape
Insights gained from liquid biopsy can be leveraged to accelerate scientific research and assist in the clinical management of cancer on a more personal level. Sequencing-based liquid biopsy tests offer tremendous promise for tailoring treatment to the tumor genomic landscape with utility at almost every stage in cancer management.
However, in order to unlock the full promise of liquid biopsy assays, exquisite sensitivity is required for a number of reasons:
- DNA that originates specifically from tumors, i.e., circulating tumor DNA (ctDNA), might make up as little as 0.01% of the total cell-free DNA (cfDNA) in the plasma. Moreover, fragmented ctDNA degrades rapidly in the blood circulation with a half-life ranging from 16 minutes to 2.5 hours.1 The extremely low concentrations of ctDNA make its detection challenging.
- Until therapies with greater potency and fewer side effects are developed, sometimes the best hope for reducing cancer morbidity and mortality is early detection. Most stage one solid tumors can be cured by surgical methods.2 The accurate and timely identification of targetable genetic alterations in presymptomatic individuals may initiate therapies faster, allow better symptom control, and improve quality of life. It may also lead to more cost-effective delivery of healthcare to patients. However, due to the lack of assay sensitivity of many ctDNA detection methods, detectable levels of ctDNA can be present in only 47% of the patients at stage one.3
- Presence of detectable ctDNA can also vary with tumor type. Most patients with stage III ovarian and liver cancers, and metastatic cancers of the pancreas, bladder, colon, stomach, breast, liver, esophagus, head, and neck had detectable levels of ctDNA with many tests. In contrast, less than 50% of patients with medulloblastomas or metastatic cancers of the kidney, prostate, or thyroid, and less than 10% of patients with gliomas, harbored detectable ctDNA with those same tests.3
Due to the lack of assay sensitivity of many ctDNA detection methods, detectable levels of ctDNA can be present in only 47% of the patients at stage one.3
Therefore, in order for ctDNA analysis to be broadly considered a tool both for comprehensive genomic analysis and quantitative analysis of disease burden, it must detect a few copies of mutants in a vast background of wild-type sequences.
Ultra-sensitive liquid biopsy mutation detection to detect low-frequency biomarkers
Sysmex Inostics’ Plasma-Safe-SeqS (PSS) technology offers ultra-sensitive mutation detection with high specificity across the most clinically relevant gene targets. According to Jonathan Craft, Associate Director of Translational Research and Product Design at Sysmex Inostics “with PSS, the limit of detection coupled with error correction, the right mutations are being detected and recorded.”
Covering large genomic area, PSS was designed specifically for measurement of ctDNA with greatest sensitivity in its class for detecting low-frequency biomarkers to accelerate research programs, provide unique insights, and improve patients’ lives. The technology demonstrates consistent sensitivity and specificity across a broad range of DNA input (3ng to 66ng) to accommodate the variability often seen in clinical samples. It is an order of magnitude more sensitive than other liquid biopsy NGS methods detecting between 5-7 mutant molecules irrespective of the amount of wildtype DNA present and/or the panel configuration. For 33ng DNA input, this corresponds to 0.05-0.07% mutant allele frequency (MAF).
For 33ng DNA input, this corresponds to 0.05-0.07% mutant allele frequency (MAF)
There are two main reasons for the best-in-class sensitivity demonstrated by the PSS technology.
- It is expertly designed to preserve all input molecules for analysis to detect low-level genomic mutations. In contrast, other NGS pan-cancer assays are known to lose up to 40% of all Input DNA during sample prep.4
- Moreover, it provides targeted adjustable genetic coverage of clinically relevant biomarkers rather than fixed indiscriminate coverage of genes. Unparalleled sensitivity of PSS technology allows following applications:
- Clinical trial enrollment — The ultra-sensitive technology allows clinical trial sponsors to detect actionable mutations facilitating the development of novel oncology treatments by screening fewer patients to achieve sufficient study enrollment. This can lead to significantly accelerated clinical trial timelines, reduced costs, and improved trial outcomes for patients.
- Therapy selection and treatment response — Quantitative detection of somatic mutations informs therapy selection and enables meaningful comparison of ctDNA levels across timepoints for longitudinal monitoring. Correlating PSS results with clinical observations may reveal promising opportunities for novel therapeutic strategies.
- Minimal residual disease (MRD) detection and recurrence surveillance — Ultra-high sensitivity is essential for reliable detection of extremely small quantities of ctDNA that may be present post-intervention, as well as for early identification of increasing ctDNA levels during patient monitoring which may indicate relapse.
- Identifying targetable resistance — Despite the recent advances of targeted therapies in treating many types of cancer, only a fraction of patients develops durable responses, which indicates the common existence of intrinsic/acquired resistance to existing treatment regimens. To improve patient survival, it is critical to discover potential therapeutic targets and prognostic biomarkers for novel biological interventions to overcome drug resistance including diagnosis, minimally invasive molecular profiling, treatment monitoring and re-testing as disease progresses, the detection of residual disease and the identification of drug resistance.
Sysmex Inostics offers research assistance
The Cancer Research Excellence Program (CREP), a new initiative by Sysmex Inostics, is a competitive award program open to select applicants performing solid tumor research in the U.S. Shinichi Sato, CEO of Sysmex Inostics, stated that “this program expands the opportunity to provide clinical researchers with another tool to uncover deeper insights into therapy response and help patients, while expanding clinical data of our Plasma-Safe-SeqS technology.”
Winning clinical researchers receive free testing services of our highly sensitive Plasma-Safe-SeqS technology, breast cancer or RAS-RAF signaling pathway panels performed in our Baltimore CLIA lab. Applications will be accepted until 11:59pm EST, April 30, 2023.
References:
- Diehl F. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985-90.
- Vogelstein B., et al. Cancer genome landscapes. Science. 2013; 339:1546-58.
- Bettegowda C., et al. Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies. Sci. Transl. Med. 2014; 6:224ra24.
- Aigrain L., et al. Quantitation of next generation sequencing library preparation protocol efficiencies using droplet digital PCR assays – a systematic comparison of DNA library preparation kits for Illumina sequencing. BMC Genomics. 2016; 17(1):458.