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When it comes to developing new cancer therapeutics, time is of the essence—for the patients that need treatments most, every day counts. Traditional benchmarks for evaluating a treatment’s effectiveness in clinical trials, such as five-year survival rates, deliver prognostic insights on a slower timeline than patients can afford. But noninvasive liquid biopsy has emerged as a promising method for evaluating treatment effectiveness to inform clinical research much sooner.
Liquid biopsy can monitor cell-free DNA (cfDNA), naked DNA released into the bloodstream, which includes DNA from normal cells as well as circulating tumor DNA (ctDNA) from malignant cells. Measurable residual disease (MRD) testing is already relied upon for predicting relapse and survival in hematological malignancies, and methodological advances have opened the door to leveraging cfDNA biomarkers in solid tumors. As analytical methods continue to evolve, the use of cfDNA measurement as an early surrogate clinical trial endpoint could unlock more efficient research, delivering lifesaving treatments to the patients who need them most.
Liquid biopsy offers high precision without invasive procedures
Liquid biopsy has emerged as a promising alternative for cancer prognosis and relapse monitoring, offering better insights for clinicians and less grueling experiences for patients. Prior to its widespread adoption, patients were subjected to imaging surveillance and tissue biopsy, which are not only imprecise but can also be time-consuming, invasive, and expensive. With liquid biopsy, patients can potentially receive better MRD detection and therapeutic monitoring, yielding information not visible in imaging and minimizing the need for costly, invasive procedures.
Technical advances have made accurate cfDNA analysis possible
The development of ultrasensitive molecular tools has been a foundational step in leveraging cfDNA analysis for liquid biopsy. Droplet Digital™ PCR (ddPCR™) is one such tool, providing absolute quantification of nucleic acids without relying on a standard curve as with traditional quantitative PCR (qPCR). ddPCR also offers industry-leading accuracy, precision, and sensitivity, making ddPCR assays ideal for robust detection of low-abundance nucleic acids in blood samples for liquid biopsy. Additionally, ddPCR technology can provide critical insights about quantifiable levels of mutated DNA without requiring the extensive bioinformatic analysis of next-generation sequencing (NGS). Because of these advantages, ddPCR technology can help clinicians analyze cfDNA and other important biomarkers to assess treatment efficacy and detect post-remission relapse as soon as possible for early intervention.
Evaluating therapeutic success in blood cancers with MRD detection
While ddPCR technology has supercharged the power of liquid biopsy, clinicians have relied on cfDNA analysis for years to monitor hematological malignancies. Because these cancers are, by nature, detectable in blood, samples can be assessed for tumor-specific biomarkers such as mutations in cfDNA. The use of ddPCR assays for monitoring hematological malignancies has given this approach a new edge. A recent study published in JAMA examined rates of survival in patients with chronic myeloid leukemia (CML) after discontinuation of tyrosine kinase inhibitors. cfDNA analysis was conducted at the time of discontinuation and revealed that the level of BCR-ABL1, a crucial mutation in CML, strongly correlated with progression-free survival.1
“In this trial, we showed that ddPCR technology is more sensitive and a better predictor of treatment-free remission than conventional PCR,” said Jerald Radich, MD, one of the study’s researchers. “A lot of the patients we tested who had showed up negative with conventional PCR actually showed positive with ddPCR assays.” The high sensitivity of ddPCR technology could offer clinicians greater security in determining whether CML patients can safely discontinue tyrosine kinase inhibitors while minimizing the risk of disease progression or relapse.
ctDNA analysis holds great potential for solid tumor monitoring
The advantages of liquid biopsy are not exclusive to hematological malignancies, as recent studies have demonstrated the promise of ctDNA analysis with ddPCR technology in solid tumors. One such study leveraged ddPCR assays to monitor ctDNA in patients with advanced lung adenocarcinoma undergoing immune checkpoint inhibitor (ICI) therapy.2 Along with assessment of PD-L1 expression, patients’ ctDNA levels were measured as a proxy of early tumor response to immunotherapy. Researchers then compared these findings with patients’ rates of progression-free and overall survival.
The study found that changes in ctDNA levels among patients with a PD-L1 tumor proportion score of ≥1% were strongly associated with tumor response. Eighty percent of patients with a durable clinical benefit (DCB) of 26 weeks or more had displayed a >30% reduction in clinically relevant target ctDNA. This decrease correlated with longer progression-free and overall survival, leading researchers to conclude that assessing changes in ctDNA along with PD-L1 expression was more effective for monitoring ICI response than either method alone. Several lung cancer studies cited in this paper endorsed the use of NGS testing with a broad biomarker panel rather than a single target. However, plasma-derived NGS of cfDNA was deemed too cost-prohibitive as a longitudinal monitoring approach. These researchers thus concluded that ctDNA analysis with a ddPCR assay was a more cost-effective alternative that was as sensitive or more sensitive than NGS.
Advancing oncology with ddPCR-based molecular testing
Liquid biopsy of cfDNA has shown promise as an accessible source of insight into cancer treatment response and prognosis. As the method continues to advance, it may supplant traditional benchmarks for assessing therapeutic effectiveness, such as five-year survival rates, and help lifesaving treatments reach patients faster than ever. Highly sensitive tools like ddPCR technology empower providers and researchers alike with precise and absolute data on each patients’ cancer, helping them to develop and deliver precision oncology care.
References
- Atallah et al. (2020). Assessment of outcomes after stopping tyrosine kinase inhibitors among patients with chronic myeloid leukemia: A nonrandomized clinical trial. JAMA Oncol 7, 42–50.
- van der Leest et al. (2021). Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors. Mol Oncol 15, 2,810–2, 922.
To learn more about how ddPCR technology can advance oncology research, visit bio-rad.com/ddPCR-oncology
