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By Jeremiah McDole, PhD

 

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From targeted immunotherapies powered by patients’ own immune systems to genetic tests that offer deeper insights than ever before, researchers have made great advancements in cancer treatments and diagnostics in recent years, offering hope to patients and clinicians alike. But bringing accurate, noninvasive molecular testing to a broad swath of cancer patients will require additional progress.

The genetic heterogeneity and variable DNA-shedding characteristics of tumors lead to inherent differences in biomarker levels in liquid biopsy samples. Therefore, solid tumor oncology has traditionally lagged behind hematological oncology in implementing certain kinds of molecular testing. But widespread adoption of ultra-sensitive tools has powered ongoing interest in molecular testing for solid tumors, which can provide accurate screening, therapy monitoring, and minimal residual disease (MRD) testing to inform clinical decision-making in the neo-adjuvant setting and beyond. Real-time, accurate measurements of neo-adjuvant therapy response can help determine the primary treatment course and increase the likelihood of achieving remission.

Monitoring blood levels of circulating tumor DNA (ctDNA) has the potential to become a key indicator of primary treatment efficacy, therapy success, and overall survival rate. Leveraging ultra-sensitive molecular tools—such as Droplet Digital™ PCR (ddPCR™) and next-generation sequencing (NGS)—is the key to making the most of this extremely promising method.

Molecular response monitoring is noninvasive and precise

Gold-standard techniques such as imaging and biopsy of solid tumors have many drawbacks despite their extensive use. Imaging cannot detect small changes in tumor size, essentially blinding a clinician to the directional efficacy of a therapy early in the treatment window. For many types of cancer, obtaining solid tissue biopsies involves surgery, putting patients at unnecessary risk of infection and internal bleeding. Serialized biopsies only add to this risk. Additionally, due to tumor heterogeneity, biopsies often provide an incomplete mutation readout, potentially limiting treatment options.

Molecular detection overcomes these limitations with multifaceted advantages inherent to the technology. Molecular detection is revolutionizing many types of disease diagnostics, from infectious diseases to cancer, by providing exact quantification of genetic information. Precise quantification takes the guesswork out of treatment because it allows scientists to observe directional changes in ctDNA levels, giving timely insight into the efficacy of a drug or other therapy. Sensitive detection gives clinicians confidence in predicting cancer recurrence based on MRD and other indicators. These characteristics of ddPCR technology are central to the implementation of molecular detection for solid tumor diagnostics and treatment.

Choosing the right technology for neo-adjuvant therapy response monitoring

ddPCR technology provides fast, ultrasensitive, and absolute quantification of nucleic acids to detect subtle changes in target levels that even real-time quantitative PCR (RT-qPCR) cannot. This technique delivers unmatched sensitivity and precision for monitoring cfDNA, ctDNA, CTCs, and biomarkers in blood samples, even though these analytes are often highly fragmented, present at low levels, and found in a complex background of other components.

While ddPCR methods are commonly implemented for hematological oncology liquid biopsy analysis, this technology has also been a driving factor behind solid tumor monitoring by providing clinicians with a method of measuring ctDNA levels to quantify molecular response, testing for recurrence, and even screening high-risk patients for hereditary mutations before they have received a cancer diagnosis. The ddPCR workflow is simple and intuitive with minimal hands-on time and results that are easy to interpret.

Next-generation sequencing (NGS) is a technology that enables screening for hundreds to thousands of mutations in a single sequencing run. Paired with the ultra-high sensitivity of ddPCR, these two technologies create a comprehensive oncology workflow. NGS enables broad mutational screening from an initial biopsy, while ddPCR technology is extremely well adapted for ongoing liquid biopsy monitoring given its ultra-high sensitivity, fast turnaround time, simple workflow, low cost, and intuitive interpretation of results.

Case study: ddPCR technology as the tool of choice for monitoring ctDNA in adenocarcinoma patients during therapy

A recent study (van der Leest et al., 2021)1 highlighted ddPCR as a promising tool for monitoring ctDNA in patients receiving immune checkpoint inhibitor (ICI) therapy for advanced lung adenocarcinoma. The study measured patients’ ctDNA levels as a proxy of early tumor response to immunotherapy to determine rates of progression-free and overall survival.

The researchers found that in patients with a PD-L1 tumor proportion score of ≥1%, changes in ctDNA levels were strongly associated with tumor response; 80% of patients with a DCB of ≥26 weeks displayed a >30% decrease in ctDNA levels at 4–6 weeks, which correlated with longer progression-free and overall survival rates. They concluded that the combination of PD-L1 expression and reduction in ctDNA is a stronger tool for monitoring ICI response than PD-L1 expression or change in ctDNA alone.

The paper cited several lung cancer studies that established the use of NGS analysis with a broad panel of biomarkers instead of a single selected marker; however, the high cost of plasma-derived cfDNA NGS was considered too cost-prohibitive for longitudinal monitoring. Therefore, monitoring ctDNA with a ddPCR assay provided these researchers with a method that was as sensitive as NGS, yet more cost-effective.

Toward a future of personalized medicine

As ultra-sensitive molecular tools make their way from bench to bedside, they will provide clinicians with more precise information, increasing confidence and enabling precision care. ddPCR technology in particular offers fast, sensitive, and reliable detection that has already begun to empower clinical decision-making in oncology. Understanding nuances of neo-adjuvant therapy response will enable clinical teams to tailor multi-stage treatment plans based on successes observed across different cancer types and individual mutations. As widespread adoption occurs, advances in the technology will ensure more patients receive the care that’s right for them.

Bio-Rad has a suite of ddPCR assays and a digital assay tool that lets users discover and design the best assay for their solid tumor oncology applications.

 

Reference
1. van der Leest P, Hiddinga B, Miedema A, Aguirre Azpurua ML, Rifaela N, Ter Elst A, Timens W, Groen HJM, van Kempen LC, Hiltermann TJN, Schuuring E. Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors. Mol Oncol. 2021 Nov;15(11):2910-2922. doi: 10.1002/1878-0261.13090. Epub 2021 Sep 25. Erratum in: Mol Oncol. 2022 Jan;16(1):310.

 

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