ES25.01 Liquid Biopsy: State of the Science

Abstract

I. The present. Molecular diagnosis in cancer certainly requires the analysis of a tumor biopsy. However, in lung cancer, there is still a 20- 30% of tissue failure rates for tumor genotyping in routine pathological samples. As a consequence, liquid biopsy (LB) has emerged as a valid alternative source of information for the analysis of tumor specific alterations. LB refers to specimens obtained from body fluid such as blood, urine, saliva, cerebrospinal fluid, among others. In the complex matrix represented by blood, the main clinical developments have focused on the analysis of: i) circulating tumor DNA (ctDNA), which represents a small part of cell free circulating DNA released from tumor cells and, ii) circulating tumor cells (CTCs), defined as disseminated cancer cells in the bloodstream. Each of these materials offers unique opportunities to test different biomarkers and to analyze characteristics of the tumors. The advantages of the use of blood samples are clear: i) it is a minimally invasive way to get relevant tumor information, ii) serial samples can be obtained capturing tumor evolution in real time, iii) LB abrogates the limitations associated with tumor heterogeneity, since nucleic acids or tumor cells present in circulation recapitulate the information belonging from different tumor locations (primary tumor and metastases), iv) the development of new sensitive assays for analyses of ctDNA and CTCs allow the assessment of minimal residual disease and v) the costs of LB analysis are comparable with other molecular biology techniques already used in the clinical setting in addition to the reduced risks of complications associated with tissue biopsy. All these factors accelerated the implantation of LB in the clinical practice in oncology in several scenarios, especially in lung cancer. I.1.Lung Cancer. Clinical applications of liquid biopsies. At present, LB is no longer a promise but a reality allowing better treatment selection, real-time monitoring of lung cancer patients and early detection of acquired resistances. Figure 1 highlights the biological basis of LB as a source for biomarkers analysis and key clinical applications in lung cancer. •Personalized therapeutics/ Resistance detection: regarding the detection of tumor-associated genetic alterations in LB samples, there are a lot of scientific data demonstrating similar response rates to targeted therapies than the obtained in tissue biopsies. In particular, in the context of NSCLC patients with progressive or recurrent disease during treatment with TKIs, the IASLC guidelines suggest the use of LB-first algorithm to detect resistance mechanism. For those lung cancer patients receiving immune-based therapeutic treatments, recent data show that assessment of tumor mutational burden in plasma (bTMB) correlated with the values found in tissue and predicts efficacy of immune-checkpoint inhibitors. •Detection of minimal residual disease: Persistent detection of ctDNA or CTCs after local therapy or after adjuvant treatments was found associated with poor clinical outcome. In this particular clinical setting it is important to highlight that sensitivity of the methods used for ctDNA or CTCs evaluation really matters. •Real-time monitoring of disease: this is one of the most interesting application of LB, since tissue biopsies are intrinsically unable to capture tumor heterogeneity while ctDNA can comprehensively recapitulates clonal evolution over time, allowing to early detect and track the emergency of resistance mutations. II. The future. Current assays for LB analysis do not meet all the needs required for the fully implementation of the Precision Oncology. There is still room for improvement to reach its maximum informative potential. Hopefully, studies on exosomes, platelets, cfRNAs, metabolites, will help to have a more integrative picture of tumor status at each time it is evaluated. One of the clinical applications in which LB is called to play a key role is in the screening and early detection of lung cancer. In this regard, there are some interesting data coming from multiparametric (DNA and protein) plasma analysis. However, caution is required since there are still some important issues, such as clonal hematopoiesis, that need to be further considered. Another important challenge for LB is standardization. It is necessary to cross-validate platforms, standardize pre-analytical issues, compare sensitivity of different methodological approaches and also to work in the harmonization of bioinformatic tools for data analysis. It is clear that in the near future, tests based on the analysis of "liquid biopsies” will be more generalized, offering complementary information to tissue biopsies and providing valuable information to early diagnose lung cancer, to detect molecular progressions even prior to radiographic or clinical progression and as a source for real-time treatment monitoring. Alix-Panabières C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov. 2016;6(5): 479-91. Bardelli A, Pantel K. Liquid Biopsies, What We Do Not Know (Yet). Cancer Cell. 2017; 31(2):172-179. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24 Calabuig-Fariñas S, Jantus-Lewintre E, Herreros-Pomares A, Camps C. Circulating tumor cells versus circulating tumor DNA in lung cancer-which one will win? Transl Lung Cancer Res. 2016; 5(5):466-482 Heitzer E, Haque IS, Roberts CE, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019;20(2):71-88. Pantel K, Alix-Panabières C. Liquid biopsy: Potential and challenges. Mol Oncol. 2016; 10(3):371-3. Rossi G, Ignatiadis M. Promises and Pitfalls of Using Liquid Biopsy for Precision Medicine. Cancer Res. 2019;79(11):2798-2804. Siravegna G, Marsoni S, Siena S, Bardelli A. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol. 2017;14(9):531-.548 circulating tumor cells, liquid biopsy, ctDNA