Liquid Biopsy in SCLC: Steps Toward Routine Clinical Use

In this interview, Giulia Pigato discusses her team's recent work exploring the use of liquid biopsy in extensive-stage small cell lung cancer (ES-SCLC). Through the combined use of sWGS and targeted NGS, the study reveals how circulating tumor DNA (ctDNA) dynamics, particularly tumor fraction (TF), can anticipate clinical outcomes early in treatment. Beyond the findings, Giulia Pigato reflects on the broader narrative surrounding liquid biopsy: its future, its promise, and its current limitations.

Can you start by telling us more about your background and how you became interested in liquid biopsies?

Giulia Pigato: Liquid biopsy has been a major focus of our research team for many years. In particular, several of our lab’s projects have concentrated on identifying early biomarkers of lung cancer (NSCLC) to enable early detection, monitor disease progression, and even anticipate therapeutic resistance prior to radiologic confirmation. Indeed, liquid biopsy and cfDNA analysis are powerful tools for detecting minimal residual disease. What was novel in this project was both the type of cancer studied (SCLC) and the newly observed association between tumor fraction and clinical outcome.

Liquid biopsies are drawing increasing attention in oncology. What makes this technique particularly useful in SCLC? And how does this relate to the wider field?

GP: Small cell lung cancer (SCLC) is a particularly aggressive tumor type, typically diagnosed at an extensive stage and often presenting with metastases. In recent years, considerable efforts have been devoted to identifying biomarkers capable of predicting clinical outcomes in response to treatment. Given the rapid progression and poor prognosis of SCLC, liquid biopsy, a non-invasive technique, offers a valuable opportunity to investigate whether circulating tumor DNA (ctDNA) can provide clinically relevant information to anticipate patients’ response to therapy.

Since the completion of the Human Genome Project, we've heard a lot about the potential of genomics in medicine, much of which is yet to be realised. More recently, there have been growing conversions around the applications of liquid biopsies. Is there a risk of repeating the same cycle with liquid biopsies?

GP: We believe that liquid biopsy is a highly powerful tool, particularly due to its non-invasive nature and the ability to perform blood draws and analyses at multiple time points, enabling comprehensive longitudinal studies. However, to date, its clinical utility has been demonstrated in only a limited number of tumor types and clinical settings. We anticipate that it will take several more years to fully establish the clinical value of longitudinal liquid biopsy in SCLC and other cancer types.

You used both sWGS and targeted NGS. Could you talk a bit more about how you balanced these two approaches, and what insights each method brought?

GP: In this study, we employed two complementary approaches to investigate different aspects of cfDNA that may be informative for predicting patient outcomes. First, using targeted next-generation sequencing, we identified variants classified as likely pathogenic or pathogenic, strongly associated with cancer. This analysis confirmed the presence of tumor-derived DNA within the cfDNA. The detected variants aligned with well-established molecular features of SCLC, notably the presence of non-actionable mutations primarily in the TP53 and RB1 genes. In parallel, we performed sWGS, which provided a specific and quantifiable measure of tumor DNA presence, along with insights into its dynamic changes throughout disease progression and treatment response.    

You also observed novel mutations emerging at disease progression. Do they hint at emerging resistance pathways?

GP: In 7 out of 32 patients, new pathogenic variants emerged at the time of disease progression, with the majority showing a low variant allele frequency (VAF <1%), except for one case. The genes found to be mutated at progression, including ALK, JAK2, and ERBB2, are known to be implicated in various cancer types and are involved in key signaling pathways regulating cell growth, differentiation, and transformation. However, the specific variants identified in our cohort are not currently actionable, and their clinical significance remains uncertain.

You used VarSome Premium for variant interpretation. How did the tool support your workflow, and were there specific features that proved particularly helpful?

GP: We found VarSome Premium particularly effective in supporting variant interpretation, especially in facilitating the classification process according to ACMG guidelines. One of the most helpful features was the integrated evidence from multiple databases, such as ClinVar, gnomAD, and COSMIC, which allowed us to quickly assess the potential clinical relevance of each variant.

Are you planning a multicenter prospective validation study to further investigate your findings?

GP: Yes, a multicenter prospective validation study is part of our future plans. Given the promising preliminary findings, particularly concerning the assessment of tumor fraction, we believe that expanding the cohort and including multiple centers will be essential to confirm the clinical relevance and reproducibility of our results.

One of your main findings was the association between early TF clearance and improved PFS. What results would you like to see to be confident moving towards routine clinical use?

GP: To advance toward routine clinical implementation, this association should be validated in larger, prospective, multicenter cohorts. Such validation could significantly enhance clinical decision-making by helping clinicians identify patients likely to experience favorable treatment outcomes, as well as those at risk of a poorer response. Notably, we observed that ctDNA clearance can occur as early as the end of the first treatment cycle, or by the second at the latest. This finding represents a powerful prognostic tool, offering clinically meaningful insights from the earliest phases of therapy.

What would you do differently if you were to re-run this study with a larger cohort or new technology?

GP: If we were to re-run this study with a larger cohort or using more advanced technologies, we would aim to implement several key improvements. First, we would consider integrating additional molecular approaches, such as methylation profiling or fragmentomics, which could complement cfDNA analysis and enhance sensitivity in detecting minimal residual disease. These technologies would be particularly valuable for patients who do not present detectable variants but display a high tumor fraction, marked chromosomal instability and poor prognosis.

Giulia Pigato, Researcher, Veneto Institute of Oncology IOV – IRCCS

Giulia Pigato is a biologist with a BSc and an MSc in Molecular Biology, both earned at the University of Padua, Italy. She further pursued her education by attending the School of Specialization in Medical Genetics, while working at the Veneto Institute of Oncology IOV – IRCCS in Padua, in the Basic and Translational Oncology Unit under the supervision of Prof. Stefano Indraccolo. Her research focuses on translational oncology and liquid biopsy in cancer, with a strong focus on Next-Generation Sequencing, RNA sequencing, and other molecular biology techniques.

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