Attendees of IASLC’s Latin America Conference on Lung Cancer (LALCA), which took place January 25-27 in Montevideo, Uruguay, heard an important lecture from David R. Gandara, MD, professor emeritus at the University of California, Davis, Comprehensive Cancer Center, on the future of ctDNA. Dr. Gandara’s lecture was part of a larger session on novel diagnostic and prognostic markers, which also included talks on next-generation sequencing in liquid biopsies and new technologies in liquid biopsies.
The liquid biopsy journey began in the metastatic setting, leading to the creation of robust data that are now used in clinical practice.1 Testing circulating tumor DNA (ctDNA) offers a minimally invasive opportunity to diagnose, characterize, and monitor disease in individual cancer patients. ctDNA can reflect the tumor burden and specific genomic state of disease, and thus, might serve as a prognostic and predictive biomarker for cancer therapies.
As discussed during LALCA, one of the advantages of liquid biopsy is its ability to capture heterogeneity and tumor cell clonal evolution, making it a good tool to monitor tumor dynamics and treatment-acquired resistance. Heterogeneity is at the center of tumor evolution and adaptation, which are dynamic, continuous, modified by treatment exposures, and may compromise the efficacy of treatment itself. The mechanisms of acquired resistance may be heterogenous and multiple mechanisms can simultaneously occur in the same patient, reflecting the clonal heterogeneity of the tumor.2
Therefore, tracking the clonal evolution of a tumor over time via liquid biopsy may allow for the implementation of tailored therapeutic approaches and represents a practical alternative source for investigating tumor-derived alterations. Although data are most robust in non-small cell lung cancer (NSCLC), other cancer types may also benefit from this minimally invasive approach to facilitate patient management.3,4,5
Historically, the first clinical application of liquid biopsy was in the advanced NSCLC setting for the detection of sensitizing and secondary EGFR mutations.6 The availability of new tools, such as next-generation sequencing (NGS), allowed for comprehensive tumor genomic profiling—shifting the use of liquid biopsy from the metastatic setting to earlier stages.
During the past few years, ctDNA analysis has moved from single-gene analysis to guideline-recommended broad-based plasma ctDNA analysis by NGS, on the basis of major technical advances and the dramatic change in application of targeted therapies in the therapeutic algorithm for patients with cancer.1 It is well established that liquid biopsy may be used to detect several gene alterations including single nucleotide variants, gene fusions, translocations, and amplifications.7,8 This topic was discussed during the session by Luis E. Raez, MD
Dr. Gandara’s lecture explored future scenarios for liquid biopsy implementation in clinical practice, including its use to detect minimal residual disease (MRD) and lung cancer early detection or interception.9,1010,12 The importance of MRD detection was first highlighted in hematological diseases and allowed clinicians to evaluate the success of therapy and to predict short- and long-term relapse.13 Multiple studies in various cancer types have already demonstrated a satisfactory positive predictive value of ctDNA detection, as the presence of MRD identified through ctDNA is associated with worse disease-free survival. Different studies have been conducted using ctDNA as a surrogate of postsurgical MRD in localized diseases, including melanoma and colorectal and breast cancers.3,14,15
Also during the session, Christian Rolfo, MD, PhD, MBA, Drhc, explored a number of ongoing trials that are investigating the use of liquid biopsy as a screening tool for early detection of cancer, demonstrating that blood testing could be combined with conventional screening, leading to detection of early stage cancer with acceptable sensitivity and positive predictive values.9,10,11 Additionally, Dr. Rolfo discussed a number of analytes and methodologies are emerging in liquid biopsy, including extracellular vesicles (EVs), exosomes, circulating tumor cells, and epigenetic methylation analysis. The idea is to integrate multiple tumor biomarkers to have a comprehensive tumor genomic profile. EVs, including exosomes, can enhance the current biological understanding of the processes involved in cancer development and progression. These small particles play a key role in mediating intercellular crosstalk in normal physiology and pathology, and they are being studied across a wide spectrum of cancer, from precancerous states to localized disease and to the creation of the pro-metastatic niche.
As an example, it has been reported by Dr. Rolfo and Dr. Diego De Miguel Perez that patients with chronic obstructive pulmonary disease who later develop lung cancer have noticeable alterations in their EVs.16 There is also evidence that kinetics of EV PD-L1 may serve as a better predictive factor than tissue PD-L1 in patients treated with immunotherapy. It has also been demonstrated that increasing dynamics of EV PD-L1 and high baseline EV TGF-β were associated with shorter progression-free survival and overall survival in these patients.17 ctDNA provides robust data on cancer, but EVs can add to this biological information in a clinically meaningful way. Therefore, integrating exosomes into a multiomics approach—where data sets from multiple -omic groups are combined during analysis—could be an important future application.
Together with ctDNA and exosomes, other circulating biomarkers may be able to integrate with liquid biopsy -omics as well. This might include circulating tumor cells (CTCs), for which there is already evidence in the published literature18, or new methods of analysis, such as methylation. The rationale behind the adoption of epigenomics, which includes methylation analysis, is that while the DNA sequence in all tissues is almost identical, unique methylation patterns determine each tissue’s biological identity. Accumulating evidence on the relationship between methylation changes and various diseases has been produced in recent years, and multiple studies have been launched in various solid tumors. Increasing evidence supports the use of methylation analysis via liquid biopsy as a promising tool for early detection of cancer.
As this LALCA session demonstrated, the liquid biopsy field is growing in multiple directions with new biomarkers, new methodological approaches, expanding use from metastatic disease to early stages, and into new frontiers of early cancer detection and interception.
- 1. Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, et al. Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16(10):1647-62.
- 2. Crucitta S, Cucchiara F, Mathijssen R, Mateo J, Jager A, Joosse A, et al. Treatment-driven tumour heterogeneity and drug resistance: Lessons from solid tumours. Cancer Treat Rev. 2022;104:102340.
- 3. Marmorino F, Prisciandaro M, Giordano M, Ortolan E, Crucitta S, Manca P, et al. Circulating Tumor DNA as a Marker of Minimal Residual Disease After Radical Resection of Colorectal Liver Metastases. JCO Precis Oncol. 2022;6:e2200244.
- 4. Cremolini C, Rossini D, Dell’Aquila E, Lonardi S, Conca E, Del Re M, et al. Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan: A Phase 2 Single-Arm Clinical Trial. JAMA Oncol. 2019;5(3):343-50.
- 5. Hsiehchen D, Bucheit L, Yang D, Beg MS, Lim M, Lee SS, et al. Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers. Nat Commun. 2022;13(1):7477.
- 6. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;376(7):629-40.
- 7. Lee JK, Hazar-Rethinam M, Decker B, Gjoerup O, Madison RW, Lieber DS, et al. The Pan-Tumor Landscape of Targetable Kinase Fusions in Circulating Tumor DNA. Clin Cancer Res. 2022;28(4):728-37.
- 8. Ou SI, Nagasaka M, Zhu VW. Liquid Biopsy to Identify Actionable Genomic Alterations. Am Soc Clin Oncol Educ Book. 2018;38:978-97.
- 9. Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, Consortium C. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31(6):745-59.
- 10. Lennon AM, Buchanan AH, Kinde I, Warren A, Honushefsky A, Cohain AT, et al. Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science. 2020;369(6499).
- 11. Chen X, Gole J, Gore A, He Q, Lu M, Min J, et al. Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nat Commun. 2020;11(1):3475.
- 12. Serrano MJ, Garrido-Navas MC, Diaz Mochon JJ, Cristofanilli M, Gil-Bazo I, Pauwels P, et al. Precision Prevention and Cancer Interception: The New Challenges of Liquid Biopsy. Cancer Discov. 2020;10(11):1635-44.
- 13. Szczepanski T, Orfao A, van der Velden VH, San Miguel JF, van Dongen JJ. Minimal residual disease in leukaemia patients. Lancet Oncol. 2001;2(7):409-17.
- 14. Tan L, Sandhu S, Lee RJ, Li J, Callahan J, Ftouni S, et al. Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA. Ann Oncol. 2019;30(5):804-14.
- 15. Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133.
- 16. Mohan A, Agarwal S, Clauss M, Britt NS, Dhillon NK. Extracellular vesicles: novel communicators in lung diseases. Respir Res. 2020;21(1):175.
- 17. de Miguel-Perez D, Russo A, Gunasekaran M, Buemi F, Hester L, Fan X, et al. Baseline extracellular vesicle TGF-beta is a predictive biomarker for response to immune-checkpoint inhibitors and survival in non-small-cell lung cancer. Cancer. 2022.
- 18. Deng Z, Wu S, Wang Y, Shi D. Circulating tumor cell isolation for cancer diagnosis and prognosis. EBioMedicine. 2022;83:104237.